• Abstract and Figures
• Public Full-text

1 1 2 1 2 3 FOOD AND DRUG ADMINISTRATION 4 5 CENTER FOR DRUG EVALUATION AND RESEARCH 6 7 8 9 10 MEETING OF THE 11 12 ARTHRITIS ADVISORY COMMITTEE 13 14 15 16 17 18 19 20 21 22 23 24 25 8:05 a.m 26 27 Monday, June 23, 2003 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 1 2 2 1 Versailles Ballroom 2 Holiday Inn 3 8120 Wisconsin Avenue 4 Bethesda, Maryland 1 3 2 1 ATTENDEES 2 3 COMMITTEE MEMBERS: 4 5 GARY S. FIRESTEIN, M.D., Chair 6 Chief, Division of Rheumatology, 7 Allergy and Immunology 8 Department of Medicine 9 University of California at San Diego 10 9500 Gilman Drive 11 Basic Science Building, Room 5098 12 La Jolla, California 92093 13 14 JOHANNA M. CLIFFORD, M.S., R.N., B.S.N. 15 Advisors and Consultants Staff (HFD-21) 16 Center for Drug Evaluation and Research 17 Food and Drug Administration 18 5600 Fishers Lane, Building 5630, Room 1093 19 Rockville, Maryland 20857 20 21 JENNIFER J. ANDERSON, PH.D. 22 Research Professor of Public Health 23 Department of Epidemiology and Biostatistics 24 Boston University School of Medicine 25 A-203 26 715 Albany Street 27 Boston, Massachusetts 02118 28 29 JOHN J. CUSH, M.D. 30 Chief of Rheumatology and Clinical Immunology 31 Presbyterian Hospital 32 8200 Walnut Hill Lane 33 Dallas, Texas 75231-4496 34 35 WENDY McBRAIR, R.N., M.S., C.H.E.S. 36 Consumer Representative 37 Director 38 Southern New Jersey Regional Arthritis Center 39 Virtua Health 40 1 Carnie Boulevard 41 Voorhees, New Jersey 08043 42 43 HOWARD J. WILLIAMS, JR., M.D. 44 Department of Internal Medicine 1 4 2 1 Division of Rheumatology 2 University of Utah School of Medicine 3 50 North Medical Drive 4 Salt Lake City, Utah 84132 1 5 2 1 ATTENDEES (Continued) 2 3 CONSULTANTS: (Voting) 4 5 STEVEN ABRAMSON, M.D. 6 Chairman of Rheumatology and Immunology 7 Hospital for Joint Diseases 8 301 East 17th Street 9 New York, New York 10003 10 11 LAURENCE BRADLEY, PH.D. 12 Professor of Medicine 13 University of Alabama at Birmingham 14 467 Boshell Diabetes Building 15 Birmingham, Alabama 35294 16 17 ALLAN GIBOFSKY, M.D., J.D. 18 Hospital for Special Surgery 19 Weill Medical College 20 Cornell University 21 425 East 79th Street 22 New York, New York 10021 23 24 MICHAEL FINLEY, D.O. 25 Western University 26 College of Osteopathic Medicine 27 309 East Second Street 28 College Plaza 29 Pamona, California 91766-1854 30 31 GARY HOFFMAN, M.D., M.S. 32 Chairman, Department of Rheumatic and 33 Immunologic Diseases 34 The Cleveland Clinic Foundation A/50 35 9500 Euclid Avenue 36 Cleveland, Ohio 44195 37 38 NATHANIEL KATZ, M.D. 39 Assistant Professor of Anesthesiology 40 Harvard Medical School 41 Pain Trials Center 42 75 Francis Street 43 Boston, Massachusetts 02115 1 6 2 1 ATTENDEES (Continued) 2 3 CONSULTANTS: (Voting) 4 5 ROLAND STAUD, M.D. 6 Associate Professor of Medicine 7 University of Florida 8 Division of Rheumatology and 9 Clinical Immunology 10 1600 SW Archer Road 11 Gainesville, Florida 32610-0221 12 13 DENNIS TURK, PH.D. 14 Professor 15 Department of Anesthesiology 16 University of Washington 17 School of Medicine 18 1959 NE Pacific Street 19 Room BB1425, HSB 20 Seattle, Washington 91895-2958 21 22 23 CONSULTANTS: (Non-voting) 24 25 DANIEL CLAUW, M.D. 26 (Center for Devices and Radiologic Health) 27 Professor 28 University of Michigan 29 Chronic Pain & Fatigue Research Program 30 24 Frank Lloyd Wright Drive 31 Ann Arbor, Michigan 48106 32 33 34 ACTING INDUSTRY REPRESENTATIVE: (Non-voting) 35 36 FRED LASKY, PH.D. 37 Director, Regulatory Affairs 38 Genzyme Diagnostics 39 1 Kendall Square 40 Cambridge, Massachusetts 02139-1562 1 7 2 1 ATTENDEES (Continued) 2 3 GUEST SPEAKERS: (Non-voting) 4 5 LESLIE CROFFORD, M.D. 6 Associate Professor of Internal Medicine 7 University of Michigan 8 Division of Rheumatology 9 5510 MSRB-1 10 Ann Arbor, Michigan 48109 11 12 GEORGE WELLS, M.S.C., PH.D. 13 Chair and Professor 14 Department of Epidemiology and 15 Community Medicine 16 University of Ottawa 17 Ontario, Canada K1H 8M5 18 19 20 PATIENT REPRESENTATIVE: (Voting) 21 22 Lynne Kennedy Matallana, M.S., B.A. 23 National Fibromyalgia Association 24 Orange, California 25 26 27 FOOD AND DRUG ADMINISTRATION STAFF: 28 29 MARIA LOURDES-VILLALBA, M.D. 30 LEE SIMON, M.D. 31 JAMES WITTER, M.D., PH.D. 32 33 34 ALSO PRESENT: 35 36 VIBEKE STRAND, M.D., FACP 1 8 2 1 C O N T E N T S 2 3 AGENDA ITEM PAGE 4 5 CONFLICT OF INTEREST STATEMENT 6 by Ms. Johanna Clifford 9 7 8 OPENING REMARKS 9 by Dr. James Witter 11 10 11 HISTORICAL BACKGROUND OF FIBROMYALGIA 12 Pre-ACR Diagnostic Criteria 13 by Dr. Laurence Bradley 31 14 15 Basic Mechanisms 16 by Dr. Leslie Crofford 58 17 18 Post-ACR Diagnostic Criteria 19 by Dr. Daniel Clauw 86 20 21 A Patient's Perspective 22 by Ms. Lynne Matallana 129 23 24 Outcomes: Multi-System Impact 25 by Dr. George Wells 138 26 27 OPEN PUBLIC HEARING 159 28 29 CHARGE TO THE COMMITTEE 30 by Dr. Lee Simon 159 31 32 COMMITTEE DISCUSSION AND RESPONSE TO FDA QUESTIONS 177 1 9 2 1 P R O C E E D I N G S

2 (8:05 a.m.)

3 DR. FIRESTEIN: Thank you very much, and

4 welcome to everybody, to this meeting of the Arthritis

5 Advisory Committee.

6 I'm Gary Firestein, currently the Chair, and

7 we have a number of new people sitting at the table. So I

8 think the first thing that we ought to do is go around the

9 table and introduce everybody. Why don't we start with

10 our august leader?

11 DR. SIMON: Hi. Good morning. I'm Lee Simon.

12 I'm the Division Director of Analgesic, Anti-inflammatory

13 and Ophthalmologic Drug Products, and a rheumatologist.

14 DR. WITTER: Good morning. Jim Witter, waking

15 up here, clinical team leader in 550.

16 DR. ABRAMSON: Steve Abramson, rheumatologist,

17 NYU and Hospital for Joint Diseases.

18 DR. GIBOFSKY: Allan Gibofsky, rheumatologist,

19 Hospital for Special Surgery, Cornell.

20 DR. WILLIAMS: Jim Williams, rheumatologist,

21 University of Utah.

22 MS. McBRAIR: Wendy McBrair, Director of 1 10 2 1 Arthritis Services, Virtua Health, in New Jersey, consumer

2 rep.

3 DR. HOFFMAN: Gary Hoffman, rheumatologist,

4 Cleveland Clinic.

5 DR. BRADLEY: Larry Bradley, psychologist,

6 Division of Rheumatology, University of Alabama at

7 Birmingham.

8 MS. CLIFFORD: Johanna Clifford, Food and Drug

9 Administration, Executive Secretary to this meeting.

10 DR. KATZ: Nathaniel Katz, a neurologist in

11 Boston, Massachusetts.

12 MS. MATALLANA: Lynne Matallana, patient

13 representative, Founder and President of the National

14 Fibromyalgia Association.

15 DR. FINLEY: Michael Finley, rheumatologist,

16 Western University.

17 DR. ANDERSON: Jennifer Anderson,

18 statistician, Boston University.

19 DR. CUSH: Jack Cush, rheumatologist,

20 Presbyterian Hospital, Dallas.

21 DR. STAUD: Roland Staud, rheumatologist,

22 University of Florida. 1 11 2 1 DR. TURK: Dennis Turk, psychologist,

2 University of Washington.

3 DR. LASKY: Fred Lasky, Director of Regulatory

4 Affairs, Genzyme, industry representative.

5 DR. FIRESTEIN: Thank you very much.

6 And before we get started, one minor change in

7 the schedule. Because there were no requests for

8 presenting at the open public hearing, that is going to be

9 canceled, and Dr. Simon's charge to committee will replace

10 that at 11:30.

11 So why don't we go ahead and get started with

12 the "Conflict of Interest Statement" from Ms. Clifford.

13 MS. CLIFFORD: The following announcement

14 addresses conflict of interest issues with respect to this

15 meeting and is made a part of the record to preclude even

16 the appearance of impropriety at this meeting.

17 The topics to be discussed today will not

18 focus on any particular product or company but rather may

19 affect those companies developing and studying products

20 for treatment of fibromyalgia. The conflict of interest

21 statutes prohibit special government employees from

22 participating in matters that could affect their own or 1 12 2 1 their employer's financial interests. All participants

2 have been screened for interests in the products and

3 companies that could be affected by today's discussions.

4 In accordance with 18 United States Code,

5 section 208(b)(3), the Food and Drug Administration has

6 granted waivers for the following individuals, because the

7 agency has determined that the need for their services

8 outweighs the potential for conflict of interest. They

9 include Gary Firestein, Dr. Gary Hoffman, Dr. Steven

10 Abramson, Dr. Allan Gibofsky, Dr. Dennis Turk, Dr.

11 Nathaniel Katz, and Dr. Laurence Bradley.

12 In addition, Dr. Daniel Clauw has been granted

13 a limited waiver that permits him to give his presentation

14 on "Post-ACR Diagnostic Criteria" and to answer questions

15 directly related to his presentation. Dr. Clauw is

16 excluded from participating in the remainder of the

17 committee's discussion.

18 A copy of the waiver statements may be

19 obtained by submitting a written request to the agency's

20 Freedom of Information Act Office, room 12A-30 in the

21 Parklawn Building.

22 With respect to FDA's invited guests, there 1 13 2 1 are reported interests that we believe should be made

2 public to allow the participants to objectively evaluate

3 their comments.

4 Dr. Leslie Crofford has been involved in

5 studies of Pfizer's pregabalin and Eli Lilly's duloxetine.

6 She consults for Pfizer and Wyeth and previously consulted

7 with Cypress. Dr. Crofford also receives speaker fees and

8 is a scientific advisory for Pfizer.

9 Dr. Fred Lasky is participating as a non-

10 voting industry representative, acting on behalf of

11 regulated industry. Dr. Lasky is a full-time employee of

12 Genzyme and has a sales relationship with Wyeth. He would

13 like to disclose that he owns a nominal amount of stock in

14 Johnson & Johnson.

15 In the event the discussions involve products

16 or firms not on the agenda for which a FDA participant has

17 a financial interest, the participants are aware of the

18 need to exclude themselves from such involvement and their

19 exclusion will be noted for the record.

20 With respect to all other participants, we ask

21 in the interest of fairness that they address any current

22 or previous financial involvement with any firm whose 1 14 2 1 products they may wish to comment upon.

2 DR. FIRESTEIN: Thank you very much.

3 The first item on the agenda is from Dr.

4 Witter, who's going to make some opening remarks.

5 DR. WITTER: Good morning.

6 We arranged for some sun for you today. We

7 haven't had that around here a lot, so please enjoy it in

8 here.

9 We have an interesting day, I think, set up.

10 This has a potential to be an historic day. We're going

11 to be discussing something today that we have not at this

12 point really discussed in any great detail at an advisory

13 committee meeting, and we have a task today, which is

14 essentially to go about and have a discussion about

15 creating a claim for fibromyalgia. So I'm sure we'll find

16 it interesting, and some folks would hope that at the next

17 meeting, we are actually talking about approving something

18 for fibromyalgia. Time will tell.

19 So we have several goals for the meeting. I'd

20 like to just review those for today. One of those is

21 essentially to gather input then regarding the development

22 and approval for drugs that treat fibromyalgia. This 1 15 2 1 discussion will help us and will enrich the analgesic

2 guidance process in rewriting the document. I think most

3 of you know that we are in the process of revising the

4 1992 guidance documents. So this will be an informative

5 meeting in that regard as well.

6 We hope to address what we've come to

7 understand is an important public health issue. Estimates

8 are, depending on where you read, it affects anywhere from

9 4 to 10 million people in the United States alone, and we

10 hope that this discussion will also help us to better

11 understand how fibromyalgia represents a "model" of

12 chronic pain. I'll be discussing a bit later what we mean

13 by the term "model".

14 So we talk about claims and labels. Let's

15 make sure that we are on the same page. It's stated quite

16 often that although label claims have legal and regulatory

17 uses, their central purpose is to inform health care

18 providers and patients about the documented, and I stress

19 documented, benefits and risks associated with a product.

20 So claims, therefore, describe clinical benefits and

21 that's really what we're going to be trying to address

22 today. What are those clinical benefits? The better that 1 16 2 1 a product is labeled, the more effective it is then to

2 allow for a useful risk management program which is

3 something that we're all very much concerned about these

4 days.

5 So fibromyalgia. What is it? Well, if you

6 look at the Arthritis Foundation's web page, you'll find

7 some of the following. They describe it as an arthritis-

8 related condition, characterized by generalized muscular

9 pain and fatigue. I'd like to stress the word "and".

10 It's described as a condition, referred to really as a

11 syndrome, because it is a set of signs and symptoms that

12 occur together. It's confusing. It's often misunderstood

13 and a lot of people, including health care providers,

14 maybe don't even believe that it exists. Part of the

15 problem is that it has very common symptoms with no

16 specific laboratory criteria.

17 How does the American College of Rheumatology

18 classify fibromyalgia? I know that that'll be a big part

19 of our discussion today. Well, there are really two

20 criteria that need to be satisfied. One is that you have

21 a history of chronic, in this case defined as 3 months,

22 widespread pain. The pain needs to be on the left side 1 17 2 1 and the right side. It needs to be both above and below

2 the waist. It needs to involve the axial skeleton, and

3 then you have to have pain when you digitally palpate in

4 11 of 18 tender spots. This palpation has to be with the

5 force of 4 kilograms and this has to be described as pain,

6 not tenderness. So what we'll be discussing today, I'm

7 sure, is whether or not this is a viable and workable

8 inclusion criteria for some of the clinical trials that

9 will be coming.

10 Well, how do we treat fibromyalgia? Again

11 turning to the Arthritis Foundation's web page, there are

12 a variety of strategies. One important one is education,

13 so that patients can understand and hopefully better

14 manage what this condition is or isn't. Relaxation

15 techniques, which are intended to ease tension and

16 anxiety. Various forms of exercise to increase one's

17 flexibility and cardiovascular fitness, and then certain

18 drugs, which are intended to decrease pain and improve

19 sleep, and again I stress the word "and".

20 There are some interesting drugs here, anti-

21 depressants, such as tricyclics and select serotonin

22 receptor inhibitors, and benzodiazepines. What is not on 1 18 2 1 this list that's interesting are things like NSAIDs and

2 Cox-2s and opioids. It may be telling us something about

3 this disease in particular.

4 So I'd like to just take a few minutes and

5 kind of get us all on the same page, so to speak, as to

6 how it is that we came to be having this particular

7 meeting today, and I think that there were two meetings

8 that occurred last year that were particularly

9 informative. One of those was the NIH-FDA workshop that

10 occurred in March of 2002. I'll be describing this, in a

11 bit, more. But one of the important features of this

12 meeting was that we came to an agreement at this meeting

13 that chronic pain is in fact an important unmet medical

14 need and needs to be addressed, and during that

15 discussion, we had a breakout session with Dr. Clauw

16 looking at fibromyalgia as an example of chronic pain.

17 A few months later, we had an Arthritis

18 Advisory Committee meeting -- and I believe it was in this

19 room -- that really was focusing on pain. We talked about

20 a variety of claims for marketing for analgesics. I will

21 describe that in a bit, and I'd just like to point out

22 that all of this information is available from our 1 19 2 1 committee meetings on our website. There's just a

2 tremendous amount of information available on the websites

3 in general at FDA.

4 Speaking of pages, I'd like to point out about

5 eight of those. This is a recent publication that just

6 came out. It's entitled "NIH-FDA Analgesic Drug

7 Development Workshop: Translating Scientific Advances

8 into Improved Pain Relief." This is a fairly complete

9 summary of that meeting back in 2002. So if you haven't

10 had a chance to look at it yet, please do so. It's worth

11 the time.

12 At that meeting then, we, as I indicated,

13 discussed about chronic pain, and we had a discussion

14 about looking for new models, and again I'll describe

15 models, what I mean by that term, in just a second, but we

16 thought it was important at this meeting to get better

17 models so that we could understand some of the important

18 clinical aspects of chronic pain, certainly part of what

19 we'll be discussing today, and if we could also then

20 better understand the chronic pain mechanisms which may

21 serve as treatment targets down the road, this would

22 hopefully allow the design of better clinical trials and, 1 20 2 1 in the long run, hopefully ultimately improve the

2 treatment of chronic pain which is the goal.

3 Now, as I've alluded to twice already, we

4 talked about models of chronic pain at this meeting, and

5 what we mean by a model is really a setting that's adapted

6 to a clinical trial to understand one of the conditions

7 listed here, for example. It's not necessarily the same

8 kind of thing that you have in clinical practice. In

9 fact, it may be quite different, but it allows us to make

10 certain kinds of decisions from a regulatory perspective.

11 So we looked at osteoarthritis, chronic mechanical lower

12 back pain, diabetic neuropathy, cancer pain, fibromyalgia,

13 AIDS, and temporomandibular disease as potential models of

14 chronic pain.

15 We also discussed at that meeting what should

16 be some of the clinical outcomes that should be studied in

17 any particular chronic pain situation. Pain, of course,

18 was first on the list, not surprisingly. We also talked

19 about the use of the patient global, health-related

20 quality of life. Those that are specific to the disease

21 itself were considered to be better, as well as we talked

22 about physical function, again anything that is specific 1 21 2 1 for the disease was felt to be better than if it was just

2 a general questionnaire. We talked about the use of

3 rescue medications, interesting economic considerations

4 which we don't usually get into at FDA, and also how to

5 position adverse events as an outcome measure.

6 Now, a few months later then at the July

7 Arthritis Advisory Committee, we talked about pain and we

8 had an interesting two-day discussion about various types

9 of claims that we might be granting for pain in general,

10 and we broke this up into really two categories. First,

11 clinical claims. So we talked about a claim for acute

12 pain and those of you that were there will recall our

13 discussion of the ABCs of acute pain which we won't

14 describe today, but they are at the website. We also

15 talked about chronic pain which will be, again, the focus

16 for today, and the potential for mechanistic claims, that

17 this might be a way to facilitate bridging studies and

18 also a way to push the field forward in the sense of

19 understanding what mechanisms may be. So, for example,

20 for fibromyalgia, one might envision, just as a for

21 instance, a claim to prevent autonomic dysfunction as an

22 example, and that's the discussion that we had at that 1 22 2 1 point in time.

2 We wrestled with the idea, as we often do,

3 about what is a minimally clinically-important difference

4 in pain relief. We talked about a responder approach in

5 analgesia, which we'll be describing again today, and we

6 talked about the need to revise the analgesic guidance

7 document.

8 So at the meeting, we specifically talked

9 about claim structures. We talked about a variety of ways

10 to approach this. One of the first things we talked about

11 was to continue to grant, which we've been doing to a

12 certain extent, a claim for general pain, and this

13 affectionately became known as the "six pack" for those of

14 you that were there, and what it really described was a

15 situation where any particular analgesic should really

16 treat a variety of pain conditions from a variety of

17 mechanistic situations. So, for example, anything that

18 would be given and granted this general claim would treat

19 something, for example, like osteoarthritis, fibromyalgia,

20 and cancer pain, trying to get at a broad swath of

21 mechanisms and etiologies for chronic pain. This was

22 thought to be too high of a hurdle as the discussion went 1 23 2 1 on.

2 We then had a limited discussion about the

3 possibility for a more limited claim, for example,

4 something that might treat all musculoskeletal pain. So,

5 for example, this would be a combination of something that

6 treats osteoarthritis, fibromyalgia, and chronic lower

7 back pain. But as the discussion continued at that point

8 in time, it seemed the best as we thought through what we

9 had heard that we should continue to push forward with

10 what we've been doing, which is really granting claims for

11 specific diseases. You know about osteoarthritis, today's

12 discussion being fibromyalgia and chronic lower back pain.

13 So that's the current tactic and again that's another

14 reason for today's meeting.

15 So this is all history. Today, we need to

16 push forward, and so the charge and the challenge for

17 today is in how do we structure a claim. We now know what

18 a claim is. It's a clinical benefit. So how should we

19 approach it? There are fundamentally two different ways.

20 One would be to approach fibromyalgia as a symptom or

21 cluster of symptoms, as is indicated on the Arthritis

22 Foundation web page, for example. Another way, which may 1 24 2 1 be more useful, is to consider fibromyalgia as a complex

2 disease state with varying clinical presentations, and

3 I'll be describing both of those briefly.

4 So taking a symptoms approach, we could then

5 look at a pain outcome. Again, this is an obvious and

6 necessary outcome, but I think we need to think it through

7 in more of a deeper fashion. For example, we don't want

8 to get into the situation of overpowering clinical trials

9 to drive meaningless endpoints, clinical endpoints that

10 may be statistically important but have no clinical

11 relevance.

12 We also should be considering the use of the

13 patient global outcome. As we've been thinking this

14 through in the division, what we are after for this

15 particular outcome is something that is not another look

16 at efficacy. It's not really another look at safety.

17 It's that something in between, that gray zone in between.

18 And we maybe then should be discussing the

19 inclusion of a physical function or a health-related

20 quality of life outcome. This seems to make sense because

21 these are quite often adversely impacted by pain,

22 particularly chronic pain, and analgesics should improve 1 25 2 1 this or at least they certainly should not worsen it.

2 I think it's safe to say that it's the feeling

3 of the division that a combination of these really allows

4 us, we feel, to get a better and improved assessment of

5 the patient's experience with the analgesic which is a key

6 feature of what we're after and will be the discussion

7 today.

8 Well, what about if we take a disease approach

9 to fibromyalgia? There has been a lot of discussion that

10 fibromyalgia represents, and in fact it was at the NIH-FDA

11 meeting, a chronic pain state. It's a centrally-mediated

12 process. So if we look at fibromyalgia as a chronic pain

13 state, like we do chronic diseases, in chronic diseases,

14 we're comfortable in thinking through treating the

15 disease, curing the disease, even potentially preventing

16 the disease. So should we be taking that same kind of

17 mentality here with fibromyalgia, and would that be useful?

18 So as we then have positioned, as is on this

19 cartoon, pain as the central player, is it more useful

20 then to think this through, that pain causes, for example,

21 sleep disturbances and pain can cause fatigue, can

22 diminish your quality of life, can lead to cognitive 1 26 2 1 difficulties, and can lead to dysfunction, either

2 autonomic or some kind of loss of functional ability and

3 that may then be all a result of the pain? So, really, we

4 need to address the pain, but it's not sufficient.

5 So as we take a step back then from the

6 hypothetical and deal with the challenge today then, in

7 either fibromyalgia or chronic pain, what really is

8 important to the patient? I think we need to keep that as

9 a focus for our discussion today. There's a large effort

10 underway at FDA, as well as outside, for something that

11 has become to be known as the PRO, or patient reported

12 outcomes, and in fact, there's a draft guidance that

13 should be coming out before the end of the year from us.

14 So what are PROs? They are essentially a

15 patient report of a health condition or treatment. They

16 are scientific, patient-centered measures that can

17 evaluate change in health outcomes. They are handled much

18 like other outcomes for both drug approval and promotion,

19 which I think is a very interesting aspect to think

20 through today, and their selection, their development, and

21 their validation have issues very similar to any other

22 clinical measure, and in particular for pain-related 1 27 2 1 outcomes, we need to then think through psychosocial and

2 all the various other aspects that can be impacted.

3 Well, what are some of the ideal

4 characteristics for a metric in, for example, pain? It

5 should, of course, be understandable to patients and

6 clinicians. We all know that pain is the fifth vital sign

7 nowadays, and so it seems to make sense that as we

8 transition from the information that we gather in a

9 clinical trial and try and write that into a product

10 label, we should be doing as much as we can to make that a

11 seamless transition, so that one understands what was

12 studied in the clinical trial when you look through the

13 label.

14 It should also be applicable across various

15 studies to allow across-trial comparisons. One of the

16 reasons a lot of people feel that pain, particularly

17 chronic pain, hasn't moved forward in a more rapid fashion

18 is because you can't do rigorous and robust meta-analyses

19 because the outcomes just don't allow it, and so we should

20 be thinking forward in that regard to prevent that

21 situation in the future. It should, as I've been

22 describing, detect a clinically-meaningful result. The 1 28 2 1 metric should be responsive to differences in analgesia,

2 and, of course, it should be valid.

3 So I'd just like to take a second and talk

4 about a highly-valid index that we utilize in the division

5 for WOMAC, in particular the WOMAC pain index subscale,

6 and WOMAC stands, for those of you that may not remember,

7 the Western Ontario and McMaster Universities. I still

8 don't know how they get MAC out of that. But what it

9 really is is a combination of five questions, and as you

10 read through the questions, these are not simple questions

11 about pain. They have in them, as you can see, a

12 functional component, at least some of the questions. So,

13 for example, walking on a flat surface, pain going up or

14 down stairs, pain at night while in bed, sitting or lying

15 or standing upright.

16 These questions are really intended to get at

17 the overall pain experienced in OA. As those of us that

18 take care of patients know, the pain of OA has many

19 different faces, and so I think these questions really do

20 a fairly good job of looking at all of these various

21 situations as we study them in osteoarthritis.

22 And as is on this slide then, we do grant for 1 29 2 1 osteoarthritis, for the treatment of signs and symptoms

2 claim, something that has to be based upon -- we've become

3 comfortable with utilizing three co-primary endpoints of

4 pain, function, and global in a trial that is 3 months in

5 length. So the WOMAC pain subscale, for example, is quite

6 often utilized for the pain component.

7 So then as we think through fibromyalgia and

8 consider some of what needs to be thought through,

9 whatever the outcome may be, some of the important points

10 are as follows. For example, as we just discussed with

11 the pain, should this be a single question or is it better

12 to come through with a composite question to get a more

13 robust assessment of the outcome? Of course, it has to be

14 both statistically and clinically meaningful.

15 We have to think through who is included and

16 excluded from the trials because it has an impact on the

17 labeling and the generalizability once this is released.

18 We need to think through whether a landmark

19 analysis, meaning at the end of the trial as compared to

20 the beginning, is the better way to go, or should we be

21 thinking through a time-weighted approach, trying to get

22 more of a feel for what happens during the entire trial, 1 30 2 1 not just at the end?

2 We need to think through about the issue of

3 daily, in this case I've written here, pain, whether it

4 should be on a daily basis or on a weekly basis. There

5 are pluses and minuses for both. There's a lot of effort

6 nowadays in looking at diaries, particularly electronic

7 diaries, as that may be better to capture the moment pain.

8 That appears to be important for fibromyalgia.

9 We need to discuss the length of the clinical

10 trials. Is 3 months enough? Is 6 months better? And

11 then, we're going to be wrestling, I'm sure today, with

12 the issue of superiority to placebo, and do we need to

13 continue to follow that paradigm?

14 So another way to look through and consider

15 how we might fashion a label and get at a response in

16 fibromyalgia would be to look at the responder approach.

17 As I said, we've discussed this at other venues. It has

18 some potential advantages to it. One of those is that it

19 can allow the outcomes of interest to really be explored

20 and studied in the same patient which can be highly

21 useful. It may lessen or eliminate data imputation which

22 is always a problem, as we're all aware. It allows a 1 31 2 1 certain flexibility in design to capture different aspects

2 of the condition, and it's something that is widely

3 utilized in rheumatoid arthritis. We've become very

4 comfortable with it.

5 So I thought I'd just take a moment to refresh

6 our memories as to what the ACR 20 responder index is.

7 ACR again stands for the American College of Rheumatology.

8 The 20 stands for 20 percent improvement. So it comes

9 also as a 50 and 70 percent variety.

10 There are two components to this index. One

11 is a required component where you have to have in this

12 case a 20 percent improvement in swollen and tender

13 joints. In addition, you have to have a 20 percent

14 improvement in three of the five following: patient and

15 physician global, patient pain score, a modified health

16 assessment questionnaire, and acute phase reactant. In

17 this case, I've written here C-reactive protein or

18 sedimentation rate.

19 So is this useful, this particular responder

20 approach, in terms of fibromyalgia, and if it is, how

21 could we fashion a particular responder endpoint? I've

22 put in this slide a "for instance." This is not at all 1 32 2 1 intended to say that this is what we would like to do.

2 This is just a for instance.

3 So we could envision that pain would be the

4 required outcome, again makes sense.

5 And then we have other important outcomes that

6 I think we need to be considering, as we've been

7 discussing: qualify of life outcome, either a general or

8 a specific; a function or, in this case I've written, a

9 dysfunction outcome; looking at sleep disturbance,

10 fatigue, cognitive impairment as outcomes; and then

11 patient global.

12 Would it be then, for example, that we would

13 say that someone is a responder if they have achieved four

14 of the important outcomes, plus pain, and then should we

15 be also thinking through that we want to have this in a

16 tiered structure like we do with the ACR 20/50/70? Would

17 that be useful for this condition?

18 I'd like to just take a minute and close out

19 here by bringing everybody up to speed on a process that

20 is ongoing. It's called the IMMPACT process. The acronym

21 stands for Initiative in Metrics and Measurements in

22 Analgesic Clinical Trials. This is an international 1 33 2 1 organization which has really been devoting itself

2 recently to looking at chronic pain, and in fact, there is

3 a publication which has been submitted entitled Selecting

4 Core Outcome Domains in Chronic Pain Clinical Trials.

5 It's interesting to look at the six

6 recommendations from this group, being as I've listed

7 here, pain, physical functioning, emotional functioning,

8 patient global, negative health states, and patient

9 disposition, as being representative and overlapping, in

10 fact, what we've been discussing at other meetings.

11 So when all is said and done and when we're

12 finally writing a label, we need to remember that the

13 label is, as I've been trying to stress here, the end

14 product of all these efforts. It's the end result of all

15 the randomized, controlled trials and everything that's

16 gone into their thinking.

17 So what should the label mean? To the health

18 care provider, for example, the label needs to be

19 describing for this person who can take it, and what type

20 of risk management should be involved in thinking through

21 any particular issues, and importantly, what should it

22 mean to the patient. What can they expect in terms of 1 34 2 1 relief of pain? What can they expect in terms of relief

2 of associated symptoms? And what is the duration of this

3 relief and the degree of this relief? All important

4 issues we need to think through today.

5 This is from the latest issue of a magazine

6 entitled Fibromyalgia Aware. It's reminding us that

7 fibromyalgia does not just involve women, but let's hope

8 that today's discussion will lead to a future where more

9 patients look like this gentleman than less that have

10 fibromyalgia.

11 And I'd like to close with something that was

12 also the close of the second meeting of the IMMPACT

13 process, which I think is an important reminder for us as

14 well today and that I think I've been stressing throughout

15 here, is that it's important really to think about the

16 patient, to assess the patient, and not just the pain.

17 So thank you very much.

18 (Applause.)

19 DR. FIRESTEIN: We have a minute or two for

20 questions from the committee.

21 Yes, Dr. Cush?

22 DR. CUSH: Jim, that was a good overview. 1 35 2 1 Do you think, though, that we can as an

2 advisory body make recommendations on outcome measures or

3 composite outcome measures when clearly there are none

4 that have been tested or validated and whatnot? So we

5 could throw it out there, but how useful is that to the

6 agency without any sort of testing or confirmation of its

7 value?

8 DR. WITTER: I think you've hit on really the

9 core of the problem, that we need to bring that discussion

10 forward, and then I think all of us wrestle whether or not

11 we can actually do this. If things are not validated in

12 the other areas, can we be pushing forward without those

13 kind of indices like we've had, for example, with

14 rheumatoid arthritis, with osteoarthritis? What do we do?

15 So I think you've hit on the head. That really is what we

16 need to be discussing today.

17 DR. FIRESTEIN: One of the advantages that we

18 had in those other indications is that there were

19 effective agents that could be then used to validate the

20 endpoints, and do you have some notion in terms of how one

21 is going to be able to validate an endpoint when there are

22 no truly effective agents? 1 36 2 1 DR. WITTER: Well, yes, but I'd prefer to hear

2 your discussion later.

3 DR. FIRESTEIN: Okay.

4 Lee?

5 DR. SIMON: Well, isn't this always the

6 dilemma, Jack? The reality is, is that, what came first,

7 the chicken or the egg, and without a discussion that's

8 public and with the experts to determine what may be

9 useful things to look at and what is this real process,

10 based on whatever science exists, then the ability to

11 validate the outcomes in the context of applying potential

12 therapies becomes very difficult until we have that

13 discussion, the fundamental beginning step-off to

14 understand what we as some experienced clinicians believe

15 might be a useful way to approach the particular

16 conundrum. So that's really the reason. Although we

17 don't have good validation of the outcomes, we don't have

18 great therapies to date, we do have to make that leap to

19 be able to begin to target what we believe, based on the

20 science, will be useful, and then hopefully people will

21 respond by coming in with potential therapeutics that will

22 actually then allow us to test and validate the outcomes. 1 37 2 1 DR. FIRESTEIN: Thanks very much.

2 The next presentation on Pre-ACR Diagnostic

3 Criteria will be given by Dr. Bradley.

4 DR. BRADLEY: Thank you very much.

5 I'm going to fumble here, the requisite

6 fumbling at the podium, while I get my presentation up.

7 I want to thank you very much for inviting me

8 here today, and I am going to try today to provide

9 something of a historical perspective on the way we think

10 about fibromyalgia, but really the primary points that I'm

11 going to try to make today are that, one, the abnormal

12 processing of sensory information in fibromyalgia is

13 something that is identifiable, it's been reliably

14 observed among different investigators and different

15 clinicians, and this abnormal processing or abnormal

16 sensitivity to pain is something that's not, at least from

17 the data we have so far, highly affected by psychosocial

18 factors. However, what people say about their pain, how

19 they report their pain, how they behave in response to

20 pain or their pain behavior is highly modifiable by

21 psychosocial factors.

22 Then, I'll also try to conclude by some 1 38 2 1 speculations regarding what types of changes might we

2 expect from compounds that are in development or about to

3 be tested for chronic pain conditions, such as

4 fibromyalgia.

5 First of all, as you've already seen from Dr.

6 Witter, fibromyalgia is characterized by several symptoms

7 and the primary characteristics of fibromyalgia include

8 widespread generalized pain and abnormal pain sensitivity

9 evoked by low-intensity stimuli that really vary in

10 nature. These include pressure stimulation, heat

11 stimulation, cold stimulation and so on. And all the

12 criteria that have been developed over the years have

13 really focused on those two primary characteristics.

14 In addition, just as Dr. Witter mentioned, there's a

15 variety of other symptoms that occur with fibromyalgia,

16 such as headache, fatigue, sleep disturbance, and a number

17 of other symptoms, too.

18 Now, there are also alterations in behavior,

19 so that fibromyalgia symptoms are associated with

20 behavioral disturbances and activity levels, social

21 interaction, functional ability, avoidance of events that

22 evoke pain, affective distress and relatively high usage 1 39 2 1 of the health care system.

2 Historically, these abnormalities and pain

3 sensitivity, difficulties in function and affect, in the

4 absence of reliable biological markers, have led

5 investigators to take different types of research and

6 clinical pathways. For many years, I think there was sort

7 of a dichotomy between those investigators who were

8 searching for a single source of symptoms versus people

9 who tended to attribute fibromyalgia to psychiatric

10 illness or other psychosocial factors.

11 When we see the different types of labels that

12 have been applied to people who show abnormal pain

13 sensitivity and widespread pain -- and these are labels

14 ranging from DaCosta syndrome and shell shock, all the way

15 to fibrositis and affective spectrum disorder -- you see

16 that most of these diagnostic labels have either focused

17 on sort of biological factors, such as concussive effects

18 on the brain, nerve dysfunction, viral illnesses, or they

19 have focused primarily on psychological and psychosocial

20 factors.

21 I think in thinking about fibromyalgia now, I

22 think this is truly a disorder where there's abnormal pain 1 40 2 1 sensitivity that's mediated by abnormal processing of

2 sensory input at the spinal and the super-spinal levels,

3 but certainly the way people act with fibromyalgia, what

4 they say about their pain, is influenced by a number of

5 factors.

6 The three factors that I think have really

7 helped us better study and understand fibromyalgia are,

8 one, the development of gate control theory back in 1965,

9 work that was done in the 1980s that at least in my mind

10 was really begun by Doug Drossman and the group studying

11 irritable bowel syndrome regarding psychosocial factors

12 that influence health care-seeking behavior, and current

13 work in fibromyalgia specifically beginning in the early

14 1990s by people like Rob Bennett and Jon Russell who began

15 to try to identify various biological factors that might

16 be associated with pain and pain sensitivity in people

17 with fibromyalgia.

18 With regard to gate control theory, very

19 quickly, the basic tenets are that multiple biological and

20 psychosocial factors influence pain perception as well as

21 pain behavior, and therefore, all pain perception and pain

22 behavior is determined by this combination of biological 1 41 2 1 and psychosocial factors. So it's really no longer

2 appropriate to identify pain and related symptoms as

3 either organic in nature or functional in nature.

4 This slide actually shows Ron Melzack's

5 current version of the gate control theory which he refers

6 to as the neuromatrix construct, and essentially what this

7 refers to is that the neuromatrix is a construct which is

8 really comprised of a complex set of pathways involving

9 the spinal cord, also various regions of the brain, limbic

10 system, somatosensory cortex, thalamus and so on. And the

11 function of this neuromatrix is in part genetically

12 influenced, but there's a variety of biological and

13 psychosocial and cognitive factors that can influence the

14 functioning of the neuromatrix which then produces pain

15 perception and pain behavior.

16 Now, I'll just show you a few slides showing

17 you sort of the robustness of the sensory processing

18 phenomena that are observed in fibromyalgia. This is a

19 slide from our group in which we compared mechanical

20 pressure pain thresholds at a subset of the ACR tender

21 points in a group of about 20 fibromyalgia patients who

22 did not meet current criteria for major depressive 1 42 2 1 disorder, a group of 10 patients who met criteria for

2 major depressive disorder but did not suffer from

3 generalized pain, and a group of healthy controls without

4 pain, without major depressive disorder. What you see is

5 that the pain threshold levels to pressure stimulation in

6 these fibromyalgia patients is about one-half the level of

7 what you see in healthy controls, and at least in our

8 laboratory and I think in most other laboratories, that's

9 a very common finding, that the pain thresholds are about

10 one-half the level in these patients with fibromyalgia.

11 What you see here in these depressed patients, their pain

12 threshold levels are really no different from what you see

13 in the healthy controls, and to us, that suggests that

14 depression alone doesn't account for the abnormal pain

15 sensitivity in fibromyalgia. I'll show you some more data

16 on this in a bit.

17 This is some other data from our laboratory

18 looking at thermal pain thresholds, thermal stimulation

19 applied to the skin, and you see a reliable, significant

20 difference in pain threshold levels where the fibromyalgia

21 patients' threshold level is about 5 degrees Centigrade

22 lower than what you see in healthy controls. 1 43 2 1 These are some data actually from Mike Geisser

2 and the group at Michigan showing differences between

3 patients with fibromyalgia which you see in this line and

4 healthy controls in magnitude estimates of pain intensity

5 in response to a variety of thermal stimuli, ranging from

6 40 degrees Centigrade to 51 degrees Centigrade, and you

7 see very reliable differences in pain intensity ratings

8 between these two groups.

9 Some additional data from Roland Staud who's

10 here. This is a slide from one of Roland's recent studies

11 showing greater temporal summation effects in patients

12 with fibromyalgia compared to healthy controls, and

13 regardless of whether the stimuli or the repetitive

14 stimuli are applied with a 3-second or 5-second

15 interstimulus interval, you see much greater evidence of

16 temporal summation in the patients compared to healthy

17 controls.

18 So what this shows is that in a variety of

19 laboratories using different techniques, different

20 stimulation, you see very robust and reliable differences

21 in responses to relatively low-intensity stimuli between

22 fibromyalgia patients and healthy controls. 1 44 2 1 Well, let's turn to the question of what we

2 know about psychosocial factors and how that affects pain

3 behavior, including health care-seeking behavior. It's

4 been established in a variety of chronic illnesses that

5 psychological distress or psychiatric illness is

6 associated with greater health care-seeking behavior at

7 tertiary care facilities. In the case of fibromyalgia,

8 there is some evidence that psychological factors are not

9 really necessary or sufficient to produce fibromyalgia

10 symptoms.

11 And the person that really, I think, got me at

12 least thinking about this and certainly has influenced

13 other investigators, too, is Fred Wolfe who originally

14 came up with this funnel slide which shows that in

15 research studies, we primarily focus on people at tertiary

16 care centers, but these people may well be very different

17 from the general population of individuals with

18 fibromyalgia or any other sort of chronic pain disorder.

19 We did a study in our laboratory where we

20 examined a group of about -- actually now about 70

21 patients with fibromyalgia and 40 individuals that we

22 recruited from the community who met criteria for 1 45 2 1 fibromyalgia but had not gone to see a doctor for their

2 pain within the past 10 years. We compared these two

3 groups of individuals with regard to a group of healthy

4 controls recruited from the community.

5 This particular slide shows the number of

6 lifetime psychiatric diagnoses among these three groups

7 that were determined by the subjects' responses to the

8 diagnostic interview schedule. What you see on this slide

9 is that the fibromyalgia patients are actually

10 characterized by a fairly high level of psychiatric

11 morbidity. The patients are characterized by a mean

12 number of 2.5 psychiatric diagnoses over the lifetime

13 compared to our healthy controls who have a mean number of

14 diagnoses of 1, and in the case of the healthy controls,

15 these are primarily social phobias and really very minor

16 disturbances. Among our non-patients, actually they show

17 a significantly lower number of lifetime psychiatric

18 diagnoses than the patients but they don't differ from the

19 healthy controls in terms of psychiatric morbidity, and as

20 you'll see in a moment, the pain sensitivity to pressure

21 stimulation of the non-patients and the patients, is

22 approximately the same. 1 46 2 1 However, when we followed the non-patients

2 over a two-and-a-half-year period, we wanted to see to

3 what extent the non-patients in a sense would convert to

4 patients, how many of those people would become patients

5 over time. What we found, and actually much to our

6 surprise and much to the surprise of our reviewers, is

7 that only 10 of the 40 non-patients actually became

8 patients, sought medical care during that first 2-and-a-

9 half years.

10 But the factor that best distinguished those

11 who became patients from those who remained non-patients

12 was the number of lifetime psychiatric diagnoses at

13 baseline, and essentially among our non-patients, those

14 who had one or fewer or zero lifetime psychiatric

15 diagnoses had about a 95 percent chance of remaining a

16 non-patient. Those with two lifetime psychiatric

17 diagnoses or greater actually only had about a 50-percent

18 chance of remaining a non-patient. So it was the number

19 of psychiatric diagnoses or psychiatric morbidity that was

20 a very great determinant of who became a patient within

21 that 2-and-a-half year period.

22 Now, returning back to the baseline data, this 1 47 2 1 slide shows in a separate study where we examined another

2 group of fibromyalgia patients, another group of

3 fibromyalgia non-patients, healthy controls, and we

4 compared these groups on pain threshold levels. What we

5 found is that regardless of whether we were stimulating

6 with pressure stimulation the ACR tender points or a set

7 of control points which were primarily points, such as the

8 mid-tibia and the forearm that would involve stimulation

9 of sort of bony skeletal tissue, and regardless of whether

10 the patients reported an insidious or a gradual onset to

11 their pain versus a traumatic onset to their pain, we saw

12 approximately the same pain threshold levels in the

13 aggregate among all three groups of individuals with

14 fibromyalgia compared to the healthy controls. And we saw

15 that again both at the tender points, as well as at our

16 set of control points.

17 So what this suggests is again that regardless

18 of psychiatric morbidity, regardless of the nature of the

19 onset of the pain or the factors that people identify as

20 the onset of their pain, you see very similar pressure

21 pain thresholds.

22 In our particular study, we also drew cerebral 1 48 2 1 spinal fluid to look at levels of substance P and again

2 you see the same relationship, very similar to what Jon

3 Russell had found in his series of studies. We found that

4 among our three groups of people with fibromyalgia,

5 regardless of whether they were patients or non-patients,

6 we found elevated levels of substance P compared to our

7 healthy controls.

8 Well, let's turn now and talk about what we

9 know about psychosocial factors and how they affect what

10 people report about their pain. The example that I'm

11 going to use in this next series of slides is reports of

12 stressors, and I think it's pretty well known that

13 patients with fibromyalgia frequently report that their

14 symptoms are intensified by emotional distress or

15 emotional stress or also physical stress.

16 Actually there was a study that came out of a

17 couple of years ago from Alex Zautra and the group at

18 Arizona State in which they examined a group of

19 fibromyalgia patients, a group of patients with knee

20 osteoarthritis and healthy controls, and asked each

21 participants to describe a stressful experience in their

22 life over a 30-minute period. What they found was that 1 49 2 1 the fibromyalgia patients at the end of that 30-minute

2 period reported a much greater increase in their clinical

3 symptoms compared to the reports of the patients with knee

4 osteoarthritis and also the healthy controls.

5 We began a study with Roger Fillingim of the

6 University of Florida, which is still ongoing, where we've

7 been looking at the effects of really very brief stressors

8 in the laboratory on patients' and controls' responses to

9 thermal stimulation of the skin, and in our particular

10 paradigm, we asked participants to very vividly imagine

11 either a very stressful event from their own life or a

12 relatively neutral or relatively sometimes pleasant event

13 from their own life right before we applied the

14 stimulation.

15 And in this particular slide, what I'm going

16 to show you are mean increases in pain unpleasantness

17 ratings among the fibromyalgia patients and the healthy

18 controls at four different levels of thermal stimulation.

19 What this slide shows is actually these bars represent

20 differences in pain unpleasantness ratings in the period

21 following the stressful imagery versus the period

22 following the relatively neutral imagery. What you see is 1 50 2 1 that at 45 degrees, 47 degrees, 49 degrees Centigrade, you

2 see substantially greater increases in pain unpleasantness

3 among the fibromyalgia patients, very little effect of the

4 imagery on pain unpleasantness ratings among the healthy

5 controls. And at 51 degrees -- this is actually a total

6 of about 15 people here -- so again you see no effect

7 among the healthy controls, and due primarily to 1 person,

8 you see actually a very large decrease in ratings among

9 fibromyalgia patients. But the primary finding is that at

10 these lower levels of stimulus intensity, just thinking

11 about a stressful event over a 4-minute period has a very

12 strong effect on pain unpleasantness ratings.

13 Now, when we asked people to give us their

14 ratings of pain intensity, the intensity ratings by both

15 groups are not really strongly affected by thinking about

16 stressful events, but ratings of pain unpleasantness are

17 affected.

18 Also, we've been drawing blood and drawing

19 saliva and what we find is, actually with both measures,

20 that our patients with fibromyalgia, about 20 minutes

21 after the stressful imagery, show a relative decrease in

22 cortisol levels compared to the neutral imagery, and we 1 51 2 1 don't see that kind of effect in our healthy controls. So

2 there's not enough people yet to look at association

3 between changes in cortisol and changes in pain

4 unpleasantness, but the point is that you do see some

5 evidence of HPA axis dysfunction as a result of the

6 stressful imagery in the fibromyalgia patients compared to

7 the healthy controls.

8 Well, what do we know about biological factors

9 that are associated with pain and distress in people with

10 fibromyalgia? I think there's very interesting work

11 that's going on now regarding both genetic influences on

12 pain and analgesia and also some very good work that's

13 being done using neuroimaging techniques that have

14 documented altered central processing of sensory input in

15 people with fibromyalgia.

16 These are data. Actually, these data come

17 from Dan Buskila's group in Israel. Martin Offenbaecher

18 in Munich was the first person to really identify this

19 finding, but both groups, using very different

20 populations, have shown that individuals with fibromyalgia

21 -- in Offenbaecher's group, it was primarily women, in

22 Buskila's group, it was all women -- actually a greater 1 52 2 1 proportion of the patients with fibromyalgia compared to

2 controls show a functional polymorphism in the 5-HTT gene

3 promoter region or in the regulatory region of the 5-HTT

4 serotonin transporter gene. And what you see is that

5 there's a greater proportion of patients with fibromyalgia

6 who show this short/short allele compared to healthy

7 controls and again that's been found in two separate

8 groups now.

9 There's also some work being done on sex-

10 related genetic influences on analgesia which may

11 eventually have some impact on fibromyalgia research.

12 This is a slide from a paper that Jeff Mogil and Roland

13 Staud, Roger Fillingim, and a large group of investigators

14 recently published showing an interaction between sex and

15 a polymorphism in the melanocortin 1 receptor gene. And

16 what this slide shows is that regardless of whether one is

17 using thermal stimulation or ischemic stimulation, that

18 among females having a particular polymorphism,

19 characterized by two variant alleles in this MC1R gene, is

20 associated with greater analgesic responses to

21 pentazocine. Among the males, you don't see this sex

22 effect, and I think this is a very interesting line of 1 53 2 1 research, particularly given the fact that fibromyalgia is

2 a disorder which affects primarily women.

3 What about altered central processing of

4 sensory input? These are some slides from Rick Gracely

5 and Dan Clauw's group at Michigan, and what this shows is

6 that when fibromyalgia patients and healthy controls are

7 exposed to pressure stimulation that varies in intensity

8 but which produces approximately the same report of pain

9 intensity -- and in this case, there was a pain report of

10 about 11 on a 20-point scale -- you see a number of brain

11 regions in which both patients with fibromyalgia and

12 healthy controls show significant activation on fMRI

13 imaging. So by equivalent levels of pain intensity or

14 perceived pain intensity, you see the same brain regions

15 being activated in patients and controls.

16 However, when you take the healthy controls

17 and you expose them to the same level of stimulation which

18 produced pain in the fibromyalgia patients but which are

19 relatively innocuous to the healthy controls, you

20 primarily see significant levels of activation in a

21 variety of regions in the patients with fibromyalgia. You

22 see very little significant activation in the healthy 1 54 2 1 controls

2 So the point that these two slides show is

3 that fibromyalgia patients are characterized by

4 augmentation of sensory input which can be identified

5 through neuroimaging of activity in the cerebral

6 hemispheres

7 Well, let me conclude the data and sort of

8 summarize the data from this talk. First of all, I think

9 what we've shown is that pain sensitivity, pain-related

10 symptoms, and behavioral disturbances in fibromyalgia are

11 reliably observed by a variety of investigators and can be

12 done so by clinicians and this can be done using a variety

13 of measurement techniques.

14 Pain sensitivity and related symptoms are

15 influenced by biological factors. There's evidence that

16 there may be a genetic predisposition for development of

17 fibromyalgia. That particular serotonin transporter gene

18 or that particular functional polymorphism in that gene is

19 also associated with chronic headaches and also some

20 anxiety disorders. So this particular gene might be

21 related to the development of a number of disorders that

22 are part of the fibromyalgia symptom complex. 1 55 2 1 Also, we've seen that abnormal pain

2 sensitivity is associated in our laboratory and in a

3 number of other laboratories with elevated cerebral spinal

4 fluid levels of substance P, and also what we will very

5 soon see in the future, I think, is that there's a number

6 of investigators using neuroimaging techniques and I think

7 we'll see a number of studies coming along soon which show

8 that abnormal pain sensitivity is associated with

9 augmented sensory neural input.

10 Now, what we've also seen is that, at least in

11 our laboratory, pressure pain sensitivity and CSF levels

12 of substance P really don't vary very greatly as a

13 function of affective illness or lifetime psychiatric

14 morbidity. However, what we do see is that changes in

15 plasma cortisol levels, reports of pain unpleasantness in

16 response to thermal stimulation, and other sorts of pain-

17 related behaviors, such as health care-seeking behavior,

18 are associated with variations in psychosocial factors and

19 affective disturbance.

20 Well, what does this mean for clinical trials?

21 I think a number of pharmacologic interventions that are

22 used currently, also the interventions that are being 1 56 2 1 developed for use in fibromyalgia are all compounds that

2 alter activity at the superspinal level. They alter

3 activity in the brain that can influence pain inhibition

4 or to a certain extent alter central processing of neural

5 input. And I think that what we should be able to observe

6 in clinical trials is that these compounds should be able

7 to influence ratings of pain intensity, and I think some

8 of the newer compounds that are in preclinical trials, for

9 example, some of the new glutamate receptor inhibitors

10 that are in development, may actually also alter abnormal

11 pain sensitivity.

12 These interventions, both the current

13 interventions and the interventions that are in

14 development, may also modify pain behaviors through

15 alterations in pain intensity, but also secondary

16 alterations on pain affect, affective disturbance, and

17 other psychosocial factors.

18 And while this wasn't really part of what

19 we're talking about today, I do want to mention that I

20 think that the development of effective compounds that may

21 alter pain in people with fibromyalgia may also be helpful

22 to clinicians who use psychosocial interventions with 1 57 2 1 fibromyalgia patients. When I look at the literature on

2 cognitive-behavioral therapy, other sorts of psychosocial

3 interventions, when you look at the studies that really

4 use adequate attention placebo controls, at least my

5 reading of those studies is that most of them don't

6 produce effects that are much greater than what you see

7 with a good placebo control, and I think one thing that

8 psychosocial investigators have yet to really think much

9 about is why do we see these relatively modest effects

10 with psychosocial interventions compared to what we see in

11 patients who are treated by psychosocial interventions,

12 patients who have rheumatoid arthritis, osteoarthritis,

13 irritable bowel syndrome and so on. And I think that one

14 of the factors is that for these other kinds of diseases

15 and disorders, there are relatively effective

16 pharmacologic compounds that influence pain, and I think

17 that so far, we really don't have very good compounds that

18 reliably influence pain in fibromyalgia. But I think that

19 once these compounds are developed and tested, and if they

20 are shown to be effective, I think that they will have a

21 secondary effect in the sense that they will enhance the

22 effectiveness of psychosocial interventions for pain and 1 58 2 1 pain behavior in fibromyalgia.

2 So I'll conclude there and thank you very

3 much, and I'll be glad to take any questions you might

4 have.

5 (Applause.)

6 DR. FIRESTEIN: Thank you.

7 Dr. Katz?

8 DR. KATZ: Yes. Hi. Thanks. Two quick

9 questions.

10 Number one, the distinction that you made

11 between the two subgroups of people with fibromyalgia, the

12 patients versus the non-patients, was the clinical

13 expression of the syndrome any different between those two

14 groups?

15 DR. BRADLEY: Yes, that's a very good

16 question, and even though the pain sensitivity was very

17 similar in the two groups, the non-patients reported

18 significantly lower levels of pain on the McGill Pain

19 Questionnaire compared to the patients. And they also

20 again -- and this is in accord with their difference in

21 psychiatric status -- reported lower levels of depression

22 and anxiety on standardized questionnaires. So the 1 59 2 1 expression of the disorder was different, although the

2 pain sensitivity was the same.

3 DR. KATZ: And the second question is, I was

4 interested in your very helpful summary of the studies

5 looking at hyperalgesia to various forms of stimuli and

6 neuroimaging, which are obviously used to suggest that

7 this disease therefore is independent from psychiatric

8 influences.

9 But my question is about the control groups

10 used in those studies. Have any of those studies used

11 patients with somatoform pain disorders as the control?

12 That would seem to be the relevant control group here.

13 DR. BRADLEY: Yes. To my knowledge, no, and

14 we've not tried to look at that. I don't know of other

15 investigators looking at that right now. I don't know if

16 your group is looking at that at present.

17 (Off microphone speaker.)

18 DR. FIRESTEIN: I have one quick question. I

19 think the data that you presented on patients versus non-

20 patients was fascinating. One of the questions is, if

21 patients don't or if individuals that meet the criteria,

22 in terms of the number of tender points, don't seek 1 60 2 1 medical attention and don't view this necessarily as a

2 medical illness, do we want an indication for treating

3 such individuals, and is it a disease only when the

4 psychiatric manifestations come?

5 The corollary of that is whether or not the

6 real full expression of the disease is really related to

7 psychiatric manifestations, and is the perception of pain

8 a self-selecting group of individuals that represent a

9 bell-shaped curve? In other words, do those individuals

10 that meet the criteria because there's a broad spectrum of

11 individuals that are tender at 4 kilograms per X number of

12 square centimeters but that's within normal human

13 experience?

14 DR. BRADLEY: I'm going to try to respond to

15 those two different dimensions of your question and please

16 tell me if I'm really responding to the issues.

17 I think with regard to the bell-shaped curve,

18 yes, there is a bell-shaped curve in terms of pain

19 sensitivity. I think what's important is that both the

20 patients and non-patients were really on the far side of

21 that bell-shaped curve. I mean, they were way up in that

22 upper 2.5 percent. So those two groups were really 1 61 2 1 equivalent in terms of pain sensitivity and that was

2 really not associated with psychological, psychosocial,

3 psychiatric factors. And we've done that study twice now.

4 So at least in our laboratory, that's a very reliable

5 finding.

6 I think in my mind, the issue is how people

7 perceive their pain and whether they seek health care for

8 their pain. I think that is very much influenced by the

9 variety of factors, and it's not just psychological or

10 psychiatric factors. I think there's a wide array of

11 socioeconomic, cultural, family learning/history variables

12 that influence that type of behavior. So I think the

13 question that you're asking is, is the identification of

14 fibromyalgia sort of a psychosocial phenomenon, and I

15 would say that the perception that one has musculoskeletal

16 pain and that one is -- well, and this is the way we

17 really did recruit people for the study, is we put out

18 advertisements in the newspaper and through the television

19 media looking for people with persistent, longer-than-6-

20 month history of widespread musculoskeletal pain. And

21 when people responded to those advertisements, we then

22 went through sort of a three-step process of screening 1 62 2 1 them.

2 We would screen them very briefly over the

3 telephone using Fred Wolfe's questionnaire from 1992, I

4 think one of his papers in '92. If they passed that

5 screen, we would then ask them to send us copies of their

6 recent medical records. In these two studies, we wanted

7 to exclude people who had other kinds of illnesses,

8 diseases, that could cause widespread pain, such as people

9 with neuropathies, people with a variety of other

10 problems, back surgeries, neck surgeries, and so on, that

11 could produce the symptoms. So these were really people

12 without other medical causes that we could identify for

13 their pain.

14 Then if they passed that screen, then they

15 came into our GCRC and one of my rheumatology colleagues,

16 Graciela Alarcon, would examine and interview each person,

17 and we would, to the best that we could, really try to

18 screen out people who had other sorts of medical problems

19 that might account for their pain.

20 So most of the non-patients really didn't have

21 a label for what they were experiencing, except that they

22 hurt all over, and the non-patients also -- I guess I 1 63 2 1 should mention this, too. If you looked at sort of

2 measures of self-efficacy and coping strategy usage, these

3 people were very, very good copers and really most of them

4 had an experience at some point longer than 10 years ago

5 when they went to see a doctor for their pain. And these

6 studies were done in the early 1990s. So they would have

7 an experience, the doctor would say, well, I don't know

8 what's causing your pain, and these people would go home

9 and just stop there and take care of themselves.

10 So the perception of pain and the pain

11 sensitivity was not influenced by psychological factors.

12 How people responded to the pain certainly was influenced

13 by psychological factors, and actually, again, the non-

14 patients were such a robust group in terms of coping, that

15 after 2-and-a-half years, again only 10 of them had become

16 patients. So I think the pain problem was not a construct

17 of their psychological situation, but their behavior

18 certainly was influenced by it.

19 DR. FIRESTEIN: Dr. Strand? Oh, I'm sorry.

20 Never mind.

21 DR. STAUD: I was wondering if you would like

22 to comment on the striking sex difference in fibromyalgia 1 64 2 1 with the ratio discussed in 8 to 1 or 8 to 2 or 9 to 1 in

2 males versus females and what particularly the

3 psychosocial aspects are that explain most of this,

4 because in the general population, males generally have,

5 on psychophysical testing, lower sensitivities to painful

6 stimuli.

7 DR. BRADLEY: That's a phenomenon that's

8 really not well understood. I mean, we all are aware that

9 in rheumatic diseases, that there's a tendency for women

10 to be more susceptible to rheumatic diseases than men, but

11 the ratio that we see in fibromyalgia is even more

12 striking than what we see in the inflammatory rheumatic

13 diseases.

14 I can really only speculate and I think that

15 there must be, for example, factors, and to some extent,

16 we already know that, for example, fluctuations in

17 hormonal status, sex hormone status, among women

18 influences their perceptions of pain.

19 So I think that certainly there's probably a

20 combination of genetic and also hormonal factors and

21 perhaps other biological and to some extent perhaps even

22 non-biological factors that account for that sex 1 65 2 1 difference, but it's really striking and it's more

2 striking than what you see in really any other disease or

3 disorder.

4 DR. FIRESTEIN: Two more quick questions. Dr.

5 Cush and Dr. Turk.

6 DR. CUSH: Last year at our pain workshop, we

7 had talked about setting up outcome measures or trying to

8 go towards outcome measures that were not only based on

9 symptomatic control but also mechanisms. So do you think

10 that we're at a point or as we try to formulate some

11 guidelines for trials and outcomes where we can talk

12 beyond symptoms and talk about sort of mechanistic control

13 of pain?

14 DR. BRADLEY: Well, yes. I think that

15 probably the state of the art is right now -- the problem

16 is not the state of the art of measurement, but I think

17 the problem is sort of the state of the art of where we

18 are in developing compounds for persistent pain. I think

19 right now, we don't have compounds that can be really used

20 safely in human beings. For example, the NMDA receptor

21 antagonists really are very problematic for use with

22 humans because they induce sort of hallucinations and all 1 66 2 1 kinds of other problems.

2 I think eventually there will be compounds

3 that will influence events more at the dorsal horn level

4 of the spinal cord, and I think at that point, I think

5 it's reasonable to then try to use measures of

6 sensitivity, whether they're biological measures or sort

7 of behavioral measures of sensitivity, as an outcome

8 measure.

9 I think for right now, I think it's really

10 interesting to use those measures as sort of secondary

11 outcome measures but without any great expectation that

12 the compounds that we have currently will have a great

13 effect on pain sensitivity, regardless of whether you're

14 looking at that from a behavioral level or from a more

15 neuroimaging or other type of biological level.

16 DR. TURK: Thank you for that overview, Larry.

17 As you presented your data, other than the

18 insidious onset, traumatic onset, you really tended to

19 look at averages across large groups of patients, and I'm

20 wondering if there's any thoughts you might have on

21 whether there may be subgroups of patients with

22 fibromyalgia based on either physiological factors, on 1 67 2 1 symptom presentations, on sensory sensitivity,

2 psychological factors, because there are several groups

3 that have tried to look at whether there may be

4 differences among those groups. I was interested in your

5 insidious onset, traumatic onset, because there's at

6 least two or three studies that have shown pretty large

7 differences in people with different reports of onset of

8 symptoms. So I wonder if you have any comments about that.

9 DR. BRADLEY: Well, I think in regard to the

10 first part of your question, with regard to subgroups,

11 yes, I think that you're right, and I'm glad you brought

12 this point up. Within the patient population, there is

13 really a variation, particularly in terms of psychological

14 functioning, actual displays of functional abilities, and

15 I think that it is important to note that patients do

16 vary. There are patients who have relatively low levels

17 of psychological distress, even though on the average you

18 tend to see very, very high levels of distress.

19 I think that it's worthwhile looking at those

20 subgroups and regardless of whether one uses techniques

21 like the MPI, for example, which is a very good technique,

22 or other types of techniques, it is worthwhile to look at 1 68 2 1 potential interactions between variations in distress or

2 function and response to pharmacologic treatments and

3 responses to behavioral treatments, too.

4 I think I've lost the second part of your

5 question. What was the last point you raised?

6 DR. TURK: I think you covered it. It was

7 just on the traumatic versus insidious onset.

8 DR. BRADLEY: It may have something to do with

9 the fact that -- again, we were very careful to screen

10 people, to eliminate people, for example, who had other

11 problems that potentially could produce chronic pain. So,

12 for example, we did not take anybody into our studies who

13 had a back surgery or a neck surgery. So there probably

14 was a certain group of people with a certain type of

15 trauma that resulted in surgical intervention who were not

16 part of our studies. So factors such as that may account

17 for the relative sort of group or the average level of

18 homogeneity between those groups which I think we're

19 probably much more stringent than other groups have been

20 in the past in looking at that issue.

21 DR. FIRESTEIN: Thank you very much for a very

22 interesting presentation. 1 69 2 1 Next, Dr. Crofford's going to talk about basic

2 mechanisms.

3 DR. CROFFORD: Thanks, Gary, and I'd like to

4 thank the FDA. I actually would like to congratulate you

5 on taking on this problem. This is a problem that we've

6 been struggling with in rheumatology for many years, and I

7 think that the FDA really ought to receive the credit that

8 they deserve for really taking this on. So I'm pleased to

9 be here.

10 In framing my comments this morning, what I'd

11 like to do is start with some thoughts about actually

12 developing effective treatments for fibromyalgia syndrome,

13 and I think from a very incredibly pragmatic standpoint,

14 which is, I think, where we need to start with this

15 condition, the first question is whether or not

16 fibromyalgia syndrome can be clinically recognized and

17 diagnosed using the current ACR criteria because that's

18 where we are.

19 I would submit that even though the ACR

20 criteria aren't perfect -- and we can certainly talk about

21 them at great detail and you'll probably get a lot of

22 different opinions -- that they actually do identify 1 70 2 1 patients with a predictable symptom profile which is what

2 we want. We want to be able to use the criteria to

3 identify a group of patients that are predictable and have

4 the opportunity to respond to certain types of

5 interventions.

6 Now, that's not to say that fibromyalgia

7 syndrome patients identified by the ACR criteria don't

8 contain subsets. I think they certainly do contain

9 subsets of patients, but when you apply these ACR criteria

10 correctly, you do get a group of patients that are a good

11 subject pool for clinical trials.

12 The second point is we need to understand what

13 are the critical symptom domains in these patients that

14 must improve for an intervention to be an effective

15 treatment for fibromyalgia syndrome, and one could jump

16 off the excellent presentation of Dr. Witter and think

17 about all kinds of different ways that you could develop

18 criteria that may be important to patients with

19 fibromyalgia syndrome. This is certainly what we're about

20 today, and I think certainly there are some thoughts that

21 I'll present later on.

22 Thirdly, what mechanisms underlie fibromyalgia 1 71 2 1 syndrome that may allow us to predict the types of

2 treatments that may be effective in fibromyalgia syndrome?

3 I think we ought to think about that or at least the

4 pharmaceutical companies ought to think about that as they

5 move forward in attempting to predict what types of

6 compounds may be useful in this syndrome, and then,

7 lastly, which I won't address at all but I think Dan Clauw

8 will address quite thoroughly and Jim has already talked

9 about it and Dr. Wells as well, how best can we measure

10 improvement in response to treatment?

11 So I brought this slide just because I think

12 it's important that we recognize that fibromyalgia

13 syndrome is debilitating, that the patients have an impact

14 on their lives for the most part by the presence of these

15 symptoms, whether they seek treatment or not. They answer

16 advertisements. So they notice that there's something

17 wrong with them.

18 In thinking about the fibromyalgia symptom

19 domains, I think the first thing that we all recognize is

20 that patients have pain. It's required that this pain be

21 widespread and involve the musculoskeletal system. That

22 having been said, patients with fibromyalgia also have 1 72 2 1 other types of pain, including regional musculoskeletal

2 pain syndromes, including temporomandibular disorder, and

3 visceral pain syndromes, and I won't spend any time

4 specifically talking about these things, but pain is one

5 of those things that has to be a given when we think about

6 fibromyalgia syndrome and when we think about its

7 management.

8 But fibromyalgia patients also have non-pain

9 symptoms, and we've already heard about some of them, and

10 I'll spend the majority of my time talking about the non-

11 pain symptoms which include fatigue, sleep disturbance,

12 cognitive dysfunction, depressive and anxiety symptoms

13 which I should be careful to distinguish between diagnosis

14 of major depressive disorder. These are not required but

15 they're almost universally present in patients with

16 fibromyalgia syndrome.

17 As we heard from Larry, the pain is widespread

18 clinical pain, and no mechanism is implied in this

19 definition of widespread clinical pain. However, the ACR

20 tender points have to be present and the tender points

21 measure a domain that incorporates probably both this

22 concept that Dr. Bradley brought up, that there's either 1 73 2 1 hyperalgesia or allodynia in these individuals, but they

2 probably also incorporate non-pain domains or something

3 that we call distress. What I'd like to just bring your

4 attention to, when Larry brings up data that demonstrate

5 that patients with fibromyalgia have an increased noxious

6 threshold for thermal sensitivity, for example, that

7 measures this domain of whatever we want to call allodynia

8 or hyperalgesia, but that the tender points probably

9 measure something in addition to this noxious stimulus,

10 and these are data that were very nicely demonstrated by

11 Dan Clauw looking at different paradigms and the

12 comparison between what tender points measure and what the

13 kind of more sensitive measures of allodynia actually

14 measure.

15 Now, I actually don't think this is a bad

16 thing because I think maybe by happenstance that's what

17 has happened when we developed the tender points, is that

18 for some reason -- and maybe this was just prescience on

19 the part of the committee that developed the tender points

20 -- these ACR tender points actually do measure some kind

21 of a combination domain.

22 Then the question of whether the pain of 1 74 2 1 fibromyalgia syndrome is real always comes up when you

2 talk to rheumatologists because many rheumatologists don't

3 believe that the pain is real, but I think that you've

4 just seen a demonstration from Dr. Bradley that with

5 respect to psychophysical testing, you can demonstrate

6 measurable differences. He didn't present data that

7 evoked potentials which Jurgen Lorenz has used to

8 demonstrate actual differences in central representation

9 of pain inputs, and then he showed data from Dan Clauw and

10 Rick Gracely's group demonstrating that the central

11 representation of pain by fMRI actually demonstrates the

12 veracity of the patient's complaint to increased pain.

13 So stimulus detection of patients with

14 fibromyalgia is normal. There is an ultranoxious

15 threshold that is multimodality, so that that is something

16 that we can point to as a mechanism of pain. As I

17 previously said, the central representation of pain

18 confirms the veracity of the subjective pain complaints.

19 And pain cannot be explained by tissue damage. That

20 having been said, pain generators are very common in

21 fibromyalgia and oftentimes you can improve the overall

22 clinical experience of pain by addressing these pain 1 75 2 1 generators, for example, in patients with rheumatoid

2 arthritis, osteoarthritis, or other types of mechanical

3 problems. Taken together, all of these implicate central

4 factors in fibromyalgia syndrome pain.

5 Now, Larry presented all the clinical data,

6 and I'd just like to make some comments about how one

7 might get there. Certainly the data that Roland Staud and

8 Don Price and their group have presented as well as data

9 from our own group and Dan Clauw's group suggest that

10 central sensitization, otherwise known as activity-

11 dependent plasticity, may be present in these patients.

12 Certainly it's difficult to prove but that's something

13 that's been suggested. Neuronal plasticity in the spinal

14 cord modifies the performance of the nociceptive pathways,

15 so that one develops an exaggerated or prolonged response

16 to noxious input, called hyperalgesia, and enables

17 normally innocuous inputs to activate nociceptive

18 pathways, called allodynia.

19 These mechanisms are transcription independent

20 and dependent and the mediators of this spinal central

21 sensitization would include such things as the excitatory

22 amino acids and their receptors, the NMDA receptors, 1 76 2 1 substance P and other neuropeptides, that are acting

2 through their G protein-coupled receptors. And certainly

3 it's known that in models of pain, that there's increased

4 activity of kinases, such as protein kinase C and many

5 others, that phosphorylate ion channels and receptors and

6 result in neuronal hyperexcitability. So that, at least

7 from animal models, the mechanisms by which this activity-

8 dependent plasticity is modulated are known and some of

9 the types of drugs that may work in this type of process

10 could be predicted from these data.

11 It's also important to note that there's

12 descending modulation of pain. It's bidirectional,

13 including inhibitory and facilitatory descending control.

14 These pathways that actually modulate the inputs at the

15 dorsal horn are mediated by serotonin and noradrenaline

16 and again this may give us some clues as to why certain

17 drugs may be effective in central pain syndromes and why

18 non-steroidals, for example, are typically not very

19 effective in these syndromes.

20 Now, it's clear that injury-induced

21 hyperalgesia is dampened by descending pathways, but it's

22 also clear that cortical and subcortical structures can 1 77 2 1 stimulate these facilitatory pathways. Most of the input

2 is integrated at the level of the peri-aqueductal gray and

3 rostral ventral medulla, but the types of inputs that come

4 into these systems would include things like vagal

5 afferents, would include things like inputs from the

6 stress axes, that Dr. Bradley nicely described the

7 influence of stress on pain perception, certainly their

8 cortical structures, including the anterior singulate

9 gyrus and many others, whose input is integrated at these

10 levels. And it also should be noted that the dynamic

11 plasticity at the level of the rostral ventral medulla is

12 also mediated by NMDA receptors.

13 Just in pictorial representation, the cerebral

14 cortex influences this descending bidirectional modulatory

15 control through many different mechanisms. Goal-directed

16 behaviors can certainly change the experience of pain.

17 Attention and distraction can change the experience of

18 pain; expectancy, interaction with the limbic system.

19 Subcortical systems would include stress-induced analgesia

20 but also hyperalgesia, and mid-brain and brain stem

21 systems integrate signals from the brain and spinal cord.

22 They're the site of opiate action. They're the principal 1 78 2 1 relays of these chemical signals to the spinal cord which

2 again include norepinephrine and serotonin.

3 So what are the treatment implications for the

4 concept of central pain? The implications would include

5 such things as the treatments that usually are used for

6 normal musculoskeletal pain do not actually work very well

7 for most patients with fibromyalgia, and that the

8 treatments must address the problem of this altered pain

9 processing in the spinal cord and potentially alter

10 descending inhibition of pain signals.

11 Now, I'd like to move on from pain and talk

12 about the non-pain symptoms and the question of whether or

13 not you can attribute these non-pain symptoms to specific

14 mechanisms.

15 Non-pain symptoms form something that

16 epidemiologists refer to as a distress cluster which is

17 often associated with multifocal chronic pain. Fatigue

18 itself is actually exceptionally difficult to attribute to

19 a specific mechanism, and I think all of us who are

20 rheumatologists, when we think about any of our connective

21 tissue disease patients, recognize this.

22 The sleep disturbance. I'll talk further 1 79 2 1 about this, but no specific alteration has been described.

2 Certainly the disturbances overlap with other conditions

3 that share this distress cluster of symptoms with

4 fibromyalgia syndrome.

5 Cognitive dysfunction is present in these

6 patients. There's evidence that cognitive complaints

7 correlate with fMRI differences. I brought this for you,

8 Dr. Turk, to show some data that there are actually

9 differences in the way that patients' brains function

10 under a cognitive load.

11 Depression and anxiety are certainly present,

12 and I think Larry nicely pointed out that there's a marked

13 increase in the lifetime prevalence, and it is associated

14 with health care-seeking.

15 So in terms of fatigue, what does it mean? In

16 general, it means decreased energy, need to rest,

17 sleepiness or unrefreshing sleep, struggle to overcome

18 inactivity. From a physical standpoint, it can mean

19 weakness, limb heaviness or post-exertional malaise which

20 is exceptionally common in these patients. On an

21 emotional side, it could be decreased motivation or

22 interest. From a mental or cognitive side, diminished 1 80 2 1 concentration or memory. Functional, difficulty

2 completing daily tasks.

3 And you can see by the diversity of what

4 patients actually mean when they say that they're

5 fatigued, that attribution to a specific mechanism really

6 is something beyond what most of us can do. Nevertheless,

7 when one thinks about a reduction in fatigue, you can see

8 how a reduction in the perception of fatigue may actually

9 imply improvement across multiple different biological

10 mechanisms.

11 Certainly the possible causes of fatigue in

12 fibromyalgia are legion, including the sleep disturbance,

13 depression, anxiety, pain, medications, deconditioning,

14 neurally-mediated hypotension, which may form a subset of

15 some patients, and central mechanisms.

16 The one thing that I will say is that fatigue

17 is correlated with many of the other symptoms, and if you

18 actually look at a correlation matrix of fatigue, you can

19 see that the symptom of fatigue is significantly

20 correlated with pain and sleep and actually less so with

21 depression and anxiety, but one can think of it as perhaps

22 a marker for many of these other non-pain symptoms. 1 81 2 1 In terms of the sleep disturbances in

2 fibromyalgia syndrome, this is probably understudied and

3 hopefully that's something that will be corrected. The

4 alpha-delta sleep disturbance was first reported by Harvey

5 Moldofsky in 1975 and was actually the first biological

6 finding in patients with fibromyalgia. Unfortunately,

7 this alpha-delta sleep abnormality is non-specific. It's

8 certainly not universal and certainly occurs in many other

9 types of illnesses and even in normal patients but not

10 nearly to the extent as seen in fibromyalgia and patients

11 with other syndromes.

12 It's also been reported that patients with

13 fibromyalgia have reduced slow-wave sleep, that's stage 3-

14 4, or delta sleep. It's also not specific, not universal,

15 and unfortunately no spectral analyses have actually been

16 reported to examine delta power or even alpha power in

17 patients with fibromyalgia syndrome. Sleep medicine has

18 certainly advanced significantly with new techniques

19 towards spectral analysis and hopefully those will be done

20 in the near future.

21 The insomnia of fibromyalgia has also been

22 described as psychophysiological insomnia and that's 1 82 2 1 altered sensitivity to extrinsic stimuli. And these are

2 the kinds of things that can actually be measured in a

3 sleep laboratory these days and hopefully will come in the

4 near future.

5 Now, changing gears to cognitive, I'd like to

6 show this slide, which is always alarming to the audience.

7 Most of us fall about halfway down this cognitive slide,

8 but you can see that in most patients, their peak of

9 cognitive prowess occurs at about 20 and we slip and slide

10 from there down to where we mostly currently are. This

11 occurs across all domains of cognition actually, with the

12 exception of semantic memory, here measured by vocabulary,

13 but that is preserved and perhaps even enhanced and most

14 of us like to think of it as wisdom that makes up for a

15 loss of actual cognitive activity.

16 This is a study that we did with Denise Park

17 and Jennifer Glass looking at information processing

18 speed, and one can see that the cognitive problems in

19 patients with fibromyalgia are actually not universal but

20 actually selective in that patients with fibromyalgia

21 syndrome, looking at age-matched controls, have their

22 information processing speed preserved, whereas one can 1 83 2 1 see the predicted reduction in processing speed that one

2 sees in older controls, and in fact, in older controls,

3 it's thought that speed of processing actually explains

4 many of the other elements of cognitive decline.

5 But when one looks at fibromyalgia patients

6 with demanding tasks, such as working memory tasks,

7 patients with fibromyalgia do not perform similar to age-

8 matched controls and, in fact, perform similar to older

9 controls that are 20 to 30 years older than the

10 fibromyalgia patients and exceptionally carefully matched

11 with respect to education.

12 Additionally, in other types of memory

13 performance, like long-term memory or free recall,

14 fibromyalgia patients perform like older adults.

15 Now, when one looks by functional imaging at

16 older versus younger adults, you can see that one of the

17 things that older adults do is that in comparison to

18 younger adults that use primarily one hemisphere of their

19 brain, and I'll just point you to the middle slide because

20 this is somewhat complicated, certainly on the left side,

21 you can see a little bit more utilization in the older

22 adults. You can see this bilaterality in the older 1 84 2 1 adults, suggesting that they're recruiting more areas of

2 their cortex to actually perform certain cognitive tasks,

3 and you can see very clearly the bilaterality in the older

4 adults compared with the younger adults.

5 We did a study recently -- this is actually an

6 unpublished study -- looking at patients with fibromyalgia

7 compared with age- and education-matched controls in a

8 working memory task where the subjects were asked to look

9 at a series of consonants for 1 second. And then in this

10 interval, they were asked to put these in alphabetical

11 order; that is, to perform a complex reorganization task,

12 while the screen was blank, and then they were given a

13 prompt and asked to determine whether or not this S was in

14 the proper position with respect to its alphabetical

15 organization. And in this trial, the patients would

16 respond yes because the letter S is in the correct

17 alphabetical position.

18 This was subtracted from a condition which we

19 called a maintenance condition where we would demonstrate

20 or show the patients letters that were actually already in

21 alphabetical condition and they were just asked to hold

22 those in their memory as a maintenance condition rather 1 85 2 1 than alphabetizing, so that they weren't asked to do a

2 manipulation.

3 Then what we did was we looked at the

4 difference between the alphabetizing condition and the

5 maintenance condition in the fibromyalgia patients versus

6 the controls, and you can see a couple of interesting

7 things. I should say that patients with fibromyalgia

8 actually performed equally well on this task. So it

9 wasn't that the task was so hard and that they couldn't do

10 it or that they weren't trying. They performed equally

11 well as the control subjects.

12 What you can see is that fibromyalgia patients

13 showed this bilaterality, bilateral activation in the

14 middle frontal gyrus while alphabetizing, increased

15 activation in the right superior parietal lobe which is an

16 area that's specialized for processing of spatial location

17 of objects, meaning and storage of items during working

18 memory tasks. They had a midline medial frontal gyrus

19 activation which was associated with eye fields, and they

20 overall showed more activation when alphabetizing than

21 when they were in the maintenance condition.

22 Additionally, there was a region bordering the right 1 86 2 1 inferior frontal gyrus and precentral gyrus in

2 fibromyalgia patients and also the right BA 44 which was

3 homologous to Broca's area in the left hemisphere and an

4 activation of Broca's area 9 thought to be involved in

5 reasoning.

6 The control subjects actually did not find

7 this task to be more difficult and the normal controls did

8 not show more activation in any part of the brain in the

9 alphabetizing minus maintenance condition. Only a small

10 non-significant region was identified, so that the control

11 subjects really did not have to work harder to alphabetize

12 compared to the maintenance control, which again

13 identifies the veracity of the patient's complaints, that

14 they're actually feeling that their cognitive abilities

15 have declined compared with what's age-appropriate.

16 Now, in thinking about depression and anxiety

17 in fibromyalgia, these psychiatric conditions are neither

18 necessary nor sufficient for the diagnosis of fibromyalgia

19 syndrome. As I mentioned a number of times, there's a

20 higher point prevalence than in the general population,

21 and certainly the lifetime prevalence in the tertiary care

22 population is quite high, with a study by Epstein and 1 87 2 1 colleagues noting depression at 68 percent and anxiety

2 disorders at 35 percent. And Larry previously showed his

3 data on health care-seeking associated with psychiatric

4 co-morbidity.

5 In thinking about how these non-pain symptoms

6 might be linked in a mechanistic way, many of us have

7 focused on the stress response systems, and I'd like to

8 spend a couple of minutes demonstrating some of the

9 mechanisms that may be operative. I certainly don't have

10 time to talk about all the potential mechanisms but I'll

11 just mention a couple.

12 The quote that "stress is life and life is

13 stress" is something that I think we all recognize and

14 can't escape, but from a strictly biological sense,

15 stressors are thought of as forces that disturb

16 homeostasis and can include any number of stressors. Now,

17 these are counterbalanced by adaptive forces and these

18 adaptive forces are collectively called the stress

19 response systems and they mediate not only central

20 adaptation because under stress, your brain certainly has

21 to adapt, and peripheral adaptation as well because your

22 body has to respond to these forces. 1 88 2 1 The stress response systems, I wouldn't think

2 of them as unitary because different stressors activate

3 different responses, as might be expected, but in general,

4 the major players are the hypothalamic-pituitary-adrenal

5 axis and the autonomic nervous system, and these are

6 critical components of the coordinated physiologic

7 response to stress.

8 Now, the response to stress because of the

9 central and peripheral factors includes physical but also

10 behavioral and psychological symptoms and these domains

11 have been linked to HPA axis and autonomic system

12 abnormalities.

13 So what is a healthy HPA axis? I'll focus on

14 the HPA axis, because that's what I do, and show you some

15 data on the HPA axis, but I don't want to suggest that

16 this is the only potential mechanism that could be

17 involved in fibromyalgia syndrome and certainly autonomic

18 nervous system pathways have been implicated as well.

19 So what's healthy? Healthy is that there's a

20 wide dynamic range and what that means is that there's a

21 circadian variation with a high cortisol in the morning

22 and low cortisol in the evening, a very wide dynamic 1 89 2 1 range. It should be responsive to physiologic and

2 stressful stimuli. We don't like to see putzy responses

3 to stress. We like to see people whose cortisol levels go

4 up in response to stress and that's healthy. It's also

5 sensitive to feedback suppression and one measures that by

6 using dexamethasone, but you can also measure it in the

7 laboratory and we like the HPA axis to be able to shut off

8 after it's been activated. And so what's really a healthy

9 stress response is that it ought to be responsive and it

10 ought to be resilient.

11 So what happens in patients with fibromyalgia

12 syndrome? I'll just show you a study that we've recently

13 completed and again is unpublished looking at a number of

14 different ways to stress the HPA axis, first using a low-

15 dose physiologic injection of corticotropin-releasing

16 hormone and then coming back with graded doses of

17 dexamethasone. I think we could have taken people and

18 done public speaking three days in a row or all kinds of

19 other things, but we used this as a potential marker for

20 elevated cortisol and what happens in response to this

21 facsimile of a stressed HPA axis.

22 First, I'll show you that the resiliency of 1 90 2 1 the HPA axis in fibromyalgia patients isn't quite normal.

2 It doesn't tend to quite get back to what happens in a

3 normal individual.

4 More interesting is what happens if you keep

5 doing this, if you have these repeated stressors, and what

6 I'd like you to focus on is this green line first which is

7 a healthy control population. This is the morning after.

8 These are salivary cortisol measurements the morning after

9 the CRH stimulation test. They have a fairly normal high

10 cortisol, not quite as high as we'd like it to be, so it's

11 still a little bit suppressed, but you can see a very nice

12 drop in the cortisol in the evening and then on a baseline

13 day when we don't do anything to them, they have this very

14 nice wide dynamic range. If you give them dexamethasone,

15 they're suppressed in the morning but again give you this

16 very low cortisol in the afternoon, and then when you

17 don't do anything to them, they go back up with this very

18 nice wide dynamic range. Again even with .5 micrograms of

19 dexamethasone, they suppress in the morning but again they

20 still have this low evening level.

21 And I'd ask you to contrast that with the

22 patients with fibromyalgia. They certainly do suppress in 1 91 2 1 response to the oCRH, but in contradistinction to the

2 patients that are normal, they actually fail to go back to

3 a normal low evening cortisol. And as we get going with

4 the paradigm, you can see that they do give you a little

5 bit of a wide dynamic range on the second day. You hit

6 them with dexamethasone, they suppress, but then they

7 actually reverse their circadian rhythm. And then you

8 start to see an impact on the dynamic range of the HPA

9 axis over time, so that the difference between morning and

10 evening becomes obliterated. And when you hit patients

11 with a half a milligram of dexamethasone, you start to see

12 this rebound or reversal of circadian rhythm.

13 What this demonstrates is that with repeated

14 facsimiles of stressors, that patients with fibromyalgia

15 syndrome actually don't have the responsiveness and

16 resiliency that one might see in a normal individual and

17 graphically, you can see that on these non-stressed days,

18 that means that the difference between the morning and the

19 evening cortisol becomes blunted and that one can actually

20 see even a reversal of that circadian variation in

21 patients with fibromyalgia syndrome.

22 Now, I don't have time to talk about similar 1 92 2 1 studies with the autonomic nervous system, but I think

2 that it's been shown by a number of studies that their

3 altered sympathetic and sympathoadrenal dynamic

4 variability, including a reduced heart rate variability --

5 so again, there's this lack of this dynamic range that one

6 would expect in a normal individual -- altered stimulus-

7 induced blood flow and altered stimulus-induced release of

8 noradrenaline and even adrenaline in some studies.

9 So that, there is evidence in fibromyalgia

10 syndrome patients, not only by groups in this country but

11 groups all over the world, that there's an altered dynamic

12 function of the stress response systems. The problem is,

13 is that, it's not always the same in every patient, and I

14 think that you ought to now keep in mind, with respect to

15 biological subsets, that these endocrine systems are much

16 like other endocrine systems that we're more familiar

17 with; that is, for example, thyroid disease. If you have

18 hypothyroidism, you can present with fatigue, but if you

19 have hyperthyroidism, you can present with fatigue and

20 musculoskeletal aches, and in hypothyroidism, you can also

21 present with musculoskeletal aches.

22 So I think what we need to keep in mind is, as 1 93 2 1 with this neuroendocrine system as well as other

2 neuroendocrine systems, that there's a concept of an

3 allostat and what that means is that there's an optimal

4 operating range and that you can go too low or you can go

5 too high and it's no longer optimal, and that some of the

6 symptoms of patients with alterations in these stress

7 response systems may actually overlap. And some of the

8 times, for example, a potential dichotomy between chronic

9 fatigue syndrome and fibromyalgia, even though the same

10 system may be involved, the symptom complex may be a

11 little bit different.

12 There's also the concept that the function of

13 these stress response axes because of their nature can

14 differ under different physical and psychosocial stress.

15 So that, whenever you have an allostat or some kind of a

16 guide that ought to stay centered, the stress on that

17 system changes, depending on the load that's applied to

18 it, and there can be minor load and there can be heavy

19 load, and the function of the allostat may perform as well

20 or not quite as well, depending on the load that's applied

21 to it.

22 I'd also like to note that there's a very 1 94 2 1 strong drive to maintain the overall hormone levels. So

2 if anybody thinks you can measure a 24-hour urine cortisol

3 and get significant findings, you can't because there's a

4 very strong drive, as you saw in my studies that I

5 presented. If you go really low in the morning, you go

6 higher in the afternoon, so that there's a very strong

7 drive to maintain those levels.

8 And I should note that current therapies

9 influence the expression of key components of the system.

10 Tricyclic antidepressants and SSRIs, for example,

11 influence the expression of mineralocorticoid and

12 glucocorticoid receptors in the central nervous system

13 perhaps better than any other treatments that are

14 available, and I should also note that exercise which is

15 an effective therapy in this condition is known to

16 modulate the set point of the allostat.

17 So what are the implications of all of these

18 comments for drug therapy? Well, I would say that

19 fibromyalgia syndrome, whether it's clinically diagnosed

20 or laboratorially diagnosed, is certainly recognizable.

21 As I said before, this does not exclude the likelihood of

22 subsets of patients with different underlying mechanisms, 1 95 2 1 but when a patient with fibromyalgia syndrome walks into

2 the office in my clinic, I can make the diagnosis

3 reliably, and I think most clinicians can do so or most

4 thoughtful clinicians can do so.

5 Clinically important improvements in pain are

6 likely to occur in response to treatments that address

7 central mechanisms and reduced pain is likely to improve

8 the health-related quality of life in patients with

9 fibromyalgia. Non-pain symptoms are also important to the

10 health-related quality of life in these patients and

11 influence health care-seeking and utilization.

12 I should point out that these non-pain

13 symptoms often cluster with central pain and

14 neurobiological mechanisms actually may be shared as a

15 cause for pain and non-pain symptoms or at least they may

16 co-occur. And clinically-significant improvements in non-

17 pain symptoms are also likely to result in global

18 improvement in patients with fibromyalgia.

19 I'll conclude there and thank you for your

20 attention. I'm happy to take any questions.

21 (Applause.)

22 DR. FIRESTEIN: Thank you very much. 1 96 2 1 Are there any questions?

2 DR. GIBOFSKY: Leslie, I was intrigued by your

3 slide earlier showing the mechanisms involved in spinal

4 central sensitization or I think you referred to it as

5 activity-dependent plasticity. I'm wondering, would it

6 follow from that that a sine qua non for any pharmacologic

7 agent to treat fibromyalgia or any of the manifestations

8 of fibromyalgia would have to be some effect on the

9 central nervous system, therefore by extension

10 physiologically an agent being able to cross the blood-

11 brain barrier.

12 DR. CROFFORD: That's a good question.

13 Certainly many of the agents that we know impact central

14 sensitization, impact some of the modulatory inputs. So

15 we talked about NMDA, for example, and the NK1 receptor

16 antagonist, for example, that might potentially influence

17 things like the effects of excitatory amino acids or

18 substance P, for example. I would think that those kind

19 of mechanisms or those kinds of agents might have to cross

20 the blood-brain barrier, but I'd certainly want to see

21 data in that regard.

22 With respect to the other types of agents that 1 97 2 1 we know influence what goes on at the spinal cord, agents

2 that influence the availability of norepinephrine and

3 serotonin certainly do exist and are among those that are

4 the most effective for this condition, which obviously you

5 can't totally draw conclusions from that, but certainly it

6 suggests the possibility that influencing those central

7 factors may be important.

8 Other types of agents, like non-steroidals,

9 for example, and I think it's been mentioned a number of

10 times that they don't seem to be quite as effective.

11 However, as you know and I know, there's certainly central

12 prostaglandin expression and I don't think it's out of the

13 realm of possibility that certain agents that might affect

14 peripheral mechanisms may have a positive impact, but I

15 doubt that they will be as effective as agents that

16 address some of these particular central mechanisms.

17 DR. FIRESTEIN: Dr. Abramson?

18 DR. ABRAMSON: Leslie, the tender points are

19 obviously important for the diagnosis. Is there any data

20 that's been able to validate tender points with regard to

21 fMRI or other kinds of pain thresholds that distinguishes

22 these areas from other areas? 1 98 2 1 DR. CROFFORD: My response to that is that

2 there's nothing special about the tender points. I think

3 you saw in Larry's slide that patients with fibromyalgia

4 are tender to control point palpation as well and that the

5 selection of the tender points -- I was not present. I

6 think Larry probably was present in the formulation of

7 these tender points. The thing about them is, is that,

8 they're widespread, so that you have to exhibit

9 hyperalgesia, allodynia in a lot of different body areas

10 to cross the threshold of 11 of 18. A lot of people have

11 strong feelings about whether the tender points are useful

12 or not.

13 So I think from a historical standpoint, you

14 could probably pick fewer tender points that are above and

15 below the waist and get a similar feeling that this was a

16 patient that exhibited widespread rather than regional

17 allodynia and hyperalgesia, and there's really nothing

18 special about them.

19 Most of the imaging studies have been done

20 using alternate mechanisms, but obviously it's difficult

21 with an fMRI to get in there and exert pressure. I think

22 Larry has done that with SPECT using tender points, but 1 99 2 1 you get the same thing no matter what you do. Dan Clauw

2 has done it with pressure on the thumbnail. The Gracely

3 studies were done with a thumbnail smasher, and I've done

4 similar studies with Ken Casey using a thermal probe that

5 give you similar results.

6 So the answer is they're a very useful tool

7 for identifying patients in the clinic. They're simple.

8 They're reliable. They're validated. There's nothing

9 special about them.

10 DR. FIRESTEIN: One last question.

11 DR. STAUD: Leslie, you showed us a lot of

12 data about the abnormalities in the HPA axis in

13 fibromyalgia patients compared to normal controls. Now,

14 this is group data, and I was wondering if you could tell

15 us something about the relationship to individuals,

16 particularly in terms of predicting abnormalities of the

17 HPA axis.

18 DR. CROFFORD: We've looked at that a lot,

19 Roland, and tried to figure out how we could use clinical

20 data to predict who was going to have the HPA axis

21 abnormalities and we've just failed. We've certainly

22 tried to do cluster analyses and I'm going to ask Dan to 1 100 2 1 help me with some of these data that we have, some older

2 data, to try to look at a clinical symptom profile that

3 would help us to predict which patients are going to

4 exhibit the most severe responses, but we haven't been

5 able to do that.

6 What you point out is correct, and I'd like to

7 certainly make that clear to the audience, that there's a

8 spectrum of responsiveness, just like there's a spectrum

9 of every other biological measure that we vary, and when

10 you look at group means, there are going to be some that

11 are going to look more normal and some that are going to

12 look more abnormal, and I certainly would agree with that.

13 You may be able to use some paradigms that

14 we're working on to actually subset the patients. As

15 Dennis pointed out, there probably are biological subsets

16 and we're continuing to try to develop simple measurement

17 techniques, so that we can actually do subsetting.

18 DR. FIRESTEIN: Thank you very much, Leslie.

19 The last talk of this session will be Dr.

20 Clauw talking about Post-ACR Diagnostic Criteria, and then

21 we'll take a short break.

22 DR. CLAUW: Let me also begin by 1 101 2 1 thanking/acknowledging the people on the FDA. Jim Witter

2 first asked me to come and talk to the agency over three

3 years ago about fibromyalgia because the agency was

4 interested in fibromyalgia and viewed that this is where

5 it should be. More recently, Lee has been a very strong

6 advocate of the whole fibromyalgia construct. This is a

7 secret that most people won't know till August or so, but

8 he and I actually co-edited an issue of Bailliere's, an

9 entire issue, having to do with fibromyalgia. So look at

10 how far Lee has come.

11 (Laughter.)

12 DR. CLAUW: I'm certainly not going to be

13 presumptuous enough to tell this audience how we should in

14 the future define chronic pain conditions, but for

15 purposes of my talk, I just want to make a couple

16 distinctions. These are distinctions that have already

17 been made by both Larry and Leslie about what is different

18 about fibromyalgia than some of the diseases that we as

19 rheumatologists or members of the panel might be more used

20 to seeing. But I think that it's really important to

21 distinguish between peripheral or nociceptive pain

22 syndromes which are primarily due to inflammation or 1 102 2 1 damage in peripheral tissues which are classically quite

2 responsive to both NSAIDs and opioids and where behavioral

3 factors are relatively minor contributors to symptom

4 expression and central or non-nociceptive pain syndromes

5 of which fibromyalgia would perhaps be the poster child.

6 Again, you've heard a lot about this, but I

7 think that as rheumatologists, the only non-nociceptive

8 pain syndrome that we see is fibromyalgia which is perhaps

9 why we find it so different and so hard to reconcile some

10 of what we think vis-a-vis pain and what should make it

11 better and how these people should act with all the other

12 diseases that we, in fact, take care of and we take care

13 of quite well.

14 But fibromyalgia is not the only central pain

15 syndrome. Irritable bowel syndrome, vulvodynia,

16 interstitial cystitis, tension and migraine headaches.

17 There's a whole host of illnesses where the pain is not

18 coming or occurring because of some damage or inflammation

19 in peripheral tissues; it's instead occurring because of

20 some central nervous system process or some process that's

21 leading to disturbances in pain processing.

22 Of course, with any attempt to make a clean 1 103 2 1 demarcation, there are going to be illnesses or diseases

2 that don't fit nicely into one category or another. An

3 example of this would perhaps be neuropathic pain.

4 Another example would be low back pain where certainly

5 subsets of individuals with low back pain have peripheral

6 causes for their pain and subsets have more central causes

7 for their pain.

8 But, again, the main reason to point this out

9 is that what I'm going to do when I talk about some of the

10 different outcomes that have been studied in fibromyalgia

11 is in particular point out the outcomes that are different

12 in fibromyalgia, especially with respect to how they

13 relate to other symptoms than they are in peripheral pain

14 syndromes.

15 One of the advantages I have in giving this

16 talk is there have been a couple nice meta-analyses that

17 have been done looking at effect sizes of various types of

18 treatments for fibromyalgia. I'll show a couple slides

19 from this study that was done by Rossy and published in

20 Annals of Behavioral Medicine in 1999 that looked at

21 pharmacologic therapy, exercise, and cognitive behavioral

22 therapy and looked at the different domains that 1 104 2 1 theoretically could be improved: symptoms, psychological

2 status and, in italics here, functional status.

3 What you see here is that for pharmacologic

4 therapies, there are moderate effect sizes for

5 improvements in symptoms and improvements in psychological

6 status, but really poor effect sizes with respect to

7 pharmacologic therapies being able to change functional

8 status in fibromyalgia.

9 Exercise does about the same with respect to

10 symptoms and psychological status, and even though

11 exercise theoretically is something where we're teaching

12 people how to improve physical function, you reproducibly

13 see again modest effect sizes in functional status when

14 exercise is used as a treatment for fibromyalgia.

15 Then finally, cognitive-behavioral therapy.

16 Again, moderate effect sizes here for symptoms and

17 psychological status and sort of a low effect size with

18 respect to functional status.

19 If you look at specific classes of

20 medications, you see here that, by and large, the

21 antidepressants are the most effective class and that they

22 again have moderate effect sizes with respect to symptoms 1 105 2 1 and lesser effects with respect to both psychological

2 status and functional status.

3 Muscle relaxants. This is a little bit of an

4 aberration because Flexeril, which is really a tricyclic

5 drug, is included in muscle relaxants. So the

6 overwhelming majority of these compounds that are studied

7 under the category of muscle relaxants are in fact

8 cyclobenzaprine which is a tricyclic compound. This is

9 probably why you see that they perform very similarly to

10 what is largely tricyclic compounds in the antidepressant

11 category.

12 And then finally nonsteroidal anti-

13 inflammatory drugs. Don't be misled by this n of 1 study

14 where one single study did, in fact, lead to a moderate

15 effect size in psychological status. None of us really

16 think NSAIDs make psychological status better and again

17 here you see that NSAIDs don't lead to any improvement, in

18 fact, in this single study led to a worsening, in

19 functional status.

20 Leslie Arnold did a nice meta-analysis looking

21 only at tricyclic compounds in fibromyalgia and again

22 looking at pooled effect sizes and found that the domain 1 106 2 1 that tricyclics affected most predictably was sleep.

2 Physician global, pain, fatigue and patient global all

3 were affected in the sort of range that we classically

4 think of as moderate effect sizes.

5 Here, you see that tenderness was the most

6 difficult domain to improve and this is something that we

7 see over and over again, that tenderness, especially as

8 measured by tender points, is not something that generally

9 gets better in clinical trials of fibromyalgia. There are

10 exceptions to this, but it's not something that is as

11 responsive to therapy as we might hope or think that it

12 should be.

13 So what I'm going to do is go through and talk

14 about potential outcome measures in fibromyalgia. I'm

15 going to spend the most time focusing on pain and on

16 functional status because those are the domains I think

17 that are perhaps most controversial vis-a-vis the

18 discussion that's going to transpire after the talks

19 today. So I'm going to present a fair amount of data with

20 respect to whether these domains move or not in the

21 setting of fibromyalgia.

22 When we're talking about pain, there's a whole 1 107 2 1 bunch of different issues. Again, all of you are quite

2 familiar with pain and how it's classically been studied.

3 One of the things that I think has been interesting about

4 this recent movement in those of us who study fibromyalgia

5 in doing clinical trials in this spectrum is that if I was

6 studying RA or OA, I really wouldn't have much of a choice

7 as to what outcome measure that I chose. If I was

8 studying osteoarthritis, I would be using the WOMAC. If I

9 was studying rheumatoid arthritis, I would be using one of

10 the ACR 20, 50, or 70, but when you study fibromyalgia,

11 basically you have a blank slate. You can do anything

12 that you want to do and then try to justify why it is that

13 you did that.

14 So I'll talk about some of the things that I

15 think in fact have been fairly innovative in some of the

16 clinical trials that have been done in fibromyalgia just

17 because of the fact that we, if you will, are allowed to

18 innovate because there's basically no one saying that this

19 is how we should or need to study fibromyalgia.

20 The next couple slides are slides that I stole

21 from Dave Williams in our group, from a talk that he gave

22 about a year or so ago, talking specifically about pain. 1 108 2 1 But I'm just going to show a couple slides showing how

2 different artists have tried to depict the complex symptom

3 that it is that we call pain. Now, I wish I knew the

4 actual artists here, but since I was putting this together

5 on the fly, I didn't actually have a chance to talk to

6 Dave about who the artists are but perhaps some of you

7 know.

8 This is a picture that most of us in

9 rheumatology have seen at one time or another looking at

10 the pain associated with gout and showing how sort of the

11 gnawing, grabbing, aching pain that's associated with gout.

12 Then finally, this is another depiction by an

13 artist of the pain that she was describing in herself.

14 She, in retrospect, is thought to actually have

15 fibromyalgia.

16 And then contrast this with our visual analog

17 scale. Basically, we ask people in clinical trials to put

18 an X on the line and say that they have pain somewhere

19 between no pain and as bad as it could possibly be.

20 Now, some of the problems with visual analog

21 scales and with current measures of pain measurement.

22 With respect to the VAS in particular, it isn't a very 1 109 2 1 good measure with respect to the dynamics of measurement

2 in that when someone moves from 3 centimeters to 1

3 centimeter on a visual analog scale, that isn't the same

4 as someone moving from 10 centimeters to 8 centimeters.

5 So there's a number of issues with respect to the

6 different areas of a visual analog scale are used

7 differently by different people. So there are scaling

8 problems with visual analog scales.

9 Another problem with the VAS is that it only

10 captures a single dimension of the pain experience, and

11 multidimensional measures, like the McGill, are certainly

12 richer with respect to looking qualitatively at the

13 differences both in different types of pain as well as the

14 differences in how different types of treatments might

15 lead to a differential qualitative response with respect

16 to pain.

17 I'm not going to talk a great deal about these

18 two issues. I am going to allude, though, to this issue

19 of the problems with retrospective report of a symptom

20 because some of the data that happens to have been

21 collected in the setting of fibromyalgia with respect to

22 pain measurement is, in fact, relevant to anyone that's 1 110 2 1 studying pain vis-a-vis problems with paper and pencil

2 diaries and perhaps improvements that could be made by

3 looking at electronic assessments of diaries.

4 And then finally some of the other problems

5 with the current measurements of pain is that they miss

6 other important domains that might be at least as

7 important as the actual intensity of the pain.

8 This is a scale that although it certainly has

9 not been well enough validated to be used in a trial for

10 registration of a drug, it's an instrument that Rick

11 Gracely took about 15 or 20 years to develop that has

12 verbal anchors where basically individuals, both patient

13 groups and control groups, were given these verbs in a

14 mixed-up version and told to rate these verbs with respect

15 to the intensity. And this, with all the work that's been

16 done on it, now turns out to be actually a fairly linear

17 scale in contrast to a VAS and such that a movement in 4

18 points from 20 to 16 is the same as a movement in 4 points

19 from 4 to 0. Again, this is of interest, I think, and

20 something that we all perhaps could aspire to and begin

21 using in pain trials but isn't nearly well enough

22 validated to be used in trials that the FDA may be looking 1 111 2 1 at.

2 Another issue that was particularly brought

3 home by an article published by Arthur Stone and his group

4 last year in the British Medical Journal was the poor

5 compliance that typically occurs with paper and pencil

6 diaries. I think most of you are probably aware of this

7 study, but for those of you who aren't, you should be.

8 This is a study where Stone and his colleagues took a

9 group of chronic pain patients over 21 days. Unbeknownst

10 to these individuals, there was a microchip embedded in

11 their paper diaries, such that the investigators could

12 tell when these diaries were opened and closed. They

13 asked people to recount their pain in a classic sort of

14 paper and pencil diary way that we all are familiar with,

15 and when they looked backwards at compliance rates, even

16 though individuals said that they were compliant, 89

17 percent of their entries, even when you gave people a 30-

18 minute window vis-a-vis compliance, the actual compliance

19 rate was only 11 percent. That is, only 11 percent of the

20 entries could have occurred within 30 minutes of when the

21 patients said they occurred because the only time they

22 could occur is if someone had their diary open. 1 112 2 1 The scary thing about this study was -- all of

2 us who do randomized clinical trials know about backward

3 filling. We all see people that come into our office and

4 are sitting in the exam room and filling in the last week

5 of their diary while they're in the exam room, and

6 although that has some problems, at least they

7 theoretically are recalling their pain and trying to

8 retrospectively sort of integrate their pain and that's

9 what they're recording.

10 One of the things, though, about this study

11 was that a surprising number of people forward filled

12 their diaries. A surprising number of people filled their

13 diaries in, they closed the diary Tuesday, it wasn't

14 opened until the investigators opened it on Friday, and

15 yet they had recordings in for Wednesday, Thursday, and

16 Friday. So the forward filling, as well as a number of

17 other issues, really raise serious questions with respect

18 to the validity of paper and pencil diaries and to the

19 validity of the data that are captured with paper and

20 pencil diaries.

21 Because of this, our group has been interested

22 in looking at what Stone and his colleagues have termed 1 113 2 1 ecological momentary assessments. Again, there's a number

2 of people that have been doing work in this field for an

3 awful long time. This is just sort of the last iteration

4 of this work. This is one such device. There are a

5 number of different devices on the market and a number of

6 different companies in fact that are marketing devices

7 looking at the real-time collection of systems. This

8 happens to be a palm-based device that randomly prompts

9 individuals as many times a day as you figure that you can

10 bother people to enter whatever symptom it is that you

11 want them to enter. In this case, we were looking at pain

12 randomly prompted five times a day over the course of

13 first a non-interventional trial and then more recently an

14 interventional study.

15 This was alluded to earlier vis-a-vis some

16 work that Alex Zautra did showing that the levels of

17 stress in fibromyalgia subjects lead to differences in

18 their pain report. Every-day stress leads to differences

19 in their pain report. This might be what we're seeing

20 here. You can't see these yellow lines very well, and I

21 apologize for that, but you see the tremendous variability

22 in this one day, for example, someone who went from a 0 to 1 114 2 1 a 9 over the course of a single day with respect to a VAS

2 rating of their pain score. This variability in fact was

3 very common in the fibromyalgia subjects, this tremendous

4 variability from hour to hour that occurred when we

5 prompted people five times a day to record their pain.

6 One of the other things that was interesting

7 and now this -- these are data from Cypress' phase II

8 study of milnacipran. I'm not going to present the

9 results of the data. All I'm going to present are the

10 data looking at the differences between different measures

11 of pain, whether you're looking at a diary that's filled

12 out or a visual analog scale that's filled out in a clinic

13 versus an electronic diary versus a paper and pencil diary.

14 There were a couple things that we saw both in

15 this study as well as in a smaller non-interventional

16 study that we had done at Georgetown using the same palm-

17 based recordings of pain, and that is, that the random

18 prompt recordings of pain were much lower than the

19 clinical reportings of pain that occurred at the exact

20 same time. So you see here that as you move from random

21 prompt where we averaged 50 random prompts to get this

22 average of 11.9 to daily ratings of pain where there were 1 115 2 1 14 that were given over a 2-week period to weekly ratings

2 to weekly paper ratings, you see here a large difference

3 in the baseline ratings of pain of individuals when that

4 pain is recorded in an EMA type of momentary way versus in

5 a clinical sample here, again the way that we typically

6 record pain.

7 Now, if that was consistent throughout the

8 clinical trial, that wouldn't cause any problems. So if

9 there was always this 4-point difference between the

10 random prompts and the weekly paper recordings of pain,

11 then that theoretically wouldn't cause a problem. All the

12 measures would just be elevated in the weekly paper

13 ratings.

14 But that isn't in fact what was found in the

15 Cypress study. What was found is that the difference at

16 the baseline was the 4-unit difference that I showed you,

17 whereas the difference at the end of the trial was 2

18 units. So what happened is there seems to be something

19 different about psychologically or perhaps there's demand

20 characteristics on the subjects when they're entering a

21 clinical trial, but there's a larger offset here between

22 the random prompts and the clinic visit here rating of 1 116 2 1 pain of 4 units -- now, this is on a 0 to 20 scale, not a

2 0 to 10 scale, just so you all are oriented -- than there

3 is at the end of the study where this difference between

4 the random prompts and the clinic samples average was 2

5 units.

6 Now, that 2-unit difference between the

7 beginning and the end of the trial would normally be

8 considered to be something that we would wrap under the

9 umbrella of a placebo response, but it's not a placebo

10 response. It's a measurement artifact. It's an artifact

11 of the fact that we classically have measured pain using

12 these paper and pencil instruments that at least

13 theoretically have a lot of inherent biases with respect

14 to recall, with respect to demand characteristics, with

15 respect to other things that influence how people report

16 pain. And this is just showing you here how this

17 difference occurred over the course of the trial.

18 So to summarize here, the random prompt pain

19 is extremely variable in fibromyalgia. We haven't yet

20 done studies to show that it's more variable in

21 fibromyalgia or other central pain syndromes than it is in

22 a peripheral nociceptive pain syndrome, but I think that 1 117 2 1 that would be the most logical hypothesis, that if someone

2 has nociceptive pain that is occurring because of

3 activation of a nociceptor, that that pain might be more

4 constant and more consistent from hour to hour and day to

5 day and week to week than central pain because there's so

6 many things that influence central pain, i.e., day-to-day

7 stress or hour-to-hour stress that people are experiencing.

8 Interestingly enough -- and again, I'm not

9 going to present all this data -- despite this difference

10 that I've shown you which is quite interesting and

11 intriguing, it didn't really make a huge difference in the

12 Cypress trial. All of the measures in fact tended to be

13 equally responsive to change, although there are issues, I

14 think, with the validity of paper and pencil diaries vis-

15 a-vis the Stone work and some of the other work that's

16 been published. It didn't seem to make a big difference

17 with respect to responsiveness to change whether we were

18 collecting these outcomes electronically in random prompts

19 or whether we were collecting them with paper and pencil

20 and looking at people's recall of information.

21 Now, with respect to functional status, I'm

22 going to make a distinction between what people are 1 118 2 1 reporting vis-a-vis functional status in fibromyalgia and

2 what really is going on vis-a-vis functional status in

3 fibromyalgia because what I hope to convince you of is,

4 again, this is an area that is inherently different in

5 fibromyalgia than it is in nociceptive pain syndromes,

6 where there is more than just a decrease in activity and

7 the sort of classic dysfunction that we think of, for

8 example, in OA of the knee, going on in the average person

9 that has fibromyalgia.

10 So the first thing I'll talk about is

11 something that was alluded to by both Leslie and Larry,

12 and this is something that Larry is largely responsible

13 for. He was giving Doug Drossman a lot of credit for

14 doing this in IBS, but his group was the one and it still

15 is the one that's really been the leader in doing this in

16 fibromyalgia, showing that people who we recruit in

17 tertiary care samples are different than people who are in

18 primary care samples who are different than people who are

19 in the general population. And that is, the tertiary care

20 samples have higher levels of distress, higher levels of

21 cognitive factors, higher levels of psychiatric co-

22 morbidities, and higher levels of other sort of 1 119 2 1 psychological factors.

2 Now, the problem with all the stuff on the

3 right side of the screen here is that this leads to

4 dysfunction and this, in particular, leads to self-report

5 of dysfunction. Yet these things are not very amenable to

6 pharmacologic therapies. These are the things that

7 cognitive-behavioral therapy really tries to target and

8 tries to impact on because when someone gets to the point

9 that they have one or more of these psychological,

10 behavioral, cognitive factors that are driving symptom

11 expression, that are driving self-report of symptoms, just

12 giving them a drug isn't necessarily going to make that

13 better.

14 And so another way of depicting this -- this

15 is another slide that I borrowed from Leslie in this case

16 of this poor little mouse here in an inner tube -- is that

17 some combination of stress plus bad genes plus environment

18 leads to symptom expression in fibromyalgia.

19 Those of us who were trained as internists and

20 rheumatologists have a tendency to focus on symptoms and

21 there's nothing wrong in particular with focusing on

22 symptoms, but over the last 8 or 10 years, as I've worked 1 120 2 1 closely with psychologists and psychiatrists,

2 psychologists and psychiatrists in fact focus on different

3 things than we focus on. They focus on psychological and

4 behavioral consequences of symptoms, things like decreased

5 activity, like poor sleep, like increased distress and

6 maladaptive illness behaviors, and the reason they focus

7 on that is they know these all make symptoms worse.

8 The reason I show this slide is again to look

9 at the interaction between symptoms and function in

10 fibromyalgia and realize that there isn't a direct

11 relationship here between symptoms and decreased function.

12 I draw the arrows, but there's not a direct relationship.

13 You could imagine a scenario where someone with

14 fibromyalgia who's had it for 10 years, is on disability

15 for fibromyalgia, if and when we ever develop the magical

16 drug that makes symptoms better in fibromyalgia, they

17 could take that drug and nothing would change vis-a-vis

18 these types of factors because fibromyalgia has

19 essentially become a way of a life. What's happened to

20 this person with fibromyalgia is their pain, their

21 fatigue, has led to isolation, has led to limitations in

22 their day-to-day activity, and just because they take a 1 121 2 1 drug that makes them feel better doesn't mean that they're

2 dramatically then going to have an improvement in

3 functional status.

4 Now, if you look at functional status in

5 fibromyalgia, there's a couple outcome measures that you

6 can theoretically use and that would be primarily the

7 Fibromyalgia Impact Questionnaire. The Fibromyalgia

8 Impact Questionnaire has a unique distinction of being the

9 best outcome measure of functional status in fibromyalgia

10 and the worst outcome measure of fibromyalgia functional

11 status because it's the only disease-specific outcome

12 measure in fibromyalgia.

13 Some of the reasons that many of us are not

14 enamored with the Fibromyalgia Impact Questionnaire are

15 that some of the questions that it asks are fairly gender-

16 specific, and I might get in trouble by saying that

17 because many women don't even do these things any more

18 like wash dishes by hand. So these are perhaps things

19 that might have been relevant 20 years ago when this

20 outcome measure was developed, but they're perhaps not

21 very germane right now. In fact everyone that's used the

22 FIQ has noted the problem with missing items in the FIQ. 1 122 2 1 People just won't fill out some of these items, like wash

2 dishes by hand, prepare meals, or vacuum a rug, because

3 they don't happen to apply to that particular individual.

4 Another problem with the FIQ is it was meant

5 as a multidimensional measure, not a pure functional

6 status measure. So when it measures function, it in fact

7 looks at domains like anxiety and depression as symptoms

8 of dysfunction. So it's a measure that is somewhat

9 contaminated. It's not a pure functional status measure.

10 It's a measure that's contaminated by, if you will,

11 psychological factors, like anxiety and depression, which

12 arguably should be measured independently by a scale that

13 purely is measuring depression and anxiety rather than by

14 an aggregate scale that includes in fact all of those

15 different measures.

16 Having said that, the FIQ is fairly responsive

17 to change in many studies that have been done in

18 fibromyalgia, but one particular problem with the FIQ is

19 this floor effect. These are data from the Cypress study

20 just to illustrate real data rather than just tell you

21 something, and this is at the end of the Cypress study.

22 The number of individuals here in the bar graphs, the 1 123 2 1 frequency of scores on the FIQ, and you see that at the

2 end of this study, there were 16 individuals who had 0's

3 on the Fibromyalgia Impact Questionnaire and a substantial

4 number of individuals who had very low scores on the

5 Fibromyalgia Impact Questionnaire.

6 Again, the problem with the Fibromyalgia

7 Impact Questionnaire is that it was developed by Rob

8 Bennett for use in tertiary care of fibromyalgia which is

9 what he was seeing. It doesn't actually perform nearly as

10 well when you start to do a randomized clinical trial and

11 you aim for looking at primary care patients with

12 fibromyalgia because a number of individuals will have

13 either pre-treatment measures or, in particular, post-

14 treatment measures that are at the end of this continuum.

15 They're basically unmeasurable because of the floor effect.

16 This shows the physical component summary

17 score of the SF-36. I indicate here just so you don't get

18 confused that the higher number is higher function in the

19 SF-36, whereas lower number is higher function in the FIQ.

20 You see here that there isn't really a floor effect with

21 the SF-36. The problem, though, with the SF-36 and the

22 PCS score is that it's a generic health status measure and 1 124 2 1 thus it's not nearly as responsive to change as the FIQ is.

2 The other measures of functional status that

3 could theoretically be used in a study of fibromyalgia

4 would include the Health Assessment Questionnaire or the

5 Modified Health Assessment Questionnaire or an instrument

6 that Fred Wolfe published about three or four years ago

7 which are some of the items of the MHAQ which he called

8 the Fibromyalgia HAQ. The problem is that no one has ever

9 used either of these in a randomized, controlled trial of

10 fibromyalgia. So there's absolutely no data on the MHAQ

11 or this new measure that Fred developed with respect to

12 using it in a randomized clinical trial.

13 I want to just talk briefly. You probably

14 wouldn't imagine that I would come and talk to an FDA

15 panel on drugs, about cognitive-behavioral therapy and

16 exercise, but I'm just going to briefly present the

17 results of this study that were published in JAMA a couple

18 months ago because I think it's very illustrative with

19 respect to this dichotomy between function and symptoms

20 and this spectrum of illness.

21 This study happened to have been done in

22 returning Gulf War veterans, and for those of you who 1 125 2 1 don't know the whole story of Gulf War Illness, Larry

2 alluded earlier to the fact that multiple different names

3 have been used to describe the spectrum of illness that we

4 now call fibromyalgia. Things like shell shock and

5 DeCosta syndrome, in fact, were terms that were used after

6 World War I and World War II to describe the returning

7 veterans from those conflicts who had chronic pain and

8 chronic fatigue and other symptoms that we might in the

9 year 2003 call fibromyalgia or chronic fatigue syndrome.

10 As we should have perhaps expected after the

11 first Gulf War, a number of veterans returned with

12 otherwise unexplained pain, fatigue, memory problems, and

13 this constellation of symptoms that Leslie and Larry both

14 talked about.

15 A number of different studies have been done

16 looking at this constellation of symptoms and syndromes,

17 and they've all concluded the same thing, that there's no

18 unique cluster of illness or syndrome that occurred in

19 returning Gulf War veterans, that the cluster of symptoms

20 that occurs in returning Gulf War veterans can also be

21 found in the general population and the general population

22 goes by names such as fibromyalgia, chronic fatigue 1 126 2 1 syndrome, or somatoform disorders.

2 The other thing that these studies have found

3 is that in fact after every war the U.S. has ever been

4 involved in, there have been a subset of veterans who have

5 returned with these symptoms and these complaints.

6 Then finally, with the exception of a single

7 study suggesting that perhaps vaccines given right at the

8 time of deployment might lead to a higher rate of this

9 spectrum of illness in deployed Gulf War veterans. All of

10 the other studies that have been done, now about $240

11 million worth of work that's been done in the United

12 States, have all suggested that no single environmental

13 exposure that occurred in the theater of operations in the

14 first Gulf War could have been responsible for the

15 symptoms that the returning Gulf War veterans returned

16 with.

17 So the CDC late in the 1990s did this series

18 of population-based studies, a couple of which Leslie

19 alluded to, and coined the term chronic multi-symptom

20 illness to describe this constellation of pain, fatigue,

21 memory problems, that sometimes also includes mood

22 disturbances, but in fact affects about 10 to 15 percent 1 127 2 1 of the population in the U.S. and in fact in most other

2 developed countries that it's been looked at.

3 This is what makes up this umbrella of chronic

4 multi-symptom illnesses. This includes diagnoses like

5 fibromyalgia, multiple chemical sensitivity, chronic

6 fatigue syndrome, somatoform disorders, and what I've

7 euphemistically referred to here as exposure syndromes.

8 The only way you can get Gulf War Illness is to have been

9 deployed to the Gulf War. You can't get Gulf War Illness

10 if you didn't go to the Gulf War, yet the symptoms that

11 people experienced that came back from the Gulf War are

12 exactly the same as the symptoms of those who have

13 fibromyalgia or chronic fatigue syndrome.

14 I put silicone breast implants here just to

15 make a point. Again, most of us in the rheumatology field

16 know the story of silicone breast implants. This was an

17 example where there was a false attribution between

18 symptoms and exposure. People thought that there were

19 symptoms of chronic pain and chronic fatigue and memory

20 problems and the like that were, in fact, associated with

21 silicone breast implants because there in fact were a lot

22 of women in the country in the early 1990s who had both 1 128 2 1 those symptoms and had silicone breast implants. But when

2 the 14 or 15 different population-based studies that were

3 done looking at whether there was a true association

4 between breast implants and those symptoms, by and large,

5 they found that there was in fact no association, that

6 those symptoms in fact were very common in middle-aged

7 women and because there were two million women in the

8 country that had breast implants, we would expect that

9 200,000 to 300,000 of those women would have symptoms of

10 chronic pain and chronic fatigue, even if there was no

11 causal association between breast implants and those

12 symptoms.

13 So for this large study that was done in the

14 VA Cooperative Trial Network that was specifically aimed

15 at improving function in returning Gulf War veterans, we

16 used the operational definition for chronic multi-symptom

17 illness. We required that people have two of three of the

18 following symptoms: pain, fatigue, and memory or mood

19 difficulties. These had to begin at or after deployment

20 and still be present in the late 1990s when the study was

21 begun. I'm not going to go into all the details, but

22 basically people were randomized to receive either 1 129 2 1 cognitive-behavioral therapy alone, exercise alone,

2 cognitive-behavioral therapy plus exercise, and all four

3 groups got usual and customary care. Both exercise and

4 CBT were given in group session, not in individual

5 sessions.

6 The primary outcome measure, this is what's

7 important here. Those of us who were involved in

8 designing this study thought that the most important thing

9 we could do for our Gulf War veterans was improve their

10 physical function, and because there was no disease-

11 specific outcome measure, we chose the physical component

12 summary scale of the SF-36 as the measure of physical

13 function that should improve. And we required a 7-point

14 improvement in the PCS to be clinically meaningful and

15 that was based on published work by Ware and others

16 suggesting that a 7-point movement in the PCS is both

17 clinically meaningful and does not occur by chance. It

18 exceeds the standard error of that measure if you give it

19 over and over again.

20 Because these were veterans, the majority of

21 these people were male rather than female, but as it

22 turned out, 55 percent of the people in this trial met 1 130 2 1 criteria for fibromyalgia, 45 percent met criteria for

2 chronic fatigue syndrome. So even though these were

3 primarily males, a substantial portion of them were tender

4 enough and had chronic widespread pain, so they in fact

5 would meet the criteria for fibromyalgia. They also had

6 high rates of disability and high rates of axis 1 mood

7 disorders which, as it turned out, the disability in

8 particular was a big problem with respect to showing less

9 of an effect of treatment than perhaps we otherwise would

10 have.

11 I think this is really illustrative here.

12 These are the veterans in this study, the 1,100 veterans

13 who were in this study. Their PCS score on the SF-36 was

14 33.7 which is almost 2 standard deviations below the

15 population mean, and another study that was done by Lew

16 Kazis that's not published yet looking at fibromyalgia in

17 VA hospitals suggests that the average PCS score of

18 veterans with the diagnosis of fibromyalgia is 28.7, more

19 than 2 standard deviations below the population mean which

20 is 50. You see here again, fibromyalgia or Gulf War

21 Illness would be significantly lower on these functional

22 status measures than these illnesses that we might 1 131 2 1 intuitively think would be lower with respect to the

2 burden that we know occurs in these illnesses.

3 This study was fairly disappointing with

4 respect to the results, even though we targeted this

5 cognitive-behavioral therapy specifically to improve

6 physical function. We only showed a modest ability for

7 the CBT to do that. 18.4 percent of the people who

8 received cognitive-behavioral therapy or cognitive-

9 behavioral therapy plus exercise had this 7-point

10 improvement in their PCS score, whereas 11 percent of the

11 veterans who had usual and customary care had this level

12 of improvement.

13 Exercise alone led to symptomatic improvement

14 in multiple domains of symptoms and there was no

15 synergistic effect between exercise and CBT, which is

16 something again that was both disappointing and a little

17 bit surprising.

18 But these are the data that are perhaps of

19 most interest to this group. When we looked at the

20 correlation between changes in symptoms and changes in

21 function in this study that was specifically done to

22 improve function, we found very modest correlations 1 132 2 1 between the improvements in PCS score over this 12-month

2 period and improvements in pain, improvements in fatigue,

3 or improvements in cognitive dysfunction. Our values of .

4 3 to .4 which would lead us to think that the percentage

5 of the variants in physical function that could be

6 explained by improvement in symptoms was perhaps 10 to 15

7 percent, that is, the r squared values.

8 Contrast this with the best review that I

9 could find looking at the comparable data for

10 osteoarthritis of the knee, where in osteoarthritis of the

11 knee, the correlations between the different subscales of

12 the WOMAC range in the .7 to .8 range which means that

13 perhaps 50 or 60 percent of the variance in function can

14 be predicted by improvement in symptoms in osteoarthritis

15 of the knee and again the huge disparity between something

16 like OA and something like fibromyalgia or chronic multi-

17 symptom illnesses where there's just not nearly as big of

18 a link between symptoms and function.

19 I'm not going to go through the conclusions.

20 So let me just try to explain why this might

21 be. Because of this huge difference in self-report of

22 physical function in individuals with fibromyalgia, our 1 133 2 1 group and others have been very interested in trying to

2 help sort of understand or explain why that might be

3 occurring. One of the ways that you can try to get at

4 this is to actually look at objective measures of

5 activity, looking at things like activity monitors, and

6 actually try to look at how these relate to self-report of

7 physical function.

8 Actigraphy is actually very well validated as

9 a surrogate measure of physical activity in that if you

10 put people, for example, on a treadmill, you have an

11 actigraph connected to them, you'll find that there's a

12 quite linear relationship between what the actigraph shows

13 and how many mats they're exercising on on the treadmill.

14 This actually has been extrapolated to a number of

15 different domains, and again actigraphy is fairly well

16 accepted now as being a surrogate measure of activity per

17 se. In fact, in the rheumatology literature in RA, there

18 are modest correlations between activity as measured by

19 activity monitoring and changes in the MHAQ over time in

20 individuals in clinical trials of rheumatoid arthritis.

21 This happens to be the Actiwatch that we use.

22 There's a whole bunch of different ones on the market. 1 134 2 1 One of the advantages of this is that you can actually not

2 only collect activity, but people can actually enter their

3 symptoms as well as activities. So at various times

4 throughout the day, as we've been known to do and being

5 annoying with our subjects, is these things beep and we

6 ask them four or five times a day to record their pain,

7 record their fatigue, record their levels of stress, to

8 determine if those actually are related to activity or

9 other measures in people with fibromyalgia.

10 This is an example of what an actigraph looks

11 like. People fill out a diary. You can see here that the

12 activity goes up when they're doing things like running.

13 It goes down when they're doing things like sleeping.

14 Although actigraphy has actually been used as sort of a

15 surrogate measure of sleep efficiency because if people

16 are thrashing around a lot during sleep, they're not

17 getting as good a sleep as they are if they happen to, in

18 fact, be resting. But again, an average look at what

19 actigraphy will show you.

20 In this particular study, we had 30 people

21 with fibromyalgia and 29 controls. The controls were

22 specifically selected to be sedentary controls, not active 1 135 2 1 exercising controls, and we were interested over this 5-

2 day period not only what the activity levels were but how

3 activity related to symptoms in people with fibromyalgia.

4 Now, for any of the fibromyalgia skeptics that

5 might be hiding in the room here, I'm not going to leave

6 this slide up very long because this slide by itself will

7 lead people to think that fibromyalgia isn't really real.

8 There was no difference at all between the

9 patients in controls in either daytime activity or

10 nighttime activity as measured by actigraphy, even though

11 there was a 20-point difference in the physical component

12 summary score in the people with fibromyalgia. So 2

13 standard deviations lower with respect to self-report

14 activity, yet no difference whatsoever with respect to the

15 mean activity levels in people with fibromyalgia.

16 However, what we did find is there were large

17 differences in the peak activity levels in people with

18 fibromyalgia. You see here the difference between the

19 peak activity levels as well as the standard deviation or

20 the variability of activity. What we basically found in

21 people with fibromyalgia is they couldn't raise their

22 activity. They couldn't meet different types of sort of 1 136 2 1 daily demands. So what you find in fibromyalgia patients

2 is that they didn't have the ability to go to these higher

3 levels of peak activity that the normal controls did and

4 you see this here depicted. Although they were very

5 similar in the morning when they woke up, at midmorning,

6 at afternoon, and at evening, you see the much higher peak

7 activity levels in the controls than you see here in the

8 fibromyalgia subjects.

9 This is just actograms of the two different

10 groups, a representative fibromyalgia patient and a

11 representative control. You see in the control, all these

12 high peaks where people can basically raise their

13 activity, and you see in certain days in the fibromyalgia

14 patients, there are certain hours where basically they

15 have to be sedentary. And we would find fibromyalgia

16 patients that for days at a time, they would basically be

17 fairly sedentary, then they would do a little bit the next

18 day and then have several days afterwards, again leading

19 to equal means or averages between the groups but markedly

20 different peaks between the two groups.

21 The other fascinating thing with respect to

22 this study is that we didn't find any relationship between 1 137 2 1 either peak or average ratings of pain, fatigue, or stress

2 in the patient groups. So the level of symptoms they were

3 having on that particular day did not correlate with what

4 they did on that particular day, but we didn't find that

5 in the control groups either, and the same held true for

6 the fact that there was no relationship in either the

7 patient or the control groups between self-report

8 function, in this case as measured by the SF-36, and

9 between objective measures of activity in either patients

10 or controls.

11 So I think what this study is telling us is a

12 couple of things. One is that what seems to be most

13 abnormal in people with fibromyalgia is sort of the

14 ability to respond to demands of day-to-day life, not

15 necessarily that they can't do sort of certain things from

16 a day-to-day basis, and also that we have to really wonder

17 what measures like the SF-36 and other functional status

18 measures really are measuring if they're not measuring

19 activity. What is it that we're capturing in these self-

20 report questionnaires, if it's not actual objective

21 activity that it is that we're capturing?

22 So to conclude, fibromyalgia patients rate 1 138 2 1 their function as being very low. This domain has been

2 very difficult to improve in clinical trials, even using

3 behavioral interventions that are specifically designed to

4 improve function. I happen to agree with what Larry said.

5 I think that when we give cognitive-behavioral therapy in

6 the setting of adequate pharmacologic therapy, cognitive-

7 behavioral therapy will work a lot better, but that's a

8 hypothesis that needs to be tested. And the dysfunction

9 in fibromyalgia, perhaps most important to this group, is

10 fundamentally different than dysfunction in other

11 rheumatic diseases in that there's not as linear a

12 relationship between symptoms and dysfunction in

13 fibromyalgia as there is in other rheumatic diseases.

14 I'm just going to talk briefly about some of

15 the other outcome measures that have been considered in

16 fibromyalgia. Patient global improvement --

17 DR. FIRESTEIN: Dr. Clauw?

18 DR. CLAUW: Yes?

19 DR. FIRESTEIN: Can you wrap up in just a

20 couple minutes?

21 DR. CLAUW: Yes. Patient global improvement

22 has been considered. It is a very valid measure but only 1 139 2 1 a couple recent studies have actually looked at patient

2 global as an outcome measure.

3 Fatigue. Again, this has been looked at over

4 and over again. There are multidimensional assessments of

5 fatigue that have been used. There are plain old visual

6 analog scales that have been used, and I happen to agree

7 with Fred Wolfe who has actually looked at this in depth,

8 that the multidimensional measures give you more

9 qualitative information about the type of fatigue that

10 people have, but they're not any more responsive to

11 change, that a VAS, a simple VAS is probably the best

12 measure of fatigue to use in a clinical trial.

13 The same holds true with sleep. One of the

14 things that you should understand about both sleep and

15 cognitive dysfunction is that self-report measures of

16 sleep do not correlate very well at all with objective

17 measures of sleep and self-report measures of cognitive

18 dysfunction do not correlate very well with objective

19 measures of cognitive dysfunction.

20 So when you are doing a clinical trial in

21 fibromyalgia, what you probably would ask people if you

22 thought that sleep and cognitive function were important 1 140 2 1 domains is ask the person whether they thought these

2 domains improved rather than trying to move towards

3 looking at objective measures of sleep, like

4 polysomnography or in the case of cognition

5 neuropsychiatric testing, because in fact you don't find

6 strong correlations between those more objective measures

7 and subjective measures, either in fibromyalgia or in

8 healthy normal individuals.

9 With respect to process measures or surrogate

10 outcome measures, this is probably the only thing that I

11 will say definitively, is that although our group does an

12 awful lot of functional imaging, a lot of evoked pain

13 testing, a lot of measures of autonomic function and

14 hypothalamic-pituitary-adrenal function, none of these is

15 ready for a clinical trial. None of these is ready to be

16 used as a primary outcome measure in a randomized clinical

17 trial because none of them are robust enough and the ones

18 that we can get to change in highly-experimental settings,

19 like in a GCRC, can't really be extrapolated to be used in

20 a large multicenter clinical trial.

21 So the last slide I have here is basically --

22 I think this is actually a relatively simple decision 1 141 2 1 because there's only really only a couple answers to what

2 should be the outcome measures in fibromyalgia. Where

3 should we set the bar?

4 But if we set the bar at one place, we could

5 say this is a legitimate syndrome with a large unmet need

6 just as osteoarthritis or rheumatoid arthritis were 30

7 years ago, where there are no currently-approved drugs,

8 and what we should do in fibromyalgia is improve pain.

9 Lynne will tell you in a couple minutes that

10 that's probably what patients want, to improve pain, and

11 as long as we use 2003 standards for randomized clinical

12 trials, that is, we look at minimally clinically important

13 differences, we look at intent-to-treat types of studies,

14 that this might be a reasonable bar for a disease like

15 fibromyalgia. This certainly would be comparable to the

16 recent approvals for IBS drugs and migraine drugs, where

17 improvement in a single domain which was pain in migraine

18 and improvement in a single domain which was patient

19 global in IBS led to approval of drugs in those different

20 domains.

21 I actually happen to agree, though. I've

22 heard Lee and Jim both say many times that we don't want 1 142 2 1 to make pain better but make the patient worse. So

2 perhaps the next level at which we could set the bar would

3 be that we show that people have both a clinically

4 meaningful improvement in pain and an improvement in

5 patient global. That would ensure us that the person as a

6 whole is getting better as well as their pain getting

7 better.

8 And then finally, the highest bar to set would

9 be to require this sort of triple primary endpoint, and

10 instead of improving function in fibromyalgia, because of

11 the fact that we know function is difficult to improve, we

12 perhaps could use an ACR 20 an ACR 50 responder analysis

13 and lead to improvement in many domains.

14 The last thing I'll say and I'll close here is

15 I think, because I can't talk any more after I get done

16 talking now, is that what I would ask all of you to do is,

17 at the end of the day, when you come up with an outcome

18 measure for fibromyalgia, think of a drug that is an

19 incredibly effective central analgesic but does nothing

20 more than improve pain, and there will be such drugs.

21 There will be drugs that are very good central analgesics,

22 whether they're NMDA receptor blockers or substance P 1 143 2 1 antagonists or whatever, that are very good at treating

2 central pain but don't independently affect fatigue or

3 other domains and just ask yourself two questions.

4 Number one, would fibromyalgia patients

5 benefit from this drug? And number two, would the outcome

6 measures that we choose, the bar that we set, allow that

7 drug to be approved?

8 There's not any such drug that's in the

9 pipeline right now that's been tested, but that drug is

10 likely to come on the scene, and again I think that my own

11 personal view would be that fibromyalgia patients would

12 benefit from that drug if it is safe. And as we think of

13 these sort of multiple domains, we should look at that as

14 sort of the acid test of whether a compound such as that

15 in fact would be able to be approved in the setting of

16 fibromyalgia.

17 Thank you.

18 (Applause.)

19 DR. FIRESTEIN: Thank you.

20 We have time for one question. This time Dr.

21 Strand really did have a question or a comment.

22 DR. STRAND: I had a comment about the SF-36 1 144 2 1 and its use in RCTs and its correlation. Actually in RA,

2 the PCS scores are virtually across all of our recent

3 trials are about 30, 2 standard deviations from the norm,

4 and the correlations proven in both the physical function

5 domain and the PCS scores with the HAQ on the order of .7,

6 .8 and .9, and we see improvements of about 10 points.

7 I think your definition of an improvement in

8 PCS score of 7 was a bit high because most of the data we

9 have now from RA and also diabetes, OA, cardiovascular-

10 pulmonary disease, suggests that the domain MCID scores

11 are about 5 to 10, but that PCS being scored from 0 to 50

12 would be more like 2.5 to 5.

13 I wonder whether you might have seen a little

14 bit better difference with the 5, the point being again

15 also that physical function domains are positively scored

16 in the PCS and are very low in RA and show a lot of change

17 and that's ostensibly what you were looking for, change in

18 your study with the vets.

19 DR. FIRESTEIN: Before you answer, Dr. Strand,

20 I've been asked if you can identify yourself and indicate

21 any potential conflicts.

22 DR. STRAND: I'm sorry. Strand, S-T-R-A-N-D, 1 145 2 1 and I teach at Stanford. I'm a consultant and I'm here on

2 my own.

3 DR. CLAUW: In answer to that question, we

4 actually looked at different cut points because we were

5 somewhat disappointed with the performance, and it didn't

6 really matter in this particular trial. Using lower cut

7 points wouldn't in this trial have done any better at

8 separating the treatment groups from placebo.

9 I do agree with what you're saying. In

10 retrospect, perhaps we set the bar a little bit too high

11 with respect to the 7-point PCS score.

12 DR. FIRESTEIN: One last comment and then

13 we're going to break.

14 DR. GIBOFSKY: Dr. Clauw, in his introductory

15 remarks, Dr. Witter asked us to think about fibromyalgia

16 either as a symptom or cluster of symptoms or as a complex

17 disease state with varying clinical presentations. You

18 suggest in some of your remarks that there might be a

19 subset of patients for whom we should think of the claim

20 as a way of life, that if the magical drug came on the

21 market that eliminated the symptoms, I think you said we'd

22 still be left with patients who have the disease. 1 146 2 1 I wonder if you could tease that out a bit

2 more so I can understand a little bit better about how to

3 structure the claim.

4 DR. CLAUW: Well, just to be clear, I didn't

5 suggest the claim was a way of life. I suggested that in

6 a subset of people with fibromyalgia that have high levels

7 of psychological and behavioral co-morbidities, which most

8 of the data suggests occur as a result of the fibromyalgia

9 rather than they begin with, but even an effective drug --

10 again, these are sort of the classic tertiary care

11 patients with fibromyalgia that probably make up a fairly

12 small subgroup of the total universe of fibromyalgia

13 patients. But even an effective drug, if administered to

14 these individuals, might not lead to a great deal of

15 improvement in function because their dysfunction has

16 occurred in large part as a result of the fact that they

17 become isolated, they become depressed. Other things

18 other than the primary symptoms of the fibromyalgia are

19 driving their dysfunction.

20 Just to be clear, the same subset occurs in OA

21 and RA, it's just not nearly as large a subset. We all

22 have patients of ours with OA or RA that are on 1 147 2 1 disability, that if we give them very effective drugs, we

2 don't see as much of an improvement in their functional

3 status as we might in someone who doesn't have that

4 psychological and behavioral burden, if you will, because

5 again these are people that, in addition to the

6 underlying, in the case of RA, sort of immunobiology

7 rather than neurobiology, just making that better doesn't

8 make the entire person better.

9 So, hopefully, I clarified an issue or

10 answered your question.

11 DR. FIRESTEIN: Dr. Anderson, you had one.

12 DR. ANDERSON: Yes. I just wanted to refer to

13 your slides about effect sizes from meta-analysis and also

14 ask you a question about pain.

15 There seemed to be quite a large number of

16 trials done and perhaps there's data there that could be

17 used in developing response criteria for fibromyalgia.

18 The measures may be somewhat different but they fall in

19 different clusters and they're similar enough that whoever

20 did the meta-analysis felt they could create effect sizes

21 for them. So I'd like your comments on that, whether they

22 would be usable for this purpose. 1 148 2 1 Also, about pain. You said a lot of things

2 about how the VAS is not at all reliable and so forth.

3 However, it has in a lot of contexts been found to be very

4 responsive. And you end up saying for fibromyalgia that a

5 VAS for fatigue was responsive. So maybe simple measures

6 of pain could be useful.

7 DR. CLAUW: Let me answer the second question

8 first. I think, as you know, there's a big difference

9 between responsive and accurate/valid. The problem, I

10 think, with VAS is not a responsive issue because in fact

11 they're responsive. The issue, especially vis-a-vis

12 diaries and things like that, is whether it's a valid

13 response on the part of the patient or whether that recall

14 bias, that filter that people use when they fill out a

15 diary, when they backward fill or when they forward fill a

16 diary and they try to guess what their pain -- that's more

17 sort of a precision/validity issue than it is a

18 responsiveness issue.

19 I did say that all of those measures, the

20 electronic measures, the paper and pencil diaries, they

21 all performed about the same with respect to

22 responsiveness in the Cypress trial. So I'm not being 1 149 2 1 critical of any of these measures with respect to

2 responsiveness. I am being somewhat critical. I think we

3 just have to be circumspect about these measures with

4 respect to sort of their accuracy and their validity.

5 With respect to your first question, I think

6 that we have very good data that we could use to model

7 something like an ACR 20, if the drug that was going to be

8 used is a tricyclic drug. That ACR 20 might be totally

9 the wrong instrument for a different compound that's

10 acting on a different part of the central nervous system.

11 Tricyclic drugs, for example, are sedating and in fact

12 many of their side effects have to do with the sedating

13 qualities of the tricyclics. A good drug for fibromyalgia

14 might be a drug that is not a good sleep drug, that is an

15 activating drug that improves fatigue and improves other

16 symptoms, but doesn't do anything at all for sleep.

17 So again, if we had an ACR 20 that included

18 sleep as a domain because we were modeling after

19 tricyclics and because that was the largest effect size,

20 it might not do very well for a compound that might, in

21 fact, be a better compound but just doesn't happen to hit

22 that domain. It doesn't happen to hit the sleep domains. 1 150 2 1 So I think that's the problem with an ACR 20

2 type of responder analysis, is it would have to incredible

3 flexibility to capture all the different types of

4 pharmacologic agents that might be effective in treating

5 subsets of people or subsets of symptoms in fibromyalgia.

6 Maybe there is such an instrument that could be developed,

7 but I guess I wonder whether that in fact is the case.

8 DR. FIRESTEIN: Before we break, I've been

9 asked if Dr. Strand can disclose for the public record the

10 relevant companies for which she consults, and you have a

11 list. Would you please read the list for the record?

12 DR. STRAND: I don't have it with me. I will

13 e-mail it to you. Would that be sufficient?

14 DR. FIRESTEIN: She will be e-mailing it.

15 Okay.

16 And then for the record, we will no longer

17 take comments from the public in order to avoid getting

18 mired in this problem for the rest of the day.

19 So in that case, without further ado, we will

20 break for 10 minutes. We'll start again at 11:10.

21 Thank you.

22 (Recess.) 1 151 2 1 DR. FIRESTEIN: Let's go ahead and get started.

2 So our first presentation of this part of the

3 discussion will be by Lynne Matallana on a patient's

4 perspective.

5 MS. MATALLANA: Good morning.

6 First of all, I would like to very much thank

7 the FDA for inviting me to be a part of this advisory

8 committee. I know that the patients oftentimes have a lot

9 of things that they would like to include in discussions

10 of this sort, and I'm very pleased to be able to be here

11 to represent that group of people.

12 I also am going to ask your indulgence as I'm

13 going to sit because I don't want to fall over. So if you

14 don't mind. If you can't see me from here, wave and I'll

15 try to kind of move so that you can see me.

16 In 1993, I had a laparoscopy for endometriosis

17 and woke up during the surgery, and at that point on, I

18 started having very unusual symptoms. I was diagnosed

19 about two years later with lupus and later rediagnosed

20 with fibromyalgia.

21 In 1997, I started an organization at that

22 time called the National Fibromyalgia Awareness Campaign, 1 152 2 1 and our original intent was just to speak out on behalf of

2 the patients, to let people know that this illness existed

3 and that we needed help.

4 As time went by and the needs of the patient

5 community as well as the medical community became more and

6 more apparent to us, we became the National Fibromyalgia

7 Association two years ago, and we now publish a national

8 magazine which some of the committee members have in their

9 packets that addresses issues that are very pertinent to

10 the patient community but also to the medical community,

11 and we were very pleased that this publication has been

12 received so well by the medical professionals.

13 I feel qualified to represent patients because

14 I talk to thousands of patients every year through

15 Internet, through phone calls, through meetings, and I

16 also am very pleased that I have had the experience of

17 working with many of you and many of the researchers and

18 doctors. We have over 50 doctors who work with us as

19 advisors. So we have quite a bit of input from them to

20 know exactly what is going on in the clinical research

21 area.

22 I've been asked to speak about the patient's 1 153 2 1 perspective, and what I will be drawing from is obviously

2 my own experiences, my own intuition, the anecdotal

3 information that I have been given by other patients, and

4 a survey.

5 I, unfortunately, was only appointed to this

6 committee a couple of weeks ago, but I wanted to be able

7 to bring some type of specific information from the

8 patients. So we sent out a survey with about 20 questions

9 to 16,000 fibromyalgia patients. To our surprise, in five

10 days, we had 1,119 responses. Obviously, I was not able

11 to tally all of that, and so we've taken a sample survey

12 response group of about 200 people. So when I give my

13 percentages, you can know that this is a group of about

14 200 people that I am referring to.

15 One of the first things I want to address is

16 the picture that you saw of the woman that looked like she

17 was close to death and extremely miserable because this is

18 something that most people with fibromyalgia feel at one

19 time or another in their life. We do have, obviously,

20 symptoms that wax and wane, but the majority of us go

21 through a time where we are almost completely disabled,

22 myself included. I spent two years in bed and four years 1 154 2 1 at home.

2 But I feel that there is very much a belief in

3 the patient community that with the right support, with

4 the right medications and treatments and with the

5 understanding that we are not crazy, that this is a true

6 physical entity, that you can improve, and I think that

7 part of the problem has been that many patients have not

8 had the support or the educational information that they

9 need in order to help improve and also have not had the

10 opportunity to try certain medications that may be now in

11 more of the experimental stages. So please keep in mind

12 whenever I'm talking that I am talking about a group of

13 people who are very distressed.

14 I'd like to answer several questions in my

15 presentation today, the first being: what are the unmet

16 needs of the fibromyalgia community?

17 One of the first things that we are faced with

18 often is how many people have this illness. I think

19 someone quoted 4 million to 10 million which is quite a

20 deviation, and we do not have any true epidemiological

21 studies that will talk about this issue, relate to this

22 issue, look at geographic considerations, the illness in 1 155 2 1 men versus women, different treatments. Many of you know

2 that fibromyalgia patients react differently to certain

3 treatments and why is that? We obviously have our lumpers

4 and our splitters who look at fibromyalgia with

5 subcategories and we need to look at that more

6 specifically.

7 The other thing that I think is so important

8 and you will hear constantly from people with fibromyalgia

9 is the level of acceptance of the illness. Acceptance

10 from society which includes their own families and

11 employers and friends to the medical community, obviously

12 having gone to doctors who have told them either there is

13 nothing they can do for you or there is not an illness

14 called fibromyalgia, and then also that feeling of having

15 the plague. Dr. Clauw mentioned the isolation that people

16 with fibromyalgia go through, and I think that this

17 obviously then intensifies the symptoms. So with the

18 acceptance and with the education, we can probably prevent

19 a lot of that isolation.

20 Another concern is where to go for treatment

21 because many of the doctors do not believe in this illness

22 and currently rheumatologists tend to be the main 1 156 2 1 caregivers. However, as you know with the multiple

2 symptoms that we have, many patients try to go to

3 neurologists or different types of pain specialists or

4 migraine specialists, gastroenterologists, and to have

5 these groups of people who are very unfamiliar with the

6 illness can be very detrimental. So we're also looking

7 for continuing medical education and especially at the

8 level of the family practice doctor because, as you know,

9 diagnosis of fibromyalgia does usually take anywhere from

10 two to five years. So if we could educate and help

11 doctors in the family practice arena, we could probably

12 cut the duration of time for diagnosis.

13 Also, it's very exciting to see fibromyalgia

14 be taken so seriously and be moving forward at the federal

15 government level. However, at the state and local level,

16 that does not seem to be the case. We recently, in the

17 state of California, worked to get a bill through that all

18 it did was ask the Department of Health to recognize

19 fibromyalgia and to include it in its list of illnesses

20 that they are concerned about. Not only was the bill not

21 passed but they placed another bill in its place that was

22 approved so that the previous bill on fibromyalgia will 1 157 2 1 not even be in the record. So state and local knowledge

2 and support of this illness is very much needed as well.

3 We've talked about diagnosis. As far as I

4 think most patients are concerned, they feel that the

5 tender point exam is a viable technique for diagnosis. We

6 don't see too many people who have been told that they do

7 meet these standards and that we don't feel have

8 fibromyalgia. However, there is the problem with people

9 not believing. So if there was a diagnostic test which

10 was not subjective, it would help us in our plight to make

11 people believe in this illness.

12 Also more research. Obviously, today the

13 experts have presented so many different questions that

14 need to be answered, and with the limited amount of

15 research funding. The National Fibromyalgia Association

16 is a non-profit organization that kind of squeaks by with

17 the contributions of other patients, but we have so many

18 doctors now coming to us, asking us for funding because

19 they have viable research studies that they want to do,

20 and it's very difficult for us to not be able to have that

21 funding to help them. So funding is definitely a need.

22 Also, we are very thrilled with the people 1 158 2 1 over the last 20 years who have been a part of the

2 research of fibromyalgia. However, several of these

3 people are starting to retire, and it's exciting when new

4 people are becoming involved, but we'd like to see even

5 more people that have new ideas and are very much not

6 afraid to look at a possible new paradigm for the

7 causation of this illness.

8 As I mentioned about the diagnosis of

9 fibromyalgia, a quantifiable test would help us in proving

10 the existence of this illness and also could help cut down

11 on the diagnostic time frame.

12 We also are interested in looking at some of

13 these subgroups. It's interesting when certain patient

14 organizations get behind a specific type of treatment,

15 such as surgery for Chiari malformation or the use of

16 guaifenesin and some of these other things. It's part of

17 the patient group and yet it's something that needs to

18 have medical evaluation. I know that, for example, on the

19 guaifenesin, that Dr. Robert Bennett has done two tests

20 which clinically prove that there is no treatment help

21 from guaifenesin. However, when we do surveying, we still

22 have a large percent, usually between 4 and 5 percent, of 1 159 2 1 people who have felt that this has been the main product

2 that has helped them in relieving symptoms.

3 The other thing that I think is important to

4 look at is the onset of fibromyalgia. We have at times

5 thought that it was about 40 percent of people that had

6 onset because of trauma. However, in an anecdotal way of

7 looking at this from talking to fibromyalgia patients, I

8 would say at least 9 out of 10 patients do attribute the

9 onset of their illness due to some type of physical or

10 emotional trauma, and I do think this could help us in

11 learning how to possibly prevent or understand better what

12 the cause of this illness is.

13 Also, the role of central sensitivity

14 syndrome. The importance of being able to identify the

15 overlapping conditions is very important because what I

16 feel, although a lot of people would like to have a

17 treatment specifically for their worst symptom, I think

18 that oftentimes patients improve if they start with their

19 easiest-to-treat symptom. So, for example, if they're

20 suffering from migraine headaches and there are medical

21 prescription drugs that help this, that even though that

22 might not be their worst problem, to look at that as a 1 160 2 1 possibility for treatment first and then work up to the

2 more difficult symptoms.

3 DR. FIRESTEIN: Thank you.

4 Could you make a concluding remark?

5 MS. MATALLANA: Okay.

6 Well, what I have here now is going into the

7 survey outcomes, and I guess what I'll have to do is just

8 kind of give you an overview as far as--

9 DR. FIRESTEIN: Just a concluding remark,

10 please.

11 MS. MATALLANA: Okay.

12 I would agree that pain is the most difficult

13 symptom and that 68 percent of people with fibromyalgia

14 are interested in finding treatment for pain.

15 Thank you.

16 DR. FIRESTEIN: Thank you very much.

17 (Applause.)

18 DR. FIRESTEIN: Next, Dr. Wells will talk

19 about outcomes: multi-system impact.

20 DR. WELLS: Thank you.

21 Just as some of the previous speakers, I'd

22 like to also commend the committee and the FDA for holding 1 161 2 1 these very timely and important meetings. Also, in terms

2 of full disclosure, I'd like to indicate that I am 53

3 years old, so you can take Leslie's cognitive age curve

4 and properly place me in that curve to know where I sit.

5 It's very difficult to speak after a patient

6 and a consumer because they bring a real face to the issue.

7 I now have to go back and take an

8 epidemiological and statistical perspective on looking at

9 outcomes in this particular area. I'll try to do that as

10 quickly as possible, also hopefully as informative as

11 possible in that process.

12 I will quickly skip through the first two

13 slides. These are the obligatory slides talking about

14 what fibromyalgia is about, also the ACR criteria.

15 I will focus a little bit on the second slide,

16 though, to say that there are two controversies here

17 really. First of all, there's the controversy of whether

18 we're dealing with medicalization of unrelated symptoms,

19 to a syndrome, to a defined disorder. The controversy I

20 want to talk about right now is what is the most

21 appropriate or combination, composite, appropriate outcome

22 measures that we can select to look at this issue. 1 162 2 1 Now, to do that, I'm going to follow the

2 following road map, and as I said, this is going to be

3 very at times statistical, so I'll quickly go through some

4 of these.

5 First of all, I want to give you an

6 unsystematic review of the types of outcome measures that

7 are used in fibromyalgia.

8 Second of all, I want to give you an intuitive

9 feel for why we choose certain measures.

10 Next, the development and selection of

11 outcomes. I do want to talk about issues, such as

12 reliability, validity, sensitivity, which are very

13 important, and people often confuse the terminology, so we

14 have to be careful there.

15 We then are going to look at some overall

16 response criteria. How can we go about this?

17 Next, the minimal clinically-important

18 difference. I'll try to put a little bit different face

19 on that rather than just giving you the definition but

20 also try to put it in context.

21 And then finally, something called low disease

22 activity state. Earlier, we heard about ACR 20, 50, and 1 163 2 1 70. I suggest to you that if you're going to do

2 something, you might as well as leapfrog and just not

3 repeat what someone else has done but think further down

4 the road and think of what the next step is, and I'm going

5 to say to you that the next step is to look at entities

6 called low disease activity states.

7 First of all, types of outcomes. This is my

8 unsystematic review. I looked at three systematic reviews

9 in the literature. Two of them were in the Cochrane

10 Collaboration Review 2003 and 2002. I also looked at the

11 review by Rossy in the Annals of Behavioral Medicine in

12 1999 and took a look at some of the outcomes that they

13 viewed. I put them into different constructs, if you

14 wish, and I found eight different areas, and I could add

15 more. I could have added the economics and so on and so

16 forth. But these are the eight.

17 When I look in pain, I can see everything from

18 visual analog scales to ordinal scales to pain drawings.

19 I also found a very interesting article by Fred Wolfe on

20 looking at regional pain scales where he's trying to take

21 a more quantitative look at this issue.

22 In tender points, we have the pain threshold 1 164 2 1 and tenderness to thumb pressure.

2 In physical function, there is a host of

3 different things we can look at. We have self-report of

4 physical pain, the FIQ which Dan talked about, also the

5 fibromyalgia HAQ which is the newer scale that was

6 developed by Fred Wolfe. We also have musculoskeletal

7 performance, various ways of measuring that,

8 cardiorespiratory fitness and various ways of measuring

9 that.

10 In terms of global well-being, we have the

11 physician-rated things. We also have the overall score of

12 the FIQ.

13 In terms of self-efficacy, there's the

14 Arthritis Self-Efficacy Questionnaire.

15 In terms of fatigue and sleep, the FIQ Fatigue

16 Subscale, the sleep VAS.

17 Psychological function, subscales again of the

18 FIQ for depression and anxiety, but remember what Dan

19 said, it was basically a visual analog scale and it wasn't

20 really potentially tapping into all aspects.

21 Quality of life and generic functional status,

22 Short Form 36, Sickness Impact Profile, and the HAQ, if 1 165 2 1 you wish to view the HAQ as being more generic in this

2 area.

3 Just to give you the background to the

4 Fibromyalgia Impact Questionnaire, it's a brief 10-item

5 questionnaire. It measures a number of physical functions

6 which are up there on the screen. It was developed in

7 1991 by Bennett. Basically, the questions are were you

8 able to do some of these particular activities, and as was

9 indicated earlier, many of these activities, people would

10 not respond to today in terms of, for example, of washing

11 dishes and so forth. There's also nine other questions.

12 All of a sudden, I noticed it's changed to dots instead of

13 numbers, but anyway, there's nine other questions and some

14 of these questions are very specific, for example, to

15 people who actually work. So you're going to find a lot

16 of missing information. This is one of the reasons why

17 Fred Wolfe in 2000 developed the FHAQ and he compared one

18 to the other because he felt that some of these items

19 would be missing too often for the FIQ to be useful and

20 also some of the items would not be applicable today.

21 Now, choosing outcomes. Okay. First of all,

22 just generalities. We like objective measurements. We'd 1 166 2 1 like to, if we could, reduce or reverse disease. We'd

2 like to improve quality of life. We'd like to reduce

3 mortality. We'd like to have a good global impression,

4 both in the patient and the physician. We'd like to

5 improve symptomatology, and we'd like biochemical

6 measures, if that was possible.

7 Now, from the patients, what do the patients

8 want? To live as long as possible. That's your first D,

9 death. To be normally functioning, so getting away from

10 disability. To be free of pain, psychological, physical,

11 social, and other symptoms, discomfort. To be free of

12 problems from treatments, drugs, side effects, and so

13 forth, and to remain solvent, the other D which is

14 destitution, if you have to pay for some of these

15 disorders. This is what the patient wants, just very

16 globally what they would want.

17 There are other ways of identifying best

18 outcomes, and let me just going to focus for a couple of

19 seconds on what influences the physician's decision. The

20 outcome measurements. This is a study that was actually

21 done by Nick Bellamy in 1998 and 1999, and he asked the

22 question: how often do you serially use the following 1 167 2 1 assessment techniques for longitudinally monitoring the

2 efficacy of antirheumatic drug therapy in your adult

3 fibromyalgia and patient practice? He did Canada and he

4 did Australia. Take a look at this. The quality of the

5 sleep is usually and always of importance. Fatigue,

6 usually and always of importance. The number of tender

7 points, important but not as important, and skinfold

8 thickness, not important at all, relatively speaking.

9 In Australia, when he did the study the

10 following year, he didn't include skinfold thickness, just

11 stuck with the other three outcomes, and they all

12 reflected something similar, except maybe a little bit

13 less in terms of being "always" for the Australians.

14 So let's look at the development and selection

15 of outcomes, and this is where I'll try to go through

16 quickly so that we can save some time.

17 We have to look at the comprehensiveness or

18 the content validity. We have to know that we've included

19 the proper components of health. We have to look at

20 credibility or face validity. What appears to be sensible

21 and interpretable is there. We have to look at accuracy.

22 Does it reflect the true clinical status of the patient? 1 168 2 1 We have to look at sensitivity to change and also

2 biological sense as a construct validity.

3 So the three key measurements are reliability,

4 validity, and sensitivity to change, and it would be nice

5 to take all the various outcomes that are around and take

6 a look at their reliability, validity, and sensitivity to

7 change. I'm going to go through a little bit of details

8 on these, just to give you a sense of what each of these

9 involves. The terminology that's used in this area is

10 often not used properly, so we might as well get it

11 correct right now.

12 Reliability is the reflection of the amount of

13 error, both random error and systematic, inherent to any

14 measurement. It determines who reproducible the scale is

15 under different conditions.

16 The reliability coefficient expresses the

17 proportion of the true variation that you would see which

18 is due to the subject's variability and not due to this

19 measurement error. Reliability can either be

20 reproducibility or internal consistency.

21 We use reproducibility when we want

22 test/retest reliability to look at intra- and inter-rater 1 169 2 1 reliabilities, which is very important for measure, or

2 internal consistency if we have a scale and we want to see

3 how consistent the items are within the scale. Some of

4 the coefficients we can use for reproducibility are the

5 intra-class correlation coefficient, the Pearson's r,

6 we've seen a few of those this morning, Kendall's Index,

7 kappa coefficient, and Bland and Altman plots.

8 Other considerations. If the test is always

9 done by the same observer or if the test has different

10 observers, then you've got to pay a bit of a price by

11 putting that component in the denominator. So that's

12 important when you're evaluating reliability.

13 Also, observer nested within the subjects. So

14 if several subjects are being evaluated by several

15 observers, you must take that into consideration. You

16 must use the right statistical techniques, in this case

17 ANOVA, to do that.

18 You could have multiple observations on an

19 individual, either because you've got several items on a

20 questionnaire, several observers, a repeated use of an

21 instrument, and again you have to accommodate that in your

22 coefficient. 1 170 2 1 Internal consistency essentially means that

2 are all the items that you're looking at within the scale

3 agreeing with one another, are they going roughly in the

4 same direction, and you would like to see correlations of

5 that nature. Correlation coefficients could be item

6 total, split-half, Kuder-Richardson, Cronbach's alpha.

7 These are all standard ways of looking at internal

8 consistencies.

9 We can improve reliability by reducing the

10 error variance through good training, increase the true

11 value by adding items, provided the items add information

12 and just not replicate information.

13 Validity. The degree of confidence we can

14 place on inferences being made on the scores in the scale.

15 We have something called content validity, so

16 to cover all the domains of interest. When we look at a

17 particular instrument, we want to ensure that patients and

18 physicians are comfortable that the key components are

19 being covered.

20 Then we have criterion validity which

21 basically means we have a gold standard, a criterion which

22 we can compare things to. 1 171 2 1 We also have construct validity. Construct

2 validity is there's no gold standard but we're looking for

3 circumstantial information, if you wish, and we look for

4 situations where the instrument that we're looking at

5 should correlate with other methods and does it, or

6 divergent, whether the instrument we're looking at should

7 not agree with something and it doesn't.

8 So we have criterion validity where you have a

9 gold standard, and we have construct validity where you

10 base everything on circumstantial evidence. These two

11 concepts are constantly misinterpreted.

12 There's other more sophisticated ways of

13 looking at construct validity through factorial analysis

14 and multi-trait/multi-method analysis, and I won't go

15 there.

16 To evaluate validity, we do it with

17 correlations. We do it with receiver operator curves, and

18 we can do it with using 2x2 tables on sensitivities and

19 specificities.

20 Sensitivity to change. So this is the third.

21 We've gone through liability. We've gone through

22 validity. Now sensitivity to change. What is the ability 1 172 2 1 of an instrument to detect small but clinically important

2 differences? That's what we're after. We can use three

3 types. There's many types of measures. We could just

4 simply do a t-test that compares baseline to follow-up to

5 see if things have changed. We can use an effect size

6 which is basically the difference of the mean and the

7 follow-up at baseline to the standard deviation, or we can

8 use an ROC curve. So there are different ways of looking

9 at sensitivity to change.

10 I'm going to take the FIQ just to go through

11 an exercise. It's the one that's been around since 1991

12 and you can see maybe some of these reliabilities,

13 validities, and responsiveness to change in action. When

14 they developed this instrument and published it, they said

15 they had test/retest reliability because they looked at

16 Pearson r correlations, and on repeated measurements

17 between raters, they got between a .56 and a .95 Pearson

18 relationship.

19 Content validity. They assessed the percent

20 missing data, and this is really a concern because 11

21 percent did not answer the washing by hand, 20 percent did

22 not answer the yard work, and 38 percent did not have jobs 1 173 2 1 or did not work outside the house, and so those questions

2 could not be answered as well.

3 They looked at construct validity by comparing

4 it to the AIMS in different items and scales, such as

5 physical functioning, pain, depression, anxiety, and the

6 values were not too bad. They also did a correlational

7 analysis by looking at specific measures of the AIMS

8 Impact Analog and Syndrome Activity and Tender Points and

9 found for the various items some very, very low

10 correlations and in other cases high, so it was quite a

11 range, and they did a factor analysis which also proved to

12 be not too bad.

13 They looked at responsiveness to perceived

14 clinical outcome. It was done in a paper published in the

15 Journal of Rheumatology in 2000. You can see that as an

16 individual patient perceived, they went from improved to

17 unchanged or worse. The FIQ did go in the right order as

18 they indeed got worse, as the patient perceived they were

19 getting worse. But Fred Wolfe, when he talked about the

20 FHAQ, did note that the FIQ systematically underestimates

21 the functional impairment because it doesn't handle

22 activities not usually performed by the patients filling 1 174 2 1 the form out.

2 6-minute walk in 2000. It was found when they

3 looked at the 6-minute walk in the group who were before

4 and after exercise, that they did find a statistical

5 change in the 6-minute walk. They didn't find that the 6-

6 minute walk was highly correlated with PVO2, so it wasn't

7 doing a very good job as a valid predictor of

8 cardiorespiratory fitness. They did find, though, that it

9 was highly related to the FIQ. So the 6-minute walk had

10 some nice properties but it didn't really pick up on the

11 cardiovascular, although it was responsive to change.

12 I won't go through this generic versus

13 specific. I'll skip that.

14 Overall response criteria. So now we have a

15 set of outcomes, outcomes that may be reliable, outcomes

16 that may be valid, and outcomes that may be sensitive.

17 And the question now as we're dealing with something

18 that's multidimensional: is there some way that we can

19 bring them together into a response or an improvement

20 criteria? I'm going to give you the five steps. Again,

21 those dots really aren't dots, they're numbers.

22 The first dot is number 1, where you would 1 175 2 1 look at the outcome measures and you would look at all the

2 various outcome measures that are used in the area that

3 the patients, the physicians, and other stakeholders are

4 interested in. You would look at the reliabilities, the

5 sensitivities, and the validity issues. I quoted some

6 papers there, but there are a lot of other papers that

7 have been published over the last 10 to 12 years on some

8 of these measures and some of those properties.

9 You would then conduct a survey of physicians.

10 You would provide them with information on randomly

11 selected patients from clinical trials and the thresholds

12 of what you think would be improvement. So basically you

13 would take for outcome measures of interest, you would

14 take data at the baseline. You'd take data at the end of

15 the study. You'd take percent change provided for each

16 patient. You would survey the clinicians and having them

17 indicate whether they felt the patient was improved on the

18 basis of the profile that you provided them with on the

19 core outcomes that you're interested in, and then the

20 analysis would then focus on the patients characterized by

21 the vast majority as having improved.

22 Once you did that, you would do a statistical 1 176 2 1 analysis of the clinical trial data for selecting

2 definition of improvement, and this is the point where we

3 would like to assemble appropriate placebo-controlled

4 trials with very efficacious. I put "very" in quotes

5 here. It obviously depends on the particular disorder

6 you're looking at, and that also included the measures

7 you're interested in. So the improvement criteria

8 selected that best discriminates the efficacious

9 intervention from the placebo would be further evaluated.

10 You would evaluate them in large comparative data sets and

11 then, finally, you do have to subject them to kind of that

12 face validity evaluation at the end of the day. So again

13 we take all the core measures that are reliable,

14 sensitive, valid, of varying degrees, come up with a core

15 set, evaluate them in the data sets, survey the

16 constituencies.

17 This is an example of one -- and I'm going to

18 go through this very quickly -- that actually Simms and

19 David Felson were involved with in 1991, taking

20 preliminary criteria for response to treatment in

21 fibromyalgia. They did look at a clinical trial where

22 there appeared to be an efficacious difference. They took 1 177 2 1 the treatment to be the proxy measure for response. So

2 everybody in the active treatment was considered to be a

3 responder, everybody in the other was not. They had

4 outcome measures that included physician global, patient

5 global, pain, fatigue, sleep, tender point score. They

6 then used a number of statistical techniques to look at

7 various combinations of outcome variables that they then

8 subjected to receiver operator curve evaluation to find

9 out the optimal sensitivity and specificity. They then

10 applied these to an unreported trial.

11 Now, what they came out with at that time was

12 a criteria that included physician global assessment was

13 less than or equal to 4. You can see the scale being 0 to

14 10, from well to poor. Patient sleep, less than or equal

15 to 6. Tender point score less than or equal to 14. The

16 most important point that they made in the paper was that

17 as more sensitive and clinically relevant outcomes are

18 developed, you can apply this methodology, which is really

19 a working action of what I described in theory a little

20 earlier, to refine the criteria or to develop more

21 criteria.

22 Minimal clinically important difference. It 1 178 2 1 will be so easy for me to in two sentences tell you what a

2 minimal clinically important difference is and then move

3 on and you'd have no concept any further than that. I'm

4 going to try to put it in a little bit of a context. I'm

5 going to go through this relatively quickly because it's

6 really to the side of the types of issues that we want to

7 deal with.

8 I'm going to give you minimal clinically

9 important differences in terms of what are called studies

10 of responsiveness. This is going to be a classification

11 system on how we can put studies that look at

12 responsiveness into context. I'm then going to tell you

13 about a systematic review that we did looking at the

14 various methods for minimally clinically important

15 differences. This is very key to, obviously, evaluating

16 various pharmacological and non-pharmacological treatments

17 for this disorder.

18 Studies of responsiveness essentially are

19 studies that evaluate the ability of an outcome measure to

20 accurately detect change when change has occurred. Each

21 study defines the change. It can define it according to

22 three key features. Is the change for an individual or is 1 179 2 1 the change within the group? Which data is being

2 compared? Are we interested in data that's within a

3 group, between groups, or looking over time? What kind of

4 change is being quantified, of which one of those changes

5 will be the minimally clinically important difference?

6 So the setting is who's the focus? Group or

7 individuals? Which scores are being contrasted?

8 Differences between groups, changes within groups, or

9 both, meaning that you're going to be looking at different

10 scores between two different groups, or what kind of

11 change? It goes all the way from minimally potentially

12 detectable to detectable beyond error to observed in the

13 population, something that's estimated to have changed as

14 something that is important and estimated to have changed,

15 and that's your minimal clinically important difference.

16 These three features all can be put at right

17 angles to one another and then you could have this type of

18 system. So the setting is the individual or the group,

19 what are you looking at, differences between, within, or

20 both, and then the type of change that you're doing.

21 Now, what's nice about the cube is that we can

22 take a study of responsiveness and we can look in 1 180 2 1 particular at minimal clinically important differences and

2 see where the holes are in the theory, see what's

3 available to us when we wanted to apply it to such a

4 problem that we're dealing with today. So let's take a

5 look at that survey, and we're going to put it inside the

6 cube.

7 So an MCID is considered as the smallest

8 change or difference in an outcome measure that is

9 perceived as beneficial and will lead to a change in the

10 patients' management, assuming an absence of excessive

11 side effects and costs, and that would be the two-line

12 definition I would give you if I wasn't going through this

13 process. We wanted to consider the different ways that

14 people try to derive MCIDs and look at the different

15 methods. We did the literature search. We read the

16 articles, in particular the methods sections, and then we

17 categorized it according to the cube, and this is what we

18 ended up with.

19 On the right-hand side, you can see different

20 types of methods appearing. There will be a little window

21 here that's going to give you a three-step process of how

22 it was done and then it's going to be dropped into these 1 181 2 1 cells and what you're going to find is that most of the

2 methods fall in this area which is basically that they're

3 looking at groups. They're not looking at individuals.

4 They're looking at groups and the changes within those

5 groups to define minimal clinically important differences,

6 whereas we should really try to look within the

7 individual. The methods may be more sensitive. So I'll

8 just click away and you'll see.

9 So the first one is looking at patient

10 perspectives, and it actually falls as changes within but

11 within a group.

12 The next one is patient conversation. Again,

13 it's looking at a group.

14 Clinical perspectives. We have two more, two

15 different ways of looking at it, both of them comparing

16 groups.

17 Clinical perspective again, patient scenario,

18 comparing groups.

19 Patient scenario comparison, two different

20 ways of looking at that but again within groups.

21 Finally, we get one that looks at the

22 individual which is called a prognostic rating scale, a 1 182 2 1 data-driven approach, discerning important improvement,

2 improvement criteria, and then finally achieving treatment

3 goals.

4 Again, these are the ways that you do it.

5 These are the different methods that were there.

6 The bottom line of this whole process is that

7 we do a lot with groups. We do not do enough with

8 individuals, and we need to develop more important

9 measures in that direction. So again, within this area,

10 if we can develop that within some of these measures as

11 opposed to falling back on old technologies.

12 Low disease activity state. This is a

13 relatively interesting concept, boring from trying to

14 control hypertension. If we can keep blood pressure

15 within a range that both the physicians and the patients

16 are happy about, then we consider that we're in kind of a

17 steady state. We're not looking at remission or anything

18 like that. We're just saying that I'm happy where the

19 patient is at, the patient is happy where he or she is at,

20 and we feel that we have everything in control.

21 So we've had workshops on this and to meet

22 many of the challenges that exist in trying to determine 1 183 2 1 what we mean by low disease activity state, we've been

2 concentrating in the area of rheumatoid arthritis, but

3 this is where I'm saying that we should be a little bit

4 more forward thinking and think about this as we're

5 thinking about the responder criteria.

6 So the working definition is that it is a

7 state that is deemed a useful treatment target by both

8 patients and physicians. That's what our working

9 definition of a low disease activity state would be. At

10 this particular workshop, we obtained a large number of

11 research agenda, all the way from looking at some of the

12 core criteria within the core set for rheumatoid arthritis

13 to including fatigue and sleep within that criteria, and

14 then the one I have highlighted is to design and conduct

15 an opinion-based and observation approach for determining

16 a low disease activity state for rheumatoid arthritis. So

17 if you wish, this is going beyond the ACR 20. Then we

18 wanted to finally then design and conduct a survey on how

19 we should present this.

20 So in terms of the design and conduct of an

21 opinion-based system, the steps are as follows. The

22 opinions of the physicians and patients will be collected. 1 184 2 1 Based on these opinions, we'll come up with candidate

2 definitions. They'll be composed and they'll be tested in

3 data sets. The results of this work will be collated and

4 circulated to workshop participants, and at the workshop,

5 we'll sit and we'll argue about it, both in plenary and in

6 small group sessions, and probably come up with a number,

7 hopefully a limited number, of top candidates that can

8 then be validated in the following steps.

9 And Chair, I think that that's the end of the

10 presentation.

11 (Applause.)

12 DR. FIRESTEIN: Are there any questions or

13 comments for Dr. Wells? Yes?

14 DR. TURK: Thank you for the presentation.

15 I wondered if you'd care to comment about

16 norms, which you didn't seem to pay any attention to at

17 all, as a lot of the measures that are available were

18 never developed and standardized in the appropriate

19 populations. Do you have any comment about that?

20 DR. WELLS: Yes. In particular, if you went

21 with something, such as the -- I mean, if a measure has

22 been properly developed, let's say the SF-36, where it's 1 185 2 1 been normed to the particular population, so you can look

2 at the deviation from the norm, I think a lot of the

3 measures that we look at have not been and should be. I

4 agree.

5 DR. FIRESTEIN: Thank you very much.

6 The next section was the open public hearing,

7 but since there were no requests for time, we're then

8 going to move on to Lee Simon who is going to charge us

9 with something.

10 DR. SIMON: First, I have to get my computer

11 to work. So I hope you'll indulge me for one second.

12 (Pause.)

13 DR. SIMON: Well, as it's coming up, I'd like

14 to first thank the committee members for arriving here and

15 bringing this on, as Dr. Witter noted. We are greatly

16 appreciative of you taking your time out of your busy

17 schedule to help inform us at the agency about this

18 incredibly complicated arena.

19 Secondly, I'd like to take the opportunity as

20 the first one at the end of all these invited speakers to

21 say how grateful we are that you all came under sometimes

22 unusual circumstances to give us your opinion about this 1 186 2 1 particularly controversial area.

2 As Dan Clauw noted, I come from a different

3 background than typically seen in the context of the

4 fibromyalgia background. Having been at the bench for 15

5 years, I'm a little driven by evidence and I tried to be

6 able to apply that over the years, and as a clinician,

7 seeing patients for 25 years, always became very

8 frustrated about seeing patients with fibromyalgia.

9 I think that the world has turned, however,

10 and there seems to be a significant amount of science that

11 is the underpinning of an understanding of what's really

12 going on here. So everyone has mentioned the uniqueness

13 of the moment, and it does appear that there's a bunch of

14 things that are all coming together that allow us to

15 finally begin to deal with this and give it the attention

16 that it truly deserves, considering the number of people

17 that have suffered with this disorder for such a long

18 period of time.

19 You'll notice that I actually have changed my

20 picture on my desktop. This is now a storm, and I

21 actually kind of feel like I'm in the midst of a storm in

22 my continuing career at the FDA. It's really quite 1 187 2 1 appropriate and also almost very appropriate for this

2 particular discussion.

3 So what are the challenges in the development

4 of the therapies for fibromyalgia? You've spent a

5 significant amount of time actually looking at that

6 particular question, and I'd like to point out a couple

7 things historically, in addition to what you've already

8 heard. In fact, however far we've come in understanding

9 and divining the description of disease states and

10 increasing the understanding of the biology of pain, the

11 drugs that are presently available for chronic pain are

12 basically the same drugs we had a hundred years ago. I

13 point out that opioids, non-steroidal anti-inflammatory

14 drugs and the congeners, sedatives, muscle relaxants, are

15 those things that are still being used, and clearly that

16 is just not adequate for our present understanding.

17 You've heard already that pain clearly is

18 real, but it is also subjective. I've mentioned before in

19 circumstances like this that in fact I need to be put to

20 sleep to have my teeth cleaned, whereas my wife gets her

21 teeth worked on with no novocaine. She claims that she

22 has no pain. I walk into the dentist's office, my heart 1 188 2 1 is racing, I'm sweating, and they haven't even touched me

2 yet. So everyone learns the meaning of pain through

3 experiences usually related to injuries in early life, and

4 some unpleasant experience or sensation becomes an

5 emotional experience a la my childhood experiences with a

6 dentist.

7 Pain is a significant stress physically and

8 emotionally and you've heard much about what stress might

9 do to certain genetic hosts that might lead to an

10 establishment of a disease, such as fibromyalgia. So

11 looking at ways to define chronic pain, and we've heard

12 some of this but not all of it, we turned to the Merck

13 Manual in 2002, the Centennial 17th Edition. In this

14 edition, chronic pain is defined broadly and arbitrarily

15 as pain which persists for greater than one month beyond

16 any acute injury, and in this context of fibromyalgia, we

17 may need to think about the acute injury as a stressful

18 event. Perhaps it was going to the Gulf War in 1991,

19 perhaps it is learning that your Medcat scores are not as

20 good as you'd like.

21 Persistent and recurring pain for at least

22 three months and pain expected to continue or progress may 1 189 2 1 be associated or not associated with ongoing tissue

2 injury. It has no adaptive role. It doesn't help one to

3 survive. You just suffer with it.

4 And vegetative signs and depression may

5 follow, and we've heard some of those issues, and in fact,

6 Art Lipman has gone along and suggested in this construct

7 that I'm going to show you that the psychosocial component

8 must be dealt with before depression becomes part of the

9 clinical picture. Chronic pain should be recognized as a

10 multifactorial disease state, requiring intervention at

11 many levels, and he pictures it like this.

12 You heard from multiple speakers this morning

13 that once it's happening and a patient is seen with this

14 particular scenario in a tertiary care setting, it almost

15 may be too late, that basically the construct that they

16 presently are dealing with is just untreatable in the

17 context of even alleviating their discomfort. So finding

18 these patients earlier on, perhaps in a primary care

19 arena, may allow us to obviate the eventual onset of some

20 of these things as drawn here, where here is the

21 pathologic process interacting with the physical factors,

22 then going up the scaler over time, leading to 1 190 2 1 psychological events, anxiety, depression, hostility,

2 loneliness, thus isolation and those other social factors

3 that play a role. Clearly, as you can see in this

4 reference, this is for cancer nursing, but nonetheless can

5 be easily applied to this particular scenario.

6 In addition, we at the agency have been

7 grappling and have had some significant energetic debates

8 with other divisions within the agency about how to

9 describe chronic pain. We can think of lots of different

10 ways and one of the really important ways is a la the 1992

11 Pain Guidance document which, for those of you that are

12 interested, we've actually applied for it being removed

13 from the docket so that people can't use this any longer.

14 What we are looking at here is the concept of

15 mild, moderate, and severe pain. We all use this kind of

16 jargon when we talk. We all kind of apply this in both

17 talking to our patients and trying to understand ourselves

18 suffering a particular injury and what it would mean. The

19 problem, of course, is it's extraordinarily subjective.

20 It's descriptive but does not provide rigor. Perhaps

21 these should be used to modify the concept of chronic pain

22 indication to allow patients to understand, but I'd like 1 191 2 1 to challenge the committee to help us understand how you

2 measure what is mild or moderate to severe. It's the bias

3 of us as the agency to determine what might be that

4 particular definition. It's the bias of the

5 investigators. It's the bias of the sponsors that are

6 developing the therapeutics, and of course, most

7 importantly left off of here is the bias of the patient.

8 How in the world can we determine what any one person

9 thinks is moderate or severe or mild? Perhaps it's partly

10 related to how they function, and of course function has

11 already been overwhelming trashed repeatedly by many of

12 the speakers as being something that's particularly

13 applicable to understand this particular scenario.

14 So in thinking about fibromyalgia, we've heard

15 a lot about the symptoms associated with fibromyalgia.

16 We've thought about and heard about the fact that there

17 are components of the disease, but in fact is fibromyalgia

18 a painful syndrome with pain as we've heard from even the

19 patient as the critical nature of the measure that should

20 be looked at to determine outcome, but in fact is the

21 disease a neuroendocrine disorder and pain just the

22 primary or most important manifestation, or is it a 1 192 2 1 painful condition with a neuroendocrine disorder

2 associated with it? Is wind-up an epiphenomenon or is it

3 causal, and if it's causal, is it important to measure?

4 And if it's important to measure, can we use it as an

5 indication for an outcome that you alter wind-up? Will

6 that then change the fundamental chronic process that then

7 would lead to not having chronic pain?

8 So that would take us to a concept where we

9 ask this question. Internally, we've had the debate

10 whether I should even ask this question of the committee.

11 Is this improvement in the pain of fibromyalgia or is this

12 improvement in fibromyalgia? It has enormous implications

13 because one is dealing with the syndrome of fibromyalgia

14 and perhaps its improvement, the other is dealing with

15 just a painful state, one component of that. You may be

16 able to measure a change, but is that actually improvement

17 in the whole scenario?

18 So many of you have seen these kinds of

19 scalers before, and we have typically in the agency, at

20 least in this division, thought about the concepts of

21 what's important for pain domains, not to exclude all of

22 these, but to actually think that these are the critical 1 193 2 1 ones where you measure pain relief, pain-related function,

2 and patient global. You heard this from Dr. Witter. You

3 heard this from others this morning. Clearly, all these

4 other things are very important, but what are the primary

5 ways that one would determine a primary outcome?

6 So in looking at that context, we have seen

7 these lists. Pain, patient global, health-related quality

8 of life, and physical function measures, we believe are

9 critically important in thinking about this as a scenario,

10 as a syndrome, not just the pain of. However, obviously

11 it's also important to know that perhaps these get better

12 or at least do not worsen in the context of interventions.

13 How to measure of these becomes important, and then

14 listening to three of the last speakers, I would even go

15 so far as to wonder whether or not we should be thinking

16 about perhaps just one of these measures at any one time

17 could be enough, as long as everything else didn't worsen,

18 as we begin to learn more and more and more about critical

19 measures associated with this particular scenario.

20 And then, obviously we don't want to ignore

21 what Dr. Witter reminded us about, which is the

22 mechanistic claim. Having heard some of the issues that 1 194 2 1 Dr. Crofford brought up, there are so many different ways

2 to be able to think about this in the context of the

3 science that now could be measured, perhaps now we can

4 begin to apply the mechanistic claim to some subsets of

5 patients with fibromyalgia. So measuring an alteration in

6 NMDA activity, which then might prevent wind-up, if that

7 construct is true, may be important. Maybe it's important

8 in some patients to reduce prostaglandin levels that you

9 can actually measure either in the CSF or some other

10 methodology that would be applicable, perhaps an imaging

11 methodology that would be appropriate, other measurable

12 biologic changes in chronic pain states that have not yet

13 even been defined.

14 At one of the meetings that we participated

15 in, Cliff Wolf presented extraordinary evidence in the

16 animal about an acute and chronic pain scenario, about up

17 regulation of 700 and something genes in the spinal cord

18 and down regulation of 545 genes. Clearly, the animal is

19 expending significant resources in these changes and

20 that's probably important. What those changes are and

21 what they represent elude us still, but that doesn't mean

22 we shouldn't be looking at them. 1 195 2 1 And then, clearly we have another recurrent

2 theme that comes up to us, which is, well, if you're

3 actually going to be able to measure change in these

4 chronic scenarios. Patients are not typically coming to

5 these to get therapy without having already been on

6 something, and thus could you measure a change in what

7 they have been on, suggesting that in fact that's an

8 improvement. In rheumatology, that has been traditionally

9 looked at as glucocorticoid use, meaning you decrease the

10 use of glucocorticoids, thus you're making improvement,

11 perhaps if you decrease the use of non-steroidals or

12 decrease the use of opioids in a measurable clinically

13 important way, and that might be an important measure for

14 a primary outcome.

15 Dr. Witter showed aspects of this slide, the

16 ideal characteristics of a pain metric, and I want to

17 remind you as we begin to grapple with this that we need

18 to think about it in the context that it's easy and

19 understandable by patients and clinicians. We've been

20 struck by the fact that most clinicians don't read the

21 label which is embarrassing since what the FDA mostly does

22 is define itself by what's in the label and that's 1 196 2 1 unfortunate. There's a lot of interesting material in the

2 label.

3 And clearly whatever we use as an outcome

4 needs to be able to be explicable within that construct.

5 It needs to be applicable across studies. Therefore, many

6 studies are done to help establish what you're going to do

7 for pivotal trials and under those circumstances, we need

8 to be able to use these outcomes to facilitate full

9 development, and as Dr. Clauw suggested, perhaps imaging

10 of the brain is not something that's going to be

11 applicable for a full drug development program as opposed

12 to a proof of concept.

13 It defines a clinically meaningful result.

14 It's valid, and I'm using the term "valid" in the context

15 of what Dr. Wells suggested. And it measures response,

16 again as per Dr. Wells, in a variety of pain conditions

17 and therapies, and it's achievable with current meds. I

18 would like to suggest, however, that that might be a wish.

19 It may well be that the current meds that we're talking

20 about are just around the corner and we need to be

21 flexible to understand how to measure these particular

22 outcomes. And it should be tiered to define important 1 197 2 1 differences in drugs.

2 So we heard about this issue about choosing

3 measurements of response and how it was done, and I'd just

4 like to point out that in our division, there are two

5 different models in the context of that, the OA model, the

6 RA model. The OA model, which is a model of chronic pain

7 which is used and applied by our division, is mostly a

8 local disease and presently requires these three co-

9 primary outcomes for approval, the VAS scale for pain,

10 WOMAC for function, and a patient global, and all three

11 must win; whereas, the RA model, which is a systemic

12 disease which may have local symptoms, is actually

13 measured through a responder index and you actually saw

14 the outcomes of this responder index.

15 I'd like to point out one particularly

16 important aspect of this responder index is that in the

17 first cut point here is tender and swollen joint counts.

18 I'd like to point out that this was designed with lots of

19 clinicians in mind, and we have learned something. What

20 we have learned is that physicians like to believe they

21 have an important impact on the measurement of outcome.

22 Thus, the ACR 20 is actually somewhat sullied by this 1 198 2 1 particular measure because the cut requires the physician

2 input and then in fact these are the ones that are

3 subjected to this particular outcome. I'd like to think

4 that we've moved along here and recognize that patient-

5 reported outcomes are equally as important as are the

6 physician observations and thus maybe we should be

7 thinking, if we're thinking about a responder index, that

8 we don't distinguish the importance between the two and

9 not think of a cut point in one versus another.

10 So also thinking about inclusion and exclusion

11 criteria, in thinking about the homogeneity versus

12 heterogeneity of the disease, one has to ask the question:

13 so, if we're going to try to get real good outcome

14 measures and we're going to apply them in a patient

15 population that seems similar, should we think about the

16 fact early on or later that patients who have a prominent

17 component of depression should be excluded or should be

18 included? And then, if they are included in the trial,

19 how do we handle the antidepressants that are used that

20 actually might have an impact on the outcome of

21 fibromyalgia per se, and how do we control for that? Do

22 we tier it? Do we stratify? How do we handle that? 1 199 2 1 Should we include -- and Dr. Crofford and others have

2 actually mentioned this this morning -- the patients that

3 have secondary fibromyalgia, whatever that might mean? I

4 don't mean to actually codify a scenario of primary and

5 second, but we all know there are patients who have a

6 disease as a stressor leading to symptoms of fibromyalgia,

7 and thus do we treat rheumatoid arthritis patients who

8 have fibromyalgia and then treat the rheumatoid arthritis

9 and find that their fibromyalgia gets better, thus the

10 treatments for rheumatoid arthritis should be approved for

11 fibromyalgia? I don't think that that's really

12 appropriate. So in learning this particular scenario and

13 building the field, we may have to think about excluding

14 these patients.

15 How long should a trial be? It's actually

16 quite interesting. I've actually just come back from

17 Europe where I spent some time at the European League of

18 Associations of Rheumatology Annual Meeting, and I

19 actually walked around asking questions helter-skelter,

20 kind of like how long should a fibromyalgia trial be, and

21 I could get no consistent answers. Europe has a different

22 opinion than the States. 1 200 2 1 In general, we would like to think of this

2 longer than shorter because this is a scenario, this is a

3 disease that's been around in the patient for a long time.

4 We'd like to be able to see a substantial response that

5 actually is maintained for a period of time, to know that

6 something is an important modifier of that particular

7 scenario. So we're thinking about at least three months,

8 if not six months, and then guaranteeing at least a year

9 of exposure for safety and recognizing that most published

10 trials to date have been much shorter.

11 Should a patient have decreased symptoms and

12 for how long and without therapies? So one could even

13 imagine a scenario that if you have improvement over three

14 months, can you think about low disease activity states a

15 la Dr. Wells or a cure by stopping therapy? Should we

16 require that a patient needs to have no therapy for a

17 period of time to be able to actually be improved with

18 this particular scenario?

19 And then, the other question, of course, which

20 comes up all the time is: what is the importance of the

21 tender points? Do we use it as a measure of outcome?

22 Should we use it as a criteria measure for inclusion, 1 201 2 1 based on how much disease activity they have, and thus do

2 we create a disease activity score as well as an outcome

3 score?

4 And a la Dr. Clauw, is the FIQ an adequate

5 measure of function or should, in fact, other outcome

6 measures be developed, or should we begin to look at

7 what's presently available, either in the FHAQ, the

8 Fibromyalgia HAQ, or in the SF-36 and begin to apply that?

9 And then, fundamentally, the two questions

10 really are represented by is it improvement in the pain of

11 fibromyalgia or improvement in the disease? We'd like to

12 think it's the latter and not just the pain of

13 fibromyalgia.

14 And what would a cure require? I will not

15 hold you to that question, but in fact it might be

16 something you want to keep in the back of your mind.

17 Then the other question would be: in the

18 context of doing and designing a clinical trial for

19 outcome, what would be allowed concomitantly? Would

20 physical therapy be allowed? Would structured exercise be

21 allowed? Would cognitive and behavioral therapies be

22 allowed? You've already seen evidence that there's 1 202 2 1 actually very good utility of cognitive and behavioral

2 therapy. We would have to stratify thus in that kind of

3 scenario, seriously increasing the number of patients in a

4 clinical trial.

5 Would psychotherapy be allowed in the trial?

6 Would ongoing therapy be allowed for patients who are

7 already on therapy as they recruit? These issues then

8 really do change whether or not you can recruit. How

9 could you recruit people if you don't allow some of these

10 issues? That's particularly true for the final one which

11 is medical therapy for depression.

12 So in coming to conclusion, I'd like to point

13 out that in fact what is the perfect drug and, a la Dr.

14 Witter, the perfect drug is totally safe and totally

15 effective. Unfortunately, none exist. Not one drug is

16 totally effective and not one drug is totally safe. The

17 problem with asking the question of what is safe, what is

18 the benefit-to-risk ratio? And even more importantly, who

19 should decide?

20 We unfortunately are living in a society that

21 sometimes doesn't like to grapple with the important

22 questions related to being diseased and in fact also 1 203 2 1 doesn't really understand and recognize all the time what

2 it means to have a chronic scenario that alters your life.

3 We have to make some decisions societally about what we

4 will accept as therapeutics, that we'll accept the costs

5 of those therapeutics, and part of the cost of those

6 therapeutics is not just money but safety. I don't have

7 any good answers to that.

8 But I do believe I feel like this slide, which

9 I've shown before in this scenario, like this individual

10 going to the diner and deciding, based on how much E.coli

11 might be infecting my hamburger, that in fact I have to

12 make the same kinds of decisions when I go to the counter

13 and make decisions about how I would apply drugs to myself

14 or to my patients, and I have to weigh the benefit-to-risk

15 ratio in each circumstance and kind of apply that in the

16 decision making process.

17 It's critical for us in our decision making to

18 allow our patients to understand that we actually do this

19 process on a regular basis and include them in that

20 decision making so that they can actually feel part of

21 that process in general.

22 So I think that what we're actually asking 1 204 2 1 from you is to think about these issues. The questions

2 we're going to be showing you are actually long. They

3 have multiple components to them, but your input will be

4 critical for us to be able to make the next steps in

5 thinking about fibromyalgia as a model of chronic pain and

6 thus is a model that we can use in that scenario and/or is

7 it also a disease state where we can determine a way to

8 identify an outcome for the disease or syndrome of

9 fibromyalgia.

10 So thank you very much.

11 (Applause.)

12 DR. FIRESTEIN: With that, we'll close the

13 morning session, and we will have a sumptuous lunch, I'm

14 sure. We will start again at 1:00. So that gives

15 everybody 42 minutes for lunch. We'll see you at 1:00.

16 (Whereupon, at 12:18 p.m., the committee was

17 recessed, to reconvene at 1:00 p.m., this same day.)

18

19

20

21

22 1 205 2 1

2

3

4

5

6

7 AFTERNOON SESSION

8 (1:05 p.m.)

9 DR. FIRESTEIN: So why don't we go ahead and

10 get started?

11 We have a list of seven questions that will

12 guide the discussion, and I think the easiest way to do

13 this is to just begin by reading the first question and

14 that will get us into the discussion. If you don't have

15 the questions, by the way, they're the back page of where

16 the agenda is. It should be in your stack of papers over

17 there.

18 The first question is fibromyalgia involves a

19 constellation of symptoms. The ACR 1990 diagnostic

20 criterion is based solely on the number of tender points.

21 This definition may exclude patients who clearly have

22 widespread pain, non-restorative sleep, fatigue, et 1 206 2 1 cetera, but have 10 or fewer tender points.

2 Should an alternative definition be developed

3 for fibromyalgia clinical trials with stratification by

4 number of tender points?

5 So that's really two rather complicated

6 questions. Thank you, Dr. Simon.

7 So perhaps somebody from the committee wants

8 to begin. Yes, Dr. Williams?

9 DR. WILLIAMS: I'm not sure that they want to

10 start by trying to redefine it because those criteria were

11 validated, and if you decide that you want to have a new

12 set of criteria, you're going to have to validate them

13 before you can use them. So even though it will eliminate

14 some patients, we have the same problem with rheumatoid

15 arthritis and lupus, that there are patients who have the

16 disease who don't meet the criteria, but those who meet

17 the criteria, everyone accepts. So I would not change the

18 criteria.

19 DR. FIRESTEIN: Of course, one of the problems

20 is that we now know, since the criteria were developed,

21 that those specific trigger points aren't necessarily

22 specific for fibromyalgia. As was pointed out, they 1 207 2 1 define diffuse pain.

2 DR. WILLIAMS: They were not specific.

3 However, when they did validate the criteria, they looked

4 at a lot of different tender points and these were the

5 most discriminating but they're not specific.

6 DR. FIRESTEIN: So is there general agreement

7 that we should or should not redefine the disease at this

8 point? Yes, Dr. Turk and Dr. Staud?

9 DR. STAUD: The question is with overlap. I

10 think this is an important question. So when does someone

11 become a patient with fibromyalgia and irritable bowel

12 syndrome and migraine headaches and so on?

13 DR. FIRESTEIN: One of the questions is if we

14 define solely by pain, then we have this overlap of the

15 non-patient fibromyalgia patients or group of individuals

16 versus the patients which were described earlier, that

17 there are those individuals that have tender points and

18 have pain who don't seek medical help and that would be

19 included in a clinical trial and might be a potentially

20 different population of patients.

21 Dr. Turk, did you have a comment?

22 DR. TURK: Just a comment. About eight months 1 208 2 1 ago, there was an NIH meeting in which they brought

2 together all the people who had NIH grants on fibromyalgia

3 and part of this meeting was to identify what should be

4 the directions for the future and for research, and the

5 number one thing that came up at this meeting was we

6 needed to have a new way of diagnosing or classifying

7 people with fibromyalgia, that it's really not a very

8 acceptable way that we're using right now. So it doesn't

9 answer your question as far as right now what we should

10 do. Larry, I think you were there. There were maybe 10

11 or 15 people at this meeting, all of whom agreed that the

12 classification system is really inadequate.

13 DR. BRADLEY: Well, I guess maybe I'm not one

14 of the 10 or 15. And granted, I think there's sort of a

15 problem with error variance when you make a decision about

16 is 10 tender points and not 11 tender points error

17 variance or is that something that's highly meaningful?

18 But I think if we radically alter the definition, then

19 essentially anything else that we produce in the future

20 will be based on different criteria. It'll be an

21 empirical question as to whether or not we're really

22 talking about the same phenomenon. 1 209 2 1 I think what's really interesting is that

2 there's a paper that came out in Pain several months ago,

3 and I've forgotten, I believe the first author's last name

4 was Corli, I believe. But in this paper, they compared

5 responses to about five different pain sensitivity tasks

6 in groups of patients ranging from patients with

7 myofascial pain, regional myofascial pain, to

8 fibromyalgia. There were about five groups of patients

9 all in all. The most important finding was that the

10 people who met the current criteria for fibromyalgia were

11 sensitive to all five sets of sensitivity tasks using

12 different stimuli.

13 So I think there is something about the use of

14 the 18 trigger points that really distinguishes the

15 phenomenon that we call fibromyalgia from other types of

16 disorders that are characterized by chronic pain and

17 feeling badly and so on. So I'm a little bit reluctant to

18 advocate that we radically revise the criteria at this

19 point.

20 DR. FIRESTEIN: Jack?

21 DR. CUSH: I, too, would argue strongly in

22 favor of using the ACR criteria because it's the one thing 1 210 2 1 that we do have that's rock solid, well tested, and it

2 should be the primary and only indication to get into the

3 study as fibromyalgia, whether you want other provisos on

4 top, that's okay, but these criteria have nothing to do

5 with what we're going to discuss henceforth, for which we

6 have less rigorous guidelines and validations. So that's

7 what I think is going to be the hard part of this

8 discussion.

9 DR. FIRESTEIN: But maybe there should be two

10 goals. One is in the short term use the current

11 definition and in the long term try to develop a broader

12 definition, in part because most of the things that we're

13 planning on measuring as outcomes go beyond just simply

14 counting trigger points or tender points.

15 DR. WILLIAMS: However, if you look at the

16 frequency of tender points, that exceeds the frequency of

17 inflammatory bowel disease or even chronic headaches. So

18 if you start adding too many things, you're also going to

19 start limiting your population.

20 DR. FIRESTEIN: Dr. Simon?

21 DR. SIMON: May I ask a modifying question?

22 If tender points then are going to succeed and survive, do 1 211 2 1 we then convert it into a dolorimetric measure which is

2 quantifiable rather than a finger measure which is

3 dependent upon who does it and how it's done? If we

4 believe that this is an important measure, should we be

5 developing a better quantifiable way of approaching it?

6 DR. STAUD: This is one point that has been

7 tried to be made in lots of different investigations and

8 it has been shown to be very, very difficult. First of

9 all, tender points are overlying very different tissues.

10 Most of them are tendon insertion points but some of them

11 are muscles. In most populations to identify pain

12 threshold is a very difficult task. So most of these

13 tests have failed. So the number of tender points seems

14 to be the most solid measure.

15 DR. FIRESTEIN: But isn't that how the

16 criteria that were developed, though?

17 DR. WILLIAMS: I think dolorimetry came in

18 later. I think they just did the tender points initially.

19 DR. FIRESTEIN: But how many people have had

20 the experience of going in to see a patient that the

21 resident has seen and has said that there are no tender

22 points, and then when we find the magic spots or push with 1 212 2 1 a little bit more vigor, then it becomes quite obvious?

2 So it's clearly operator-dependent. Is there not a better

3 way of standardizing this?

4 I guess we'll start over here. Yes, Dr. Turk?

5 DR. TURK: There have been several attempts to

6 develop procedures either dolorimetry or by patient

7 reports, and there are a couple standardized approaches

8 that have actually been published with standardized

9 training tapes of how to actually perform the exam. It's

10 called the Manual Tender Point Survey. I think Okifuji,

11 Terry Starz, David Sinclair, and myself were involved in

12 publishing some of those, and we showed they can be very

13 reliable by both physical therapists as well as physicians

14 performing a standardized protocol.

15 We also in that trial had patients not only

16 say yes or no, it hurt, but to rate how severe the pain

17 was and showed that the distribution of scores were much

18 better if you use a quantitative score than an absolute

19 number which was basically a normal distribution. If you

20 use the absolute number of tender points, it was a very

21 skewed distribution. So I think there is merit to

22 consider whether there are some ways, whether it's 1 213 2 1 dolorimetry or whether it's by patient ratings, that we

2 can get much more sensitive measure than just the absolute

3 number of tender points.

4 DR. FIRESTEIN: Dr. Katz and then Dr. Cush.

5 DR. KATZ: I think the other issue, though, is

6 whether that might be more appropriate for phase II rather

7 than phase III studies. My own experience of trying to

8 standardize dolorimetry in a multicenter study is that

9 it's very difficult, very time-consuming. You can never

10 train enough and there are always reliability problems.

11 However, if the distributions are better,

12 there might be some use in phase II proof of concept

13 trials, if there's an increase in sensitivity or

14 responsiveness to be gained from all that additional

15 effort, but in phase III, I would think that again you'd

16 probably want something more generalizable to the doctor

17 out there anyway who won't be doing dolorimetry. So I

18 would be opposed myself to requiring it in those studies.

19 DR. FIRESTEIN: Could you just clarify? Do

20 you mean for entry criteria or for following response to

21 therapy or both?

22 DR. KATZ: Either one. 1 214 2 1 DR. FIRESTEIN: Jack?

2 DR. CUSH: I agree in that this has to be a

3 tool which has parallels with real-life practice and

4 dolorimetry would never be done in real-life practice, and

5 Gary, when you say that we went in and found these trigger

6 points, it really isn't because we pressed harder, it's

7 because we knew where to go more often than not. It

8 wasn't because we jumped on the patient, exerted 12 pounds

9 per square inch, and I think it was just a simple blanch

10 of the finger pad. I think that it has to be a clinical

11 skill.

12 If this is clinical skill, and it's to be part

13 of the biometrics of clinical trials, then the clinical

14 trial design has to account for that in some way with

15 appropriate training and instruction at the outset of

16 those who will be the assessors, and this is what we've

17 done for RA trials. Especially in situations where the

18 person doing the assessments may not be the investigator

19 and may not be a rheumatologist, trying to standardize

20 your assessors in some way through training, I think, is

21 the best way to get around this without having to be too

22 mechanistic about it. 1 215 2 1 DR. FIRESTEIN: Although we heard earlier that

2 the location of the pain was not necessarily specific. So

3 that, that would belie what you had just commented on.

4 DR. CUSH: But getting back to Jim's point, it

5 is discriminatory, and it is part of the criteria. So

6 that's why we're talking about these tender points as

7 opposed to pain here, there, wherever. We know they hurt

8 all over. We're only going to count these 18 spots.

9 DR. STAUD: One very important point, in order

10 to decide if you want to do tender point counts or tender

11 point scores, is the tender points per se or tender point

12 scores do not really add anything to the overall

13 examination of these patients because they mostly highly

14 correlate with distress and not with measures that we're

15 actually trying to look at, like for example pain. So

16 that's why in most trials, people have gone away from

17 tender point scores. They just do tender point counts.

18 DR. FIRESTEIN: Do you mean gone away from

19 tender points as an outcome or again as an entry criteria?

20 Because most people do require it for entry criteria but

21 you don't necessarily need to count changes in number of

22 tender points as an outcome. 1 216 2 1 DR. STAUD: Actually, I was referring to using

2 the tender point scores.

3 DR. BRADLEY: Just to beat the horse one more

4 time, the dolorimeter is also operator-specific, and in

5 our lab at least, it takes anywhere from three to six

6 months to train a very bright graduate student to use the

7 dolorimeter reliably with our master doloritress. So it's

8 very difficult to use it for outcomes.

9 DR. KATZ: I'd like to raise a related point.

10 We've been talking about which criteria to use for entry

11 into the trial and we've been talking about the ACR

12 criteria, but a separate issue is whether we should

13 recommend that investigators further characterize their

14 population in some way so we can understand exactly what

15 type of fibromyalgia population they've studied. We've

16 heard already today that different populations with

17 fibromyalgia can really be on very wide range of disease

18 burden.

19 Should we require that we characterize the

20 population in terms of what proportion have irritable

21 bowel syndrome, have migraine, have some of these other

22 features? Because that might make different trials 1 217 2 1 comparable or not comparable. Should we require that

2 there be some assessment of their severity of depression

3 or mood disturbance at baseline, so that we can know

4 whether we're comparing apples with apples when we look at

5 different studies?

6 DR. FIRESTEIN: Jack?

7 DR. CUSH: To answer Nate's point, I would

8 suggest that along with this entry, belief in this entry

9 criteria, I think we should make strong statements about

10 exclusions to try to again unify the population. I think

11 that I wouldn't discount symptoms that may go along with

12 the disease, but I would try to eliminate confounders of

13 the disease. So whether that be uncontrolled psychiatric

14 illness, for instance, patients who have over-reliance on

15 narcotics. There are many issues that we may want to

16 exclude at entry to try to unify the population, and I

17 think that that's important and maybe even drugs might be

18 a key exclusion to being in the study.

19 DR. FIRESTEIN: Lee?

20 DR. SIMON: Well, it's all very interesting

21 that you've now pointed these out, both Nate and Jack. So

22 of those things that you would leave in, would you 1 218 2 1 stratify for them, recognizing what that would mean from a

2 numbers point of view and the implications of that?

3 Obviously, to allow you to have a larger population, not a

4 smaller population.

5 DR. KATZ: My own thought would be not to

6 stratify. My own view of stratification is when you have

7 robust knowledge that something is a clear-cut prognostic

8 variable and you have some sense for in what way it might

9 be prognostic, then it makes sense, but with these things,

10 I think we have a general sense that people that are

11 sicker will probably not do as well, but right now, it's

12 just observational, I think.

13 DR. FIRESTEIN: Dr. Williams?

14 DR. WILLIAMS: I would agree. I think that if

15 you start stratifying for these other various variables,

16 that you're going to have unmanageable numbers required.

17 At least in my population, pain is the most prominent

18 feature, and if you're going to evaluate for pain, that's

19 a whole different set of variables than if you're

20 evaluating for irritable bowel.

21 MS. MATALLANA: Also, we hear from the

22 patients quite often that they're upset that they are not 1 219 2 1 able to participate in clinical trials because they're on

2 certain medications and things, and because of that,

3 there's the fear that there are groups of people that

4 maybe have more severe symptoms that are not being

5 included in the clinical trials.

6 DR. CUSH: You might want to stratify for

7 medicines, so people who are on tricyclics or SSRIs, that

8 may be important because they may have some pain

9 modifiers, but I think you have to decide whether you're

10 going to allow pain modifiers. Should people who are on

11 background amitriptyline or terazadone be allowed in a

12 trial? That's an important factor, and I think that other

13 clinical symptoms which are basically manifestations of

14 disease and more severe disease will have more of those

15 IBD or numbness or headache or back pain or TMJ, whatnot

16 are not as important.

17 DR. FIRESTEIN: That question in terms of

18 concomitant medicines is going to come up with one of the

19 later questions. We'll probably discuss that because

20 that's one of the major issues in terms of designing these

21 studies.

22 But in terms of stratifying for number of 1 220 2 1 tender points, I think, is there general agreement that

2 that's not going to be particularly useful?

3 DR. WILLIAMS: I understood Lee's question not

4 only stratifying by number of tender points but

5 stratifying by other associated conditions.

6 DR. FIRESTEIN: Right, although the actual

7 question as originally stated was by tender points, and

8 then the second question is whether or not one looks at

9 different subpopulations as just pain or pain with

10 concomitant syndromes, like cognitive impairment, et

11 cetera.

12 Lee, did you have another comment or question?

13 DR. SIMON: No.

14 DR. FIRESTEIN: So.

15 DR. HOFFMAN: A question, Gary?

16 DR. FIRESTEIN: Yes.

17 DR. HOFFMAN: Not being someone who has

18 studied fibromyalgia in a pharma way, a question for some

19 of the panelists who have would be related to the

20 specificity of the current ACR criteria.

21 What hasn't come up today is the patient who

22 perhaps comes in with a dozen trigger points but perhaps 1 221 2 1 not any of the specified 18 and these are non-articular

2 and do not follow a pattern of peripheral inflammatory

3 disease. What kind of specificity is lost if such people

4 are included, if they have other characteristics that

5 we've listed here, non-restorative sleep, fatigue,

6 headaches? Are we losing from some of these studies a

7 significant number of people who should be included?

8 DR. FIRESTEIN: Are there any comments?

9 DR. STAUD: Yes. I think really one of the

10 hallmarks of fibromyalgia is widespread pain and

11 widespread tenderness. So I think the distribution and

12 number of tender points or the number of tender points

13 really expresses the widespread distributions is extremely

14 important. So we couldn't really cut back and say we

15 don't care where tender points are measured or tender

16 areas. It has to be in a widespread distribution as

17 originally defined by the ACR criteria. It should be.

18 DR. CUSH: But I think adhering to the ACR

19 criteria which are not dependent upon fatigue and

20 cognitive impairment but instead are dependent upon

21 widespread pain and its definition, if you meet that, then

22 I think the stringency is not that different than what we 1 222 2 1 have for RA, that you are going to get patients with more

2 severe disease, but then again there may be patients with

3 enough severity or enough pain that it's also modifiable

4 by some intervention.

5 So while we're going to miss a lot of people

6 in the real world -- they're poorly characterized but

7 nonetheless are going to get treated in the real world --

8 I still think that sticking to more rigid criteria allow

9 you to work with the data in a way that's going to either

10 show the benefit or non-benefit of an intervention.

11 DR. FIRESTEIN: Well, the group has spoken.

12 DR. WITTER: Could I just ask maybe for a

13 little bit more discussion, and it might be useful then

14 for the other questions? If we are to evolve in terms of

15 an approved outcome or inclusion criteria or definition

16 for fibromyalgia, suggestions on how that would be done in

17 trials that come to us? This might be a safe place to

18 begin that discussion.

19 DR. CUSH: Could you rephrase that?

20 DR. WITTER: Well, it's nice to say that while

21 we should come up and develop this, that, or the other

22 thing, but I think in this area in particular, as we're 1 223 2 1 moving forward, we don't have the luxury of the

2 experiences that we had in RA or OA and that we may have

3 to do more or less kind of real-time validation of new

4 whatever it is.

5 Could you begin to discuss that maybe now? Is

6 this the place? Would you like to entertain that? On how

7 we on this side of the fence could encourage that kind of

8 a process and not compromise what it is that we see?

9 DR. FIRESTEIN: Jack?

10 DR. CUSH: I think you have to go with our

11 primary outcome variable, and with RA and other diseases,

12 we have composite measures, and I think that this is a

13 syndrome that has many facets to it, to stick to only pain

14 as a single outcome variable by whatever measure would be

15 a major mistake. I think that we should invoke pain as a

16 primary outcome that must be achieved but others as well,

17 and so whether that is sleep, function, fatigue, I

18 wouldn't go much beyond that. I wouldn't want to start

19 listing headache and numbness and TMJ and IBS and all the

20 other things that go along with it, but I would try to

21 choose those features of the disease which are major --

22 they may be inter-related amongst each other. Pain and 1 224 2 1 fatigue go together. Sleep and pain go together.

2 Nonetheless, I think that they may also have their

3 independent contributors to the disease.

4 So an intervention or set of interventions

5 that could improve more than one domain is what I think we

6 should be going after.

7 DR. FIRESTEIN: Dr. Katz?

8 DR. KATZ: Just a clarification, Jim. I heard

9 you ask about developing improved diagnostic criteria, but

10 I think Jack's point was addressing mainly developing

11 outcome measures. So in terms of your question about

12 entry criteria, I think we have to ask ourselves whether

13 it's appropriate for us to require that sponsors of

14 studies develop new diagnostic criteria for fibromyalgia.

15 As Dennis has already said, there are already

16 efforts going on in that regard or that hopefully will go

17 on at the NIH level, and obviously whatever we develop has

18 to be responsive to improve diagnostic criteria that

19 develop. But as far as entry criteria go, I think we need

20 to decide whether it's our role to require somebody to

21 develop a new entry criteria.

22 Outcome measures, I totally agree with what 1 225 2 1 Jack is saying. I think it would be more appropriate

2 there to encourage sponsors of research to develop

3 appropriate outcome measures for the medications that

4 they're trying to get approved, but for entry criteria, I

5 don't feel the same way.

6 DR. FIRESTEIN: But was your question

7 primarily at entry criteria or outcomes?

8 DR. WITTER: It's really a general how-to

9 question. Outcome variables, anything to move this

10 disease in particular forward. It's really a question of,

11 in terms of from our end, how do we do it? What are the

12 ways that would not come up with undue burdens to the

13 sponsors, would not be compromising what's going on in the

14 research community in general. I think we're searching

15 for ways that we can be helpful in the process but not be

16 burdensome, and so I think it's a how-to question more

17 than anything.

18 DR. FIRESTEIN: You're precisely right that

19 it's going to end up being real time, and although we have

20 acceptance of the ACR criteria, for instance, for RA, it

21 is still being re-evaluated constantly real time, and

22 there's some discussion as to whether or not measuring 1 226 2 1 tender and swollen joints adds anything to some of the

2 other outcome measures.

3 So I think what in the end is going to happen

4 is we take our best guess at what makes the most sense,

5 and those would include a few different domains that have

6 been discussed, including pain, patient global

7 assessments, and perhaps some measure of patient function,

8 and then use that to go forward and then have to, again,

9 validate it real time.

10 Jim?

11 DR. BRADLEY: I think with regard to the

12 question of function, I think expecting that a trial of a

13 pharmacologic compound to change function over a very

14 short period of time would be very unrealistic, and I

15 think it would be overly restrictive in terms of measuring

16 outcome. I think one has to remember that apart from the

17 measurement problems of function that were described this

18 morning, function in the patients who come for treatment

19 and patients who would enter these trials, functional

20 disability is in part determined by long periods of

21 sitting and inactivity and it's a whole conglomeration of

22 factors that influence current physical function. 1 227 2 1 So I think to expect any compound to change

2 function in a short period of time would be really

3 unrealistic, and I think it'd really be much more

4 appropriate to focus on alterations in pain and

5 alterations in global assessment.

6 DR. FIRESTEIN: Lee?

7 DR. SIMON: So we've actually moved on to

8 question 2.

9 DR. FIRESTEIN: I was going to say. We're

10 well into question 2 right now, which relates to would it

11 be reasonable to expect that a product that is truly as

12 efficacious, but I assume you mean effective, --

13 DR. SIMON: Yes, but we don't use the term

14 effective in this world.

15 DR. FIRESTEIN: I understand. For the

16 treatment of the syndrome would show improvement in pain,

17 some measures of physical function, and the patient global

18 assessment, and then what would be the optimum duration?

19 Because as you pointed out, a short duration trial might

20 improve patient global assessment but might not have an

21 impact on patient function.

22 DR. SIMON: And I'd like to address that 1 228 2 1 particular issue since in fact we had a recent meeting in

2 the rheumatoid arthritis arena to discuss the issue of

3 physical function, and we presented evidence that within

4 16 weeks -- so thus 4 months and remember we're talking

5 maybe a 6-month trial here -- that in the context of a

6 chronic disease with structural implications, you can

7 actually against placebo measure differences in

8 improvement in physical function. For those of you on the

9 committee who will remember that discussion just two-three

10 months ago.

11 That's actually a very important point. In OA

12 and RA, there's a high correlation between pain and

13 function. The functional outcomes are robust and well

14 developed. Those measures are robust and well developed.

15 The FIQ, you've already heard about here, has not been a

16 terrific instrument, based on the particular activities

17 that people are doing today and thus might need to be

18 addressed. Nonetheless, we know at least using the FIQ

19 that there isn't a great correlation between pain and

20 function.

21 I find that a little weird. I think that in

22 almost all other circumstances, there's a tremendous 1 229 2 1 correlation between pain and function. So I don't

2 understand if it's unique to fibromyalgia that there's not

3 or it's just that it's a lousy functional measure and

4 that's why there's no good correlation. So we at the

5 agency are uncomfortable in thinking about an improvement

6 in a scenario such as fibromyalgia that does not include

7 some measure of function as pain improves.

8 We have actually had an example of a therapy,

9 based on trial design which was statistically significant

10 improvement in pain of several millimeters in measurement,

11 but in fact in the concept of function failed miserably in

12 a traditional realm where function and pain are linked.

13 So we are very uncomfortable in not looking at this as a

14 gestalt rather than just the pain of.

15 Might we entertain a little discussion here

16 about whether or not there is any linkage between pain and

17 function, and if there is, should there be a requirement

18 that we begin to work on a different kind of functional

19 assessment that might be better or unique and give us a

20 better correlation? Not because we're just trying to

21 create the better correlation, because we're trying to

22 measure the overall state of the patient. 1 230 2 1 DR. FIRESTEIN: Dr. Cush?

2 DR. CUSH: Lee, would you accept a quality of

3 life measure as a functional measure as well? So like SF-

4 36 in whole and then take out the physical component in

5 part. What's your comment on that?

6 DR. SIMON: I think that I have been educated

7 by any number of brilliant people to be convinced that

8 health-related quality of life measures are similar to

9 function but not always the same. SF-36 as a generic is

10 not necessarily not applicable to specific diseases, and

11 HAQ, which is supposedly non-generic, might be generic,

12 depending on the circumstances. So I think that this is

13 an evolving field.

14 I think I've learned to think of the SF-36 as

15 a very good measure, a very robust measure. You have to

16 be specific about which components of it you can use. It

17 has not been validated in all these diseases, but every

18 time I look at it being applied to various different

19 syndromes and diseases, when done correctly, it looks like

20 it discriminates and is valid.

21 So under those circumstances, I would not

22 distinguish, and I think that if a generic measure, such 1 231 2 1 as the SF-36, is proven to be useful and have utility, I

2 think that would be great.

3 DR. FIRESTEIN: One doesn't necessarily need

4 to have an improvement in function in order to have a drug

5 approved for rheumatoid arthritis.

6 DR. SIMON: No, and that's a very interesting

7 point. From an educational point of view, we approve

8 drugs for a separate indication, meaning there's the

9 indication of signs and symptoms, there's the indication

10 for x-ray progression, meaning inhibition of x-ray

11 progression, and a separate indication that the sponsor

12 has to go for for the improvement of physical function,

13 and that's exactly right.

14 We could create the same scenario here and not

15 just apply that in the context of improvement of outcome.

16 However, the caveat to that is the HAQ is now being

17 considered as very important for even getting signs and

18 symptoms, and we're actually evolving to consider that all

19 studies in rheumatoid arthritis would have to include some

20 physical function outcome, even though it may not be

21 measured or expressed in the HAQ.

22 DR. FIRESTEIN: Does anybody have any comment 1 232 2 1 on whether or not there should be a separate physical

2 function component that's required for fibromyalgia? Yes?

3 DR. TURK: To answer part of your question,

4 Lee, in back pain area as an example, there are lots of

5 data to show that the correlation between function and

6 pain is about .3 and there are studies in neuropathic pain

7 to show that the relationship between pain and function is

8 fairly low. So I don't think it's unique to fibromyalgia

9 that there isn't a high correlation between pain and

10 function. What that says to me is that function is an

11 important outcome that should be considered, in addition

12 to looking at pain.

13 Unlike Dan Clauw who's left, his last

14 statement that if there was a treatment that was effective

15 in reducing pain but had no beneficial effect on function,

16 he would view that that's positive. My response would be

17 to have someone who's a 45-year-old person with a 7-year

18 history of fibromyalgia who had a statistically

19 significant improvement on pain but then said but I'm not

20 doing anything any differently and not functioning any

21 better, to me, that's not a great outcome.

22 Now, we could debate and I'm sure you might 1 233 2 1 argue with me about that, but at least it does speak to my

2 concern that I agree with you. I think that we should

3 come up with some measure of function, whether it's the

4 FIQ, we could again talk about that, but I don't think

5 that we should take pain -- I disagree with Larry. I do

6 think you could take functional changes because it depends

7 on how you're defining function, Larry. If you're talking

8 about lifting huge amounts or walking great distances, you

9 might not expect to see that in a couple weeks, but if

10 you're talking about improvement of sleep and improvement

11 in ability to do things around the home, in fact, you

12 might see those kinds of changes. So it really depends on

13 how you're thinking of function.

14 DR. BRADLEY: Yes, I agree with you on that

15 point, Dennis.

16 DR. FIRESTEIN: Lynne, Jack, and then Jim.

17 MS. MATALLANA: From the patient's viewpoint,

18 our survey showed that even 20 percent improvement in pain

19 would be a worthwhile outcome. I agree, that I don't

20 think pain has as much of an effect on functionality. I

21 think the fatigue issue does. But at this point, we don't

22 have many options for fatigue improvement. So if we can 1 234 2 1 eliminate the human suffering of pain, I think that the

2 benefits would be tremendous to the patient population.

3 DR. CUSH: I think that we have to sort of

4 move forward. In the past, with all of the diseases we

5 consider, we have always done short-term trials, single

6 variable outcomes, mainly looking to improve a single

7 symptom or a group of symptoms, and I think the trend has

8 been at the FDA and as mandated or required by clinicians

9 and researchers that we should go towards longer-term

10 trials with multivariate outcomes which are more true to

11 life that actually don't speak to symptom improvement,

12 really to true disease improvement, and that that has

13 long-term implications that impact on a patient's life and

14 employability and whatnot.

15 I think that we should go toward a functional

16 indication. I think that since we don't know which is the

17 best, I think that the FDA should accept a group as being

18 reasonable measures, whether it's the four being the FHAQ,

19 SF-36, FIQ, or even WOMAC, and require a sponsor to do out

20 of those four. And if you improve in one, that's good

21 enough. Overall, it shouldn't be function and pain

22 because, as has been said here before, there are people 1 235 2 1 that may not improve their function, even in a 6-month

2 trial.

3 So again, going towards a multivariate

4 definition, we should require function as one of several

5 measures that we may accept. Pain is first and we may

6 accept some others as being part of some overall

7 definition that we're going to call a response in

8 fibromyalgia.

9 DR. WILLIAMS: I don't have a lot more to add,

10 except I agree with both of them.

11 I have a question on what Jack said. I would

12 not require long term on the initial studies. I would

13 require 3 to 6 months with longer-term follow-up to see

14 how long the response lasted, but I wouldn't require them

15 to show benefit over a 1- or 2-year study like we do in RA

16 now. And I agree that I think physical function is an

17 important variable.

18 MS. McBRAIR: I also agree that physical

19 function is important. You're talking about younger

20 people. They have a long life ahead of them, and we need

21 to see them make some progress in that area. However, as

22 long as it's part of a number of variables like Dr. Cush 1 236 2 1 mentioned, I think I could be comfortable with that.

2 DR. FIRESTEIN: Nobody is disputing that

3 physical function is important. The question is: is that

4 going to be a primary outcome? If you improve symptoms,

5 for instance, is that good enough to get a drug approved?

6 The gold standard would be that not only would symptoms

7 improve but also people would have improved function, go

8 back to work or whatever, but is that going to be the

9 standard to which anything that gets approved for myalgia

10 be held?

11 Jim?

12 DR. WILLIAMS: I think pain has to be the

13 primary outcome measure. That's what the patients are

14 complaining of, but I think an important other measure

15 would be physical function and patient global assessment

16 which would include the fatigue and everything else.

17 DR. KATZ: I'd like to emphasize and maybe

18 elaborate a little bit more on that proposal with an

19 analogy.

20 If you think of something like pneumonia where

21 somebody has chest pain, cough, fever, sputum production,

22 whatever, if you give them morphine, it's going to help 1 237 2 1 with their chest pain. It's going to reduce that symptom.

2 It's going to reduce their cough, but you wouldn't call it

3 a treatment for pneumonia. Yet, thank God, it's there and

4 we should be applying it to people with pneumonia or

5 something like it, codeine, dextromethorphan, what have

6 you.

7 Likewise, if there's a treatment that improves

8 the pain of fibromyalgia, I think that we should have some

9 mechanism by which that medication can be made available

10 to the patients who just told us that they'd be happy to

11 see something like that come down the pike. So my own

12 thought is that we should have a label that says improves

13 the pain of fibromyalgia, and I don't know, maybe we

14 should even extend that to the fatigue of fibromyalgia or

15 other things. I guess it could get complicated.

16 But then, in addition to that, recognize that

17 there are treatments for pneumonia and if something does

18 reduce the whole symptom complex of fibromyalgia, it

19 reduces the patient's pain and fatigue, cognitive

20 dysfunction, whatever, and we feel that by some

21 biologically plausible mechanism, it's actually addressing

22 the underlying disease, well, that should be further 1 238 2 1 recognized by a label that says this is a treatment for

2 fibromyalgia and, obviously, it will reduce the symptoms

3 that go along with that disorder.

4 DR. FIRESTEIN: Dr. Anderson, and then Dr.

5 Lasky.

6 DR. ANDERSON: I just wanted to say that

7 although pain is of primary importance, the question

8 before us is whether if a product is supposed to be truly

9 efficacious for the treatment of the syndrome, you should

10 expect it to show improvement in pain, physical function

11 and patient global, and I would answer yes to that.

12 DR. LASKY: My concern would be the definition

13 of functionality because I've heard agreement around the

14 table that certainly improvement in functionality is a

15 positive outcome. There's no question about that. But

16 without clear definitions of what would constitute

17 functionality, I think the manufacturer would be at a

18 specific disadvantage.

19 In addition, in terms of the length of the

20 study, it's possible that pain relief may occur first and

21 functionality later, and by continuously monitoring

22 patients, the trials can continue after the drug has 1 239 2 1 already come to market. But in order to make that claim

2 for an indication, there has to be a line in the sand

3 defining, in fact, what functionalities would be

4 approvable by the FDA.

5 DR. FIRESTEIN: So, Lee, would the agency

6 consider dividing things up as has been commented upon,

7 where you have the pain and fatigue of fibromyalgia versus

8 fibromyalgia as a global indication?

9 DR. SIMON: Well, I think that we'll consider

10 anything that the committee suggests. That's why we're

11 here. We have no preconceived notions. That's the other

12 reason why we're here. A responder index might be exactly

13 the way to go about doing this in the context of each of

14 those areas, the pain of, the fatigue of, the blah-blah-

15 blah of, and we are partial to that in a multidimensional,

16 multisystemic disorder, such as this one. It has a lot of

17 logic to it.

18 What doesn't have a lot of logic is to have to

19 create a bar where you have to win on multiple things that

20 there's a lot of argument about.

21 DR. FIRESTEIN: I think most people would

22 agree with that. 1 240 2 1 Yes, Jim?

2 DR. WITTER: Can I just have a bit of a

3 discussion then on the pain metric itself in terms of, I

4 had mentioned earlier, we're always concerned about

5 overpowering of studies, that you can get a statistically

6 important result, but it has no clinical meaning. John

7 Farrar has come out recently with something suggesting

8 that a 33 percent effect size is what you should shoot for

9 in a chronic pain condition.

10 Could I have some discussion on if it's the

11 pain component, what should that look like?

12 DR. FIRESTEIN: Sure. Who would like to

13 comment on the pain component? Dr. Katz?

14 DR. KATZ: Dennis and I are having a secret

15 visual communication.

16 (Laughter.)

17 DR. KATZ: We just finished having this

18 IMMPACT meeting that has been alluded to several times,

19 and I think Jim, you were there, and just to reiterate for

20 the rest of the group, that's a group of people who spent

21 a lot of time reviewing all of the pain measures that have

22 been used for chronic pain clinical trials. Basically the 1 241 2 1 long and the short of it is that after that extensive

2 review, that group came up with a recommendation of if

3 we're looking for a unidimensional pain intensity measure,

4 then a 10-point numerical rating scale was, for a variety

5 of reasons, the recommendation.

6 DR. CUSH: How much improvement required?

7 DR. KATZ: The issue of what's a clinically

8 significant improvement is a completely different question

9 and to comment on that, it seems to me that the proportion

10 of reduction of pain intensity that's clinically

11 significant depends somewhat on the scenario. John Farrar

12 has work related to neuropathic pain and also to cancer

13 pain, just those two entities, but we don't have any

14 evidence that those results necessarily extend to other

15 areas.

16 My understanding of that same issue in the

17 acute pain literature where people have tried to compare --

18 say, for example, with the stop watch techniques where you

19 see when the patient clicks the watch is meaningful versus

20 what the pain intensity difference is, my understanding is

21 that it's closer to a 50-percent reduction in acute pain.

22 And in our own study on chronic low back pain, 1 242 2 1 looking at a non-steroidal anti-inflammatory drug -- we

2 haven't published this yet but we're working on it, and it

3 looks also like it's more like about 50 percent relief.

4 It correlates with the patient global improvement of

5 meaningful.

6 So I think that if people wanted to find what

7 the clinically significant differences are in

8 fibromyalgia, it will have to be defined in the context of

9 the specific field.

10 DR. STAUD: I was wondering if you could

11 elaborate on this somewhat more, because I think most of

12 us are aware of the problems with 10-point scales

13 regarding linearity and comparison. So you could easily

14 have someone who improved from a 9 to an 8, and the

15 difference from 9 to 8 may be much less than a difference

16 from a 4 to a 5. So I think for this reason, VAS scales

17 have shown in multiple validation trials to have linearity

18 and seem to be a better measure of change compared to 10-

19 point scales.

20 DR. KATZ: Dennis, I don't know if you want to

21 comment on that. My understanding is that there are some

22 studies that suggest that the VAS is a ratio scale whereas 1 243 2 1 the numerical scale doesn't have quite those ratio

2 properties, but that in practice they both do exactly the

3 same thing. Dennis, I don't know if you want to elaborate

4 on that.

5 DR. TURK: I'm not sure I want to elaborate,

6 but the IMMPACT process did commission a background paper

7 that addressed that particular issue, and in addition to

8 raising the point that Nat just made about the linearity,

9 and it looks like it's basically the same, whether you

10 have a 10-point numerical scale or the visual analog scale.

11 There are several studies showing, especially

12 with older populations, difficulty using visual analog

13 scales and not understanding how to use mid-points and

14 tend to use extremes. So the IMMPACT group recommended

15 against using visual analog scales, mainly because of the

16 difficulty with using it across populations of different

17 ages.

18 DR. FIRESTEIN: Jim?

19 DR. WITTER: Could I press Nat a bit to expand

20 upon your earlier comment then? If fibromyalgia should be

21 viewed differently from other chronic pain models, I'll

22 use that term, why should that be the case in terms of a 1 244 2 1 33 percent with, let's say, lower back pain? I mean, why

2 should this be different?

3 DR. KATZ: Well, I think it's an empiric

4 question. If the question is what percent reduction in

5 pain intensity is best predictive of the patient global

6 response as being good to excellent or better or

7 meaningful on a stop watch of wherever you decide the

8 patient is going to report to you their own sense of

9 whether their response is meaningful, to me, it's an

10 empiric question as to whether that number is the same

11 across multiple different disease entities. I don't think

12 there's any reason to think that God made it that way and

13 that it has to be the same across all different disease

14 entities.

15 In terms of what data exists to address that

16 empiric question, the only data that I'm aware of is John

17 Farrar's work with the pregabalin in neuropathic pain and

18 the work he did with the Actiq lozenge where he showed

19 that if you use the metric of the patient's behavior of

20 taking a second rescue dose as a sign of meaningful

21 analgesia, a 33 percent reduction of the pain intensity

22 that they started with at the time of that breakthrough 1 245 2 1 episode was the degree of pain reduction that best

2 predicted that the patient would not need to take a second

3 rescue dose. So two different ways of getting at the

4 clinical meaningfulness question. Both miraculously gave

5 about a 33 percent reduction as the answer which is

6 interesting that it's so consistent but still doesn't

7 prove that it's going to be the same in other disorders,

8 and we have these counter-examples.

9 My understanding in the acute pain scenario is

10 that in fact it's not 33 percent but it's more like 50

11 percent, and our preliminary work with chronic low back

12 pain and NSAIDs suggests that it's more like 50 percent.

13 The other issue is that we don't have any

14 reason to believe that it's the same across drugs. The

15 amount of reduction in pain intensity that may be

16 associated with a patient rating of satisfaction may be

17 different with opioids and with NSAIDs. My own sense of

18 the literature, having looked at that informally, is that

19 probably patient satisfaction may be associated with a

20 lower pain intensity difference with the opioids which may

21 independently modulate affective components of pain

22 compared to the NSAIDs. So there's no reason to think 1 246 2 1 that it's the same across all these different situations.

2 In fibromyalgia, if there's literature that

3 directly assesses the degree of pain reduction that's best

4 correlated with patient global assessments, I'm not aware

5 of it, but it would have to stand on its own for

6 fibromyalgia, I think.

7 DR. FIRESTEIN: Dr. Gibofsky?

8 DR. GIBOFSKY: I don't pretend to know what

9 metric should be used to measure pain and since I don't

10 know what metric should be used to measure pain, I don't

11 know what the MCID for that metric should be, but the one

12 thing I would argue strongly for -- and I'm influenced by

13 what Ms. Matallana had to say -- is that whatever metric

14 we recommend should be one that can be simply applied and

15 utilized by the non-specialists. Our patients are telling

16 us that they want care from a non-specialist and most of

17 the trials will be done by the non-specialists.

18 The incidence and prevalence data of

19 fibromyalgia suggest that it's just not possible for all

20 of our patients to be seen by any of the specialties

21 represented here today, and so we need metrics that go

22 beyond the sophistication of the specialists that can be 1 247 2 1 easily applied.

2 The dichotomy between the devices that we

3 determine for clinical trials and the actual data that we

4 collect in clinical practice is often quite wide, and I

5 think it would be problematic if we devise metrics for

6 clinical trials that could not easily be adapted to

7 clinical practice, particularly by non-specialists.

8 DR. FIRESTEIN: The number that came from your

9 study was approximately a 20 percent improvement, and I

10 think that's a reasonable place to start when trying to

11 sort through. That is, what do patients find would be a

12 clinically meaningful improvement in terms of at least

13 pain? I mean, that number needs to be validated in some

14 way obviously, but at least it's a reasonable starting

15 place. You know, from an empiric perspective, amounts

16 like 50 percent sound to me to be too high of a bar in

17 terms of trying to achieve in a clinical trial.

18 Jack?

19 DR. CUSH: I agree with those comments, and

20 moreover, I think that the studies that I think Nat is

21 talking about are using pain as primary outcome variables,

22 and here, pain would be part of a composite definition, 1 248 2 1 wherein such stringency is really not required. A lower

2 level or minimum threshold of 20 percent could be

3 reasonable if linked to a sequence of other "if"

4 statements that then lends further credence to that

5 initial 20 percent in pain improvement.

6 DR. FIRESTEIN: Dr. Witter?

7 DR. WITTER: Just two things on clarification.

8 In acute pain, the discussion I think we should -- if we

9 wander into acute pain, we should do so carefully.

10 There's no argument, I think, from our end that in an

11 acute pain setting, pain and function are essentially the

12 same thing, and it's a very different setting, being post-

13 op, I think you would agree, than having fibromyalgia. So

14 I think we should wander into that carefully.

15 I just wanted a clarification. The 20 percent

16 that we're referring to for fibromyalgia, that is the 200

17 responses from the 16,000 actually sent out?

18 MS. MATALLANA: We sent out 16,000. We had

19 1,119 responses, of which 200 we were able to tally, and

20 of that 200, 20 percent was the majority figure of needing

21 to have improvement at that point.

22 DR. WITTER: Thank you. 1 249 2 1 DR. FIRESTEIN: I mean, that's obviously a

2 very limited sample, but it does make some empiric sense

3 that that's the general range that people might find

4 useful in a treatment that had minimal side effects.

5 Just to come to the second part of the

6 question in terms of the duration of clinical trials, most

7 of the numbers that have been tossed about have been sort

8 of in the 3- to 6-month range. Is there a lot of

9 discussion on that? Of course, Dr. Cush.

10 DR. CUSH: I think to go anything less than 6

11 months would be a mistake, but at the same time, I do

12 think that whatever guidelines we put forth, that they

13 should be ones that are, A, meaningful but also, B, tend

14 to promote investigation and drug development in this

15 area, and so to develop too many hoops to jump through for

16 studies that are too long, then who cares if there's 10

17 million people with the disease. We're just not going to

18 go there. We'll go after simple pain indication and do it

19 that way. So I think that again if 3 months actually

20 improves the likelihood of that, then fine, but I think

21 ideally 6 months should be the minimum.

22 DR. FIRESTEIN: Yes, I would agree with that. 1 250 2 1 Jennifer?

2 DR. ANDERSON: I'd just like to comment that I

3 agree that 6 months is a good length, but for these sorts

4 of trials, that you presumably would have multiple

5 observations made during the trials, so you could

6 determine how long it took for the drug to begin to be

7 effective, so that the speed of action could also be

8 determined.

9 DR. FIRESTEIN: Gary?

10 DR. HOFFMAN: I agree with Jack that 6 months

11 seems like a reasonable minimal period of time, but the

12 question is what would be the optimal duration, and given

13 that this is a chronic disease and that the drugs that are

14 going to be tested may be agents to which there is some

15 adaptation and loss of effect over time, I think it'd be

16 terribly important to know what the treatment response

17 curve was over a more chronic period of time. So I'd be

18 in favor in responding to the charge of what would be

19 optimal duration to be thinking more in terms of a year.

20 DR. FIRESTEIN: Why don't we move on to the

21 next question then, which is not posed with equipoise. It

22 says: does the committee agree that placebo-controlled 1 251 2 1 studies with analgesic rescue are a primary requirement in

2 fibromyalgia?

3 I think placebo-controlled studies are a

4 reasonable approach to this, Dr. Simon. Does anybody

5 disagree with that? Dr. Simon disagrees with his own

6 question.

7 (Laughter.)

8 DR. SIMON: If we are to accept the

9 possibility of true placebo-controlled trials, what does

10 that mean to everybody around this table? What would be

11 the background therapies that would be acceptable in that

12 there is really no standard of care? Standard of care is

13 very much up in the air and has a lot to do with

14 components of treating aspects of the disease. There are

15 many antidepressants, such as tricyclic antidepressants,

16 that, as Nat previously noted, treat fundamentals of

17 fibromyalgia, at the same time treating the depression.

18 So I would presume the committee is not really

19 thinking about a 6-month trial of absolute real placebo

20 compared to standard of care. So could someone comment

21 about those implications?

22 DR. FIRESTEIN: That's not really the 1 252 2 1 question. You didn't ask if this would be an add-on or

2 not, but whether it's as an add-on or a single agent, I

3 think everybody agrees that it should have a placebo

4 control to it.

5 Now, that actually brings us to the next

6 question, which is: what are the concomitant medicines

7 and in particular those related to depression?

8 DR. WILLIAMS: Can I address question 3 first

9 with analgesic rescue? Because we've done OA trials with

10 analgesic rescue using 4 grams of acetaminophen and have

11 patients who tolerated that. Now, whether fibromyalgia

12 patients will do that or not, and to respond to the

13 question as written, I would say you could have a placebo-

14 controlled trial with acetaminophen rescue.

15 DR. SIMON: I'd just like to point out the

16 caveat to that. There's a very famous study with

17 hyaluronic acid with concomitant acetaminophen rescue

18 where there was no evident capacity of the study drug to

19 actually benefit the patient since they achieved

20 appropriate analgesia with the acetaminophen. So one

21 thinks of rescue in two different ways. Is analgesic

22 rescue with acetaminophen withdrawal and failure of the 1 253 2 1 study drug or is it concomitant therapy and background

2 where then you're measuring from where you start off with

3 with the analgesic background a la add-on trial, and then

4 how do you ascertain the benefit? Would you then expect

5 the same 20 percent improvement that you would with no

6 background therapy?

7 So the first question is: would the analgesic

8 rescue be failure of the study drug, thus withdrawal? And

9 the second question is: if you're thinking about it as

10 concomitant background therapy, would you then design a

11 different kind of trial analysis defining a disease

12 activity score at the inception of the new study drug on

13 the context of the background therapy and following and

14 determining the outcome with the same disease activity

15 measure subsequently?

16 DR. WILLIAMS: You make it a lot more

17 complicated now. I think that if acetaminophen is going

18 to complicate your response, then they don't need another

19 drug. But you can't ask them to go on placebo without any

20 benefit of anything else. So that, in the OA studies,

21 using that as an example, we didn't expect acetaminophen

22 to give total control, but we gave them some analgesic 1 254 2 1 benefit if they needed it, and I think if that complicates

2 the response to analgesia, then probably the drug doesn't

3 offer a lot of extra benefit.

4 DR. FIRESTEIN: We'll now move on to the next

5 question, which is related to treatment of depression and

6 other concomitant medications.

7 So who would like -- Dr. Cush?

8 DR. CUSH: So the answer is no, patients with

9 depression on full dose regular daily meds for depression

10 should not be excluded. However, patients with

11 uncontrolled depression with a BDI, Beck Depression

12 Inventory, of a certain scale should be excluded as a

13 measure of being uncontrolled. I think that would be

14 reasonable.

15 I think con meds should be allowed, SSRIs. I

16 think the real issue, I'd rather defer this to Nat and

17 others who may know because my impression is that the use

18 of tricyclics could clearly confound all this. Unless

19 that were to be stratified for in trial design, I would

20 not like/allow/want to have pain modifiers, such as

21 tricyclics, in the trial.

22 DR. WILLIAMS: I would think if you're using 1 255 2 1 pain as a primary outcome measure, you'd also want to

2 excludes opiates.

3 DR. FIRESTEIN: Well, would opiates be written

4 in as your analgesic rescue since NSAIDs are of marginal

5 value?

6 DR. WILLIAMS: Well, previously, I said I'd

7 use acetaminophen as analgesic rescue, and I wouldn't use

8 NSAIDs, but I think that if you're using pain as your

9 primary outcome measure, once you start using narcotics,

10 you really complicate things because they may give you

11 benefit with adding complications further down the road.

12 DR. FIRESTEIN: What about studies with either

13 tricyclics or SSRIs or various combination drugs? How

14 does one manage a clinical trial if they're being treated

15 with an SSRI, for instance, or tricyclic for depression?

16 DR. WILLIAMS: I actually agree with Jack,

17 that I think you do eliminate tricyclics, and I think if

18 they have depression that is controlled and you have to

19 figure out how long you want it to be controlled. We do

20 this with steroids in RA trials. They can be on steroids,

21 if they've been on them for a period of time and they

22 don't change. You could say that if they have depression 1 256 2 1 and they're being treated with an SSRI or some other

2 antidepressant drug, not a tricyclic, that if they've been

3 controlled for X period of time, and that could be

4 determined, and it doesn't change during the trial, then

5 it's fine.

6 DR. FIRESTEIN: But if the mechanism of action

7 of the clinical trial agent is related either to serotonin

8 or norepinephrine or a variety of other --

9 DR. WILLIAMS: See, I'm not as convinced as

10 some of you that SSRIs are as beneficial as tricyclics in

11 fibromyalgia.

12 DR. KATZ: I think it's helpful to not lump

13 all the kinds of clinical trials together and make blanket

14 rules that cover both early proof of concept trials and

15 late phase III trials because the goals of those trials

16 are different. They're testing different hypotheses, and

17 the risk to the trial of allowing potential confounders,

18 such as concomitant depression or treatment for

19 depression, is different in those two stages.

20 Clearly, all these drugs and the existence of

21 concomitant co-morbidity, like moderate to severe

22 depression, is a potential confounder, and so for an early 1 257 2 1 proof of concept trial, it might be prudent to exclude

2 patients with all those issues and even maybe have a

3 shorter duration trial where you're trying to just test

4 your concept, whereas in later stages of development where

5 you want to know -- and yes, the people out there in the

6 world of fibromyalgia do have depression, are on these

7 drugs, and yes, you may need to stratify it. So it may be

8 appropriate to include those patients later on in drug

9 development where the generalizability of earlier findings

10 to those other populations becomes the question of

11 relevance.

12 DR. BRADLEY: He convinced me.

13 DR. WITTER: I wonder if I could ask the chair

14 to ask Drs. Crofford and Clauw to make comments on their

15 opinion as to whether opioids are effective in the sense

16 that we've been discussing today, effective for

17 fibromyalgia in terms of treating pain.

18 DR. FIRESTEIN: In terms of rescue, you mean?

19 Yes, not Dr. Clauw, but Dr. Crofford, I will immediately

20 reflect that question without repeating it.

21 DR. CROFFORD: Thanks, Jim.

22 I actually don't think opioids are 1 258 2 1 particularly effective in this syndrome, and I would agree

2 completely with whomever it was, and I think it was a

3 consensus of the panel, that opioids should not be allowed

4 as rescue nor do I think it's really necessary.

5 But I do think, if I could elaborate just

6 briefly, if you want to do a monotherapy trial that's

7 placebo-controlled, I think you should carefully consider

8 whether 3 or 6 months may be the most appropriate duration

9 of a trial in a condition where there's no approved drug

10 and where therapies may not be particularly effective.

11 Certainly I agree with everybody that the ideal is that it

12 works forever and it stays the same and the effectiveness

13 is maintained, but if you're considering a trial where you

14 actually don't have concomitant meds or rescue meds, I

15 think -- and you may ask your patient -- it may or may not

16 be tolerable.

17 DR. FIRESTEIN: The ethics of placebo controls

18 have been considered extensively in a variety of other

19 disease states, and it's even more pertinent, for

20 instance, in rheumatoid arthritis, for instance, where the

21 window for being able to allow placebos has gotten

22 narrower and narrower. 1 259 2 1 In this particular instance, unlike rheumatoid

2 arthritis where there is now an alternative effect of

3 therapy that can alter the natural history of the disease,

4 there isn't really such a treatment right now for

5 fibromyalgia, and my guess is that most patients, when

6 they enter a study such as this, will already have been

7 tried on the standard available approaches. So I don't

8 see a particular problem with, for instance, a 6-month

9 clinical trial under those circumstances.

10 DR. CROFFORD: I'm not arguing against placebo

11 control. Don't misunderstand what I'm saying. In fact,

12 I'm not even arguing against a 6-month trial. I actually

13 think a 6-month trial would be useful. I'm just hoping

14 not to discourage people that may want to start clinical

15 trials from actually doing them.

16 MS. MATALLANA: When we asked patients what

17 was their first choice of treatment, the number one

18 medication currently on the market was Ultram or Ultraset

19 and following that was Vicodin, Oxycontin and Darvoset.

20 But I personally feel that the reason why so many patients

21 are on these narcotics is because doctors do not have many

22 other options, and I know personally that I was put on a 1 260 2 1 lot of heavy narcotic medication, weaned off of it and

2 then put on basic Tylenol and Ultram and had quite a bit

3 of improvement. So I think you definitely need to take

4 them off these medications in order to see the efficacy of

5 the new treatment.

6 DR. FIRESTEIN: Jack?

7 DR. CUSH: You could also say that people who

8 responded to your survey were Ultraset, Ultram, Vicodin

9 users and not non-steroidal Tylenol responders.

10 DR. SIMON: I'd like to assure Leslie and

11 others around the table that we would not be considering

12 an active comparator trial for 6 months that would require

13 true placebo in that.

14 I would like to reiterate Nat's point, that we

15 would like to see at some stage in development a proof of

16 concept that would demonstrate perhaps in only just 6

17 weeks, maybe even less, that there is a signal of

18 improvement that would warrant going further in

19 development to allow then the large pivotal trials to be

20 appropriately designed that would allow patients to be in

21 appropriately. So no one should think that we're

22 withholding therapy for 6 months of a period of time. 1 261 2 1 But proof of concept is a very useful way to

2 think about a short-term exposure that may allow us to get

3 a real signal of real measurement that's not confounded

4 and that's always very important to have, not just for

5 efficacy but also for safety.

6 DR. FIRESTEIN: Lee, I think you have to be

7 careful about referring to a placebo as withholding

8 therapy.

9 DR. SIMON: Well taken.

10 DR. CUSH: Lee, were you intimating that you

11 would consider an active comparator trial in an

12 environment when there is no reasonable active comparator,

13 like proven efficacious standard of care, or would you

14 have to go with, as your active comparator, a drug that's

15 approved as a pain indication, for instance, albeit not

16 for fibromyalgia?

17 DR. SIMON: Given the fact that this is an

18 evolving field, we would be open to any suggestion that

19 would be legitimate, that would be able to show a signal

20 of improvement, and recognizing, of course, if you're

21 doing an active comparator trial, you're going to need to

22 be superior to your active comparator if your active 1 262 2 1 comparator is not already labeled in that particular

2 field. So that then becomes standard of care or

3 "placebo." So it just depends on what you mean.

4 A non-inferiority trial which obviously would

5 be very difficult to design in this construct, would

6 require a comparator that's already approved on the market

7 and thus accepted. Tricyclic antidepressants would not

8 fulfill that requirement at this time.

9 DR. FIRESTEIN: Nat, did you have a comment?

10 DR. KATZ: I had a question for the group. I

11 know that people who in their world of rheumatology have a

12 lot of experience in considering the purpose and the

13 methodology in analyzing these very long-duration trials.

14 The pain trial tradition that I come from typically uses

15 much shorter trials.

16 But my question would be if the purpose of the

17 trial is to show that the effect, the analgesic effect is

18 durable over time, it seems like there are a number of

19 different techniques that one could consider for

20 demonstrating that aside from having a prolonged

21 comparison, and it would also seem to me that the

22 prolonged placebo comparison as the primary means by which 1 263 2 1 to judge the durability of therapy is fraught with all

2 sorts of methodological issues. You've probably got much

3 more dropouts in your placebo group, I would think, that

4 on your active group, and you've got only the people in

5 the placebo that are placebo responders. I would ask the

6 group in rheumatology who do these sorts of things all the

7 time whether you consider other alternative study designs

8 for demonstrating durability of effect, like withdrawals

9 down the line or other sorts of methods one could imagine.

10 DR. FIRESTEIN: Yes, we've considered them.

11 (Laughter.)

12 DR. FIRESTEIN: Well, I think most of our

13 experience, in terms of these chronic disease states,

14 suggests that you really do need to have prolonged

15 treatment and that there are issues in terms of dropouts

16 that can be statistically handled, and maybe Jennifer can

17 comment on that in terms of using intention-to-treat

18 analysis and making the appropriate corrections.

19 But the gold standard really has been long-

20 term placebo-controlled studies for most of the agents

21 that are currently approved for chronic rheumatic

22 diseases. In particular, rheumatoid arthritis is where 1 264 2 1 there's by far the most experience but also osteoarthritis.

2 DR. STAUD: I was wondering. In a disease

3 where we have no short-term knowledge of effectiveness of

4 most analgesic therapies, why we would initially go and

5 require such long-term effectiveness and not say we are

6 already happy if there is effects for 3 months instead of

7 6 months.

8 DR. FIRESTEIN: Well, in part, because of the

9 rather prominent placebo effect that can occur and the

10 lack of durability of many placebo effects.

11 DR. STAUD: I understand this, but we assume

12 that the trial drug will be more effective than placebo.

13 DR. FIRESTEIN: Well, we don't assume that

14 actually. That's what the purpose of the study is.

15 DR. STAUD: I know.

16 DR. ANDERSON: I could make some comments

17 about this. Using the term "placebo-controlled trial"

18 isn't meant to mean that all therapies are withheld from

19 the placebo group because placebo, as has been discussed

20 here already, includes some background medication

21 generally these days. So although one might anticipate

22 that there would be more dropouts from the placebo group, 1 265 2 1 if you're really going to do an intent-to-treat analysis

2 and get a handle on the effectiveness of the new therapy

3 that you're looking at as distinct from its efficacy, you

4 have to include all patients for the full duration of the

5 trial. So even if people "drop out" in the sense that

6 they're no longer taking the therapy that they began with

7 -- and this applies to the intervention group and the

8 control group -- you have to continue. The group that's

9 doing the trial, the sponsor, whomever, has to make every

10 possible effort to continue to get information at the

11 appropriate time points from all of the participants, so

12 that you can really do an intent-to-treat analysis. So

13 that's my shtick.

14 I don't know whether I addressed what you

15 wanted me to address or not.

16 DR. FIRESTEIN: Jim?

17 DR. WITTER: Maybe, could you just expand a

18 bit? To some extent, there's almost some magical thinking

19 when it comes to rescue medications, even the term

20 "rescue," and I think one of the ways that we need to fix

21 that, to use that term, is to keep analyzing the patients,

22 even after they start taking this rescue, to give us an 1 266 2 1 idea of did it work, did it rescue. Could you maybe

2 comment on that strategy to kind of help us fill in some

3 of these blanks?

4 DR. ANDERSON: Well, from what I've seen of

5 the write-ups of clinical trials, there has been a

6 tendency to just stop collecting any information on the

7 patients once they're "rescued" or deviate in any way from

8 the desired protocol. But I guess my point is that you

9 really do need to keep getting the reports from them and

10 making the measurements on them, so as to do the efficacy

11 analysis and so that you can do what you're referring to,

12 to see whether this rescue was really a rescue, and you

13 can learn a lot and maybe it isn't all together in favor

14 of -- well, I don't know. Who knows what it's going to

15 show, but I don't think the sponsors should be scared of

16 doing these analyses.

17 DR. WITTER: Should we be asking then sponsors

18 to do that in the trials as they propose, that they look

19 at this, even if patients are rescued, they continue to

20 look at these outcomes, particularly pain?

21 DR. ANDERSON: Yes, yes.

22 DR. FIRESTEIN: Just to come back to the 1 267 2 1 questions, are there any concomitant therapies that should

2 definitely be excluded? I think we talked a little bit

3 about this, but should tricyclics be excluded, for

4 instance?

5 DR. WILLIAMS: Well, I think Jack and I both

6 have said that we thought tricyclics ought to be excluded,

7 opiates ought to be excluded, and there was some

8 discussion about whether SSRIs should be excluded.

9 DR. FIRESTEIN: Are there other comments from

10 the committee with regard to SSRIs, for instance?

11 DR. CUSH: I would modify it according to what

12 Nat said earlier, that in the short term, yes, more rigid,

13 but in the long term, no, because it's more real life. I

14 think that patients on antipsychotics should be excluded.

15 I think patients with primary CNS issues, whether it was

16 meningoencephalitis, head trauma as an inciter, inciting

17 events getting in, should be excluded. I have another

18 exclusion somewhere but I can't find it right now.

19 DR. FIRESTEIN: Yes?

20 DR. TURK: Just a caution for us as we think

21 about excluding antidepressants or depressed patients. I

22 work in research in a tertiary care rehabilitation center, 1 268 2 1 so obviously it's a select sample, but somewhere in the

2 neighborhood of 50 to 60 percent of those patients are

3 coming into us and they're receiving antidepressant

4 medication which would mean that if we were using them in

5 clinical trials, we're basically chopping off half of the

6 sample of patients who are being treated in at least that

7 type of facility. So what you're left with is a

8 potentially unusual subsample of people with fibromyalgia.

9 DR. FIRESTEIN: Is there disagreement about

10 concomitant use of tricyclics? For instance, you would

11 exclude tricyclics?

12 DR. WILLIAMS: I would exclude tricyclics. I

13 actually like Nate's approach where we have proof of

14 concept and then later on, you can add some of these other

15 drugs in on stable doses and see what happens with that,

16 but I think that for initial demonstration that you've got

17 an effective drug, you have to exclude tricyclics.

18 DR. FIRESTEIN: Right. But for registration

19 purposes later on? For phase III studies, I think it

20 would be very difficult --

21 DR. WILLIAMS: -- to show you've got some

22 benefit. 1 269 2 1 DR. FIRESTEIN: One assumes that you're

2 already done a short-term proof of concept study. At that

3 point, it would be very difficult to --

4 DR. WILLIAMS: I think there are two studies.

5 One, you have to do without tricyclics and one you do with

6 stable tricyclics.

7 DR. BRADLEY: I would agree. I think

8 especially over time, I think there's a number of trials,

9 particularly Carette's trials, in the early 1990s showing

10 that the effects of the tricyclics really do fade over

11 time. After about 3 months, they really tend to fade out.

12 So when you get to the longer trials, I think then it's

13 appropriate. You can include tricyclic use.

14 The other issue with regard to other

15 exclusionary criteria. I'm concerned about including

16 people in trials who have had maybe even one but certainly

17 multiple spinal surgeries, spinal fusions. I'm not sure

18 that the pain that those people experience is exactly the

19 same as the fibromyalgia syndrome, and I would be careful

20 about these people with really dramatic trauma done to

21 their spines.

22 DR. FIRESTEIN: The point you make about the 1 270 2 1 duration of response to tricyclics also, by the way, is

2 again one of the reasons why it's important to have a

3 longer duration study.

4 Well, the next question relates to ancillary

5 therapies, such as physical therapy, exercise, behavioral

6 therapy, psychotherapy, particularly for people requiring

7 dental procedures.

8 (Laughter.)

9 DR. FIRESTEIN: Should that be allowed during

10 the trial?

11 I think from my perspective, these things are

12 all reasonable to include.

13 DR. WILLIAMS: I think it's very analogous to

14 using steroids in rheumatoid arthritis. You have them on

15 a background, but they have to be stable on that

16 background before you start the study. You can't start

17 the exercise therapy at the same time you start your

18 intervention. So as long as they're stable on those

19 backgrounds and they don't change.

20 DR. FIRESTEIN: Yes?

21 DR. ANDERSON: But in rheumatoid arthritis

22 trials, are people prevented from taking an exercise class 1 271 2 1 or something during the trial? Does anybody notice?

2 DR. WILLIAMS: No. Often, we don't ever

3 discuss physical therapy in rheumatoid arthritis because

4 we don't think it changes the course of the disease. It

5 may change long-term mobility of the joints and so forth,

6 but it doesn't change the arthritis.

7 I was more using the analogy of

8 corticosteroids, where that is an effective therapy, but

9 as long as they're on a stable dose and it's been stable

10 for 2 months and you don't change it during the course of

11 the disease, that it's allowed, and I would say if these

12 people are on these interventions mentioned here and they

13 were stable on those interventions, you can add in another

14 intervention for your trial, as long as these didn't

15 change.

16 You're the statistician. You look troubled.

17 DR. ANDERSON: Well, I just think that -- and

18 I'm not sure that this is from a statistical point of

19 view. I don't think you should say that none of these

20 should be allowed to be started during a trial. I guess

21 if somebody starts to feel better, they may want to start

22 doing some exercise or something like that and to be 1 272 2 1 prevented from doing it because it's during a trial, I

2 think, is a problem. I just think that any of these

3 therapies that people decide to do should be noted and the

4 information should be there that they've been doing them

5 and for how long as part of reporting on the trial and

6 finding out and looking at the results.

7 DR. FIRESTEIN: Dr. Hoffman, then Dr. Staud.

8 DR. HOFFMAN: I would agree with those

9 comments. I think it has to be approached the same way an

10 adjunctive pharmaceutical therapy would be approached,

11 that if the people providing the study design feel that

12 exercise is an important adjunct to treatment, then the

13 same guidelines for exercise should be provided for

14 everyone. Everybody is being randomized to both groups.

15 It shouldn't then be a confounder.

16 DR. STAUD: Yes. I can see this only works if

17 the adjunctive therapies are standardized across the trial

18 which I think is very difficult for psychotherapy,

19 behavioral therapy and so on, and so for this purpose, it

20 will pose a major problem.

21 DR. FIRESTEIN: You think that it's a major

22 problem, did you say? 1 273 2 1 DR. STAUD: Yes, because I think the

2 standardization of these interventions across the trial is

3 very difficult, and so what was mentioned here, this would

4 have been part of the trial itself, that it could not be

5 just something that these subjects do on the side.

6 DR. FIRESTEIN: But do you think any of these

7 have a significant impact on the disease in a short-term

8 or relatively short-term trial, like 6 months?

9 Psychotherapy for 6 months?

10 DR. STAUD: CBT does. Acupuncture does. So I

11 think all these things need to be considered.

12 DR. WILLIAMS: I think exercise can.

13 DR. FIRESTEIN: But again, it will be very

14 difficult to strap patients into a couch with a remote

15 control for the duration of the study, if part of the

16 response to the treatment would lead them to want to

17 exercise more. It would be very difficult to build in a

18 lack of exercise requirement.

19 Jack?

20 DR. CUSH: I agree with Roland. I think that

21 this is fraught with difficulty because you can require

22 them to have a stable course of whatever these therapies 1 274 2 1 are for 2 or 3 three months at entry, but more

2 importantly, you're going to have to continue those same

3 therapies throughout the trial, otherwise the patient is

4 in violation of the protocol and would have to be dropped,

5 and so the wording should almost be written to discourage

6 such patients but you should allow them in.

7 The problem in reality is that if I can get my

8 patients to go to CBT or to go to yoga to Tai Chi or to go

9 to a pool program, they'll do it and they'll do it for a

10 few months and then they stop doing it. They stop doing

11 it for the most minor of reasons, because they got a

12 little bit of benefit, they don't want to go any more, the

13 bathing suit doesn't fit, whatever, and they stop going.

14 So they become actually quite noncompliant with a regimen

15 that has been shown to work, and you don't want to have

16 that happen in the context of the trial.

17 So while you may let them in, that's well and

18 fine. One thing we didn't discuss earlier on is what's

19 the criteria by which they actually get into the study,

20 meaning we talked about ACR criteria, fine, but what's the

21 activity measure that allows them to get in and that's

22 going to be an important part. So is it going to be as 1 275 2 1 simple as a VAS of greater than 4 on a 10-centimeter

2 scale. That's an important and difficult issue.

3 DR. SIMON: Yes. In thinking about this

4 question, it was actually a little trick question here

5 because we actually think that cognitive and behavioral

6 therapy is not the same thing as even standardized

7 exercise. I think that we think that cognitive and

8 behavioral therapy is as therapeutic as is a tricyclic

9 antidepressant in this particular realm. I know it's hard

10 for anybody to believe that I actually might say that. So

11 under those circumstances, I think that we would likely

12 either stratify for that or not allow it as part of the

13 component.

14 The other components, one might think about

15 this slightly differently. Perhaps if a population begins

16 to exercise, perhaps that's a positive outcome and maybe

17 it's a measurable positive outcome, how much exercise they

18 actually can do. We've actually thought about turning

19 that question around and using that as an additive outcome

20 to be determined. So we're actually not adverse to that,

21 but we are a little adverse to leaving in cognitive and

22 behavioral therapy. 1 276 2 1 DR. FIRESTEIN: But you're quite right, it was

2 not on your list of alternative therapies that would be

3 available.

4 Were there a couple other comments?

5 DR. BRADLEY: I guess with regard to the

6 exercise question, actually I think that perhaps it's the

7 same sort of situation that we talked before, the

8 difference between a short-term trial just as a

9 demonstration versus a longer-term trial. I think, for

10 example, it's almost like a forward pass in Woody Hayes'

11 point of view. Multiple things can go wrong. If you have

12 someone who begins exercise at the start of a short

13 demonstration trial for a pharmacologic agent, one might

14 be that exercise might make the person feel better and

15 then you obscure the effect of the agent. The other is,

16 is that, oftentimes people with fibromyalgia, when they

17 begin to exercise, actually feel worse at first, and then

18 you might actually have a negative effect on your agent.

19 So I think we have to sort of make some decisions about

20 the short-term projects versus the longer-term projects.

21 DR. HOFFMAN: I'm not sure adding in the

22 exercise variable really presents a problem because 1 277 2 1 patients are being randomized between groups, and if

2 they're randomized at each site, then the same standard of

3 care is being provided, except for those exclusions that

4 you would want to list otherwise. So those in the placebo

5 group and those in what you hope is the active drug, the

6 test drug group, have equal access to that modality and

7 that should even out in the final analysis.

8 DR. STAUD: I think exercise is not the same

9 as study application. This can vary within one subject so

10 dramatically over time that I think it's going to be a

11 very difficult variable to consider in this trial.

12 DR. FIRESTEIN: I'm confused as to why it's

13 more difficult than in any other of the clinical trials

14 that have been evaluated. For instance, again we don't

15 prevent patients with rheumatoid arthritis from walking on

16 a treadmill during a study with other anti-inflammatory

17 agents. We don't prevent them from doing that in

18 osteoarthritis. Why would we entertain that in

19 fibromyalgia? That's different from again cognitive-

20 behavioral therapy. This is again part of activities of

21 daily living plus.

22 DR. STAUD: I mean, part of it is that the 1 278 2 1 effect of short-term exercise is very unpredictable in

2 this patient population. So that's the main reason. So I

3 think long-term exercise, doing it steadily, I think it

4 will have not dramatic impact on trials but short-term

5 starting and stopping, I could see that happening.

6 DR. FIRESTEIN: Right. But we live in a real

7 world and we have to let patients seek their own level in

8 terms of activity, and if they're feeling better and they

9 want -- there will be some potentially confounding issues

10 if people are exercising more and that causes more pain

11 for other reasons because they're deconditioned or other

12 things that can cause some confounding issues, but

13 overall, this has got to be a real world trial for the

14 same reason it has to be real world with regard to

15 concomitant medications as we've talked about.

16 So one or two more quick comments and then

17 we'll go on to question 6.

18 MS. McBRAIR: I agree on the issue of

19 exercise. We need to allow patients to do whatever they

20 can do to help themselves, and as long as that's

21 documented, what has happened, I think we can look at it

22 more closely. But to say someone couldn't exercise or 1 279 2 1 couldn't do more and we're looking for increased function

2 as one of the things we'd like to see happen, I think

3 would be a wrong message for the patients.

4 DR. FIRESTEIN: The next question really

5 relates to fibromyalgia with overlap diseases and how one

6 decides clinical studies. Should patients with rheumatoid

7 arthritis, lupus, Sjogren's, etc., be excluded from these

8 clinical trials?

9 DR. WILLIAMS: If pain is your primary outcome

10 measure, these are diseases that cause pain by a different

11 mechanism, and I would exclude them.

12 DR. FIRESTEIN: I would agree with that. It

13 just makes it too complicated to assess. That can be

14 something that can be done later on, but if you're looking

15 for efficacy in fibromyalgia, it will make it hopelessly

16 complicated, I think. Everybody agrees with that.

17 DR. WILLIAMS: If you prove its effective in

18 fibromyalgia, it'll be used in these patients anyway.

19 DR. FIRESTEIN: The last question is: which

20 of the available instruments appear most appropriate for

21 evaluation of physical function, sleep disturbances,

22 cognitive impairment, and fatigue? 1 280 2 1 I would open it up. We had a number of these

2 sorts of things discussed. Anybody want to comment on

3 this?

4 DR. WILLIAMS: We really discussed physical

5 function earlier, and I don't know that there's a better

6 one than the SF-36 right now for this particular disease.

7 For sleep disturbance, it was Dr. Wells that suggested the

8 VAS was as effective as anything. I'm not sure I can tell

9 you anything about cognitive dysfunction as a good

10 instrument. And for fatigue, I'd use the VAS.

11 DR. FIRESTEIN: Any other -- yes?

12 DR. TURK: At the IMMPACT meeting, when we

13 looked at the question of functional measures, we

14 separated it into disease-specific or general measures,

15 and within the general measures, we recommend that the

16 interference scale of the Multidimensional Pain Inventory

17 was as good, if not the best, measure to use, followed by

18 the BPI, or the Brief Pain Inventory. Now, the Brief Pain

19 Inventory is a pain-specific measure. The Sickness Impact

20 Profile, the reason we had concerns with that is because

21 the literature on its sensitivity to change is pretty poor

22 and therefore it might not be the best outcome measure to 1 281 2 1 use.

2 DR. CUSH: Of these, I would have physical

3 function and sleep disturbance in there. I would not do

4 cognitive impairment. I think fatigue is up in the air

5 because I think that at some point, they're all inter-

6 related. You might as well add headache and irritable

7 bowel and everything else onto this. It gets a little

8 crazy with 54 visual analog scales to come up with what's

9 going on in fibromyalgia.

10 I think that we should go towards a

11 responsiveness, an FM-20, if you will, that goes after

12 three domains. You must meet pain and any one of two or

13 three others. Certainly two that are potential areas are

14 pain and fatigue and quality of life or function, and to

15 improve in pain plus something else would be enough.

16 Now, what you choose for each of these domains

17 has got to be left up to whatever the state of the art is,

18 and I think that we've heard what's reasonable as far as

19 function. I think that there are sleep scales that can be

20 used or as simple as a visual analog scale. I don't know

21 that you improve things more than the visual analog scale

22 for pain and then for fatigue. There are specific fatigue 1 282 2 1 questionnaires, not well worked out, I don't think, in

2 fibromyalgia, but in other diseases they have been, like

3 cancer and whatnot.

4 So they're there, and to go with, again, a

5 composite definition of response is reasonable, both for

6 short term or long term, and I think it would be a major

7 advantage or major leap forward in trying to promote drug

8 development. Again, the idea is to go after not just

9 symptom improvement but actual disease improvement, as Lee

10 suggested earlier.

11 DR. FIRESTEIN: But with symptom improvement

12 alone, would that not be a contribution?

13 DR. CUSH: Not much more than what we've done

14 in the past or what we're currently doing because then

15 you're always talking about single symptom improvement,

16 and I think that that's a major step backwards. I think

17 that maybe we're limited by our lack of understanding of

18 disease. Nat's correlation with pneumonia was

19 interesting, but also we're in the era where we truly

20 understand the pathogenesis of pneumonia, the bugs that

21 are involved, and the consequences of pneumonia and

22 whatnot. If we were in the 18th Century, giving opium for 1 283 2 1 pneumonia would probably make a great deal of sense, and I

2 think that we may well be in the 18th Century with regard

3 to fibromyalgia.

4 DR. FIRESTEIN: Well, again --

5 DR. CUSH: It's a little strong, I know.

6 DR. FIRESTEIN: It is a little bit strong, and

7 it's because in the end, we are in the 18th Century

8 because we don't have a specific therapy, unlike

9 pneumococcal pneumonia, and so treating symptoms alone,

10 which by the way was a gold standard for rheumatoid

11 arthritis for a long, long time -- except for injectable

12 gold, there were no disease-modifying agents, and we know

13 how good an agent injectable gold was. So just signs and

14 symptoms was good enough without having a specific

15 treatment for rheumatoid arthritis, and I think the same

16 thing might be true for improving the lives of patients

17 with fibromyalgia. Just improving the symptoms may well

18 be a significant contribution.

19 Nat?

20 DR. KATZ: I would just re-agree with myself

21 and with you now.

22 (Laughter.) 1 284 2 1 DR. FIRESTEIN: Unlike Lee who argues with

2 himself.

3 (Laughter.)

4 DR. KATZ: Before someone looks up the rules.

5 I mean, we just should keep in mind that there's been this

6 traditional discordance between what's important to

7 patients and what's important to physicians. I think we

8 all have had pain at one time or another. If you can

9 recall back to when you've had pain, you'd look at pain

10 relief as being a godsend, regardless whether it improved

11 some other parameter that interested your doctor and more

12 than interested you.

13 Now, again, I'm not disagreeing. I also feel

14 that ultimately, there is a notion of treatment of disease

15 that obviously is the long-term goal of drug development.

16 Maybe one day, we'll understand this disease better and

17 we'll have treatments and maybe that'll be in 5 years,

18 maybe that'll be in 50 years. But in the meantime, if

19 there are agents available that can treat symptoms, that's

20 what patients are really looking for.

21 It's worth keeping in mind that drug

22 development has been going on for thousands of years and 1 285 2 1 effective drugs have been developed. In fact, the ones

2 that we still use for pain have been developed long before

3 anybody understood anything about the diseases that were

4 being treated and anything about the mechanisms of the

5 drug and that's how these what are regarded as boons to

6 mankind have been developed.

7 So to minimize the importance of treatment of

8 individual symptoms that occur in the constellation of all

9 sorts of diseases would be, I think, a terrible mistake.

10 DR. FIRESTEIN: Steve, and then Lee.

11 DR. ABRAMSON: Yes, I would agree, and I think

12 what we're really talking about is to have an isolated

13 pain indication is not necessarily unacceptable, but to

14 mandate that in all of these studies that function and

15 quality of life and all of these studies be standardized

16 so that information is captured, maybe you don't have to

17 win on all three domains, but you need to know that this

18 drug works for pain but not for function. I think over

19 time, that will be very important as these drugs sort out

20 in the market.

21 I think there would be a hazard of a company

22 going just for a pain indication. I think we'll lose a 1 286 2 1 lot of information. So I think capturing information but

2 having separate indications is still important.

3 DR. SIMON: Just actually as an extension, not

4 to be terribly concrete, but for those of you that have

5 had experience with the Krupp Fatigue Scale as opposed to

6 a VAS scale for fatigue, might you comment on a

7 multidimensional fatigue outcome versus just are you tired

8 or how you ask the question to be dependent upon one

9 question? Is there any comment about that in such an

10 issue as fatigue?

11 DR. KATZ: Since it doesn't seem like anybody

12 else knows the answer, I'll chime in with this tiny amount

13 of information I have. There has been a lot of instrument

14 development work that's gone on in the fatigue world.

15 Talk to anybody at Ortho-McNeil Pharmaceuticals and

16 they'll tell you all about it. Initially, they started

17 with large fatigue inventories and then ultimately at

18 least their one was reduced down to the so-called Brief

19 Fatigue Inventory that's commonly used, and so in their

20 psychometric process, they were not able to effectively

21 reduce their instrument down to one item.

22 DR. FIRESTEIN: Are there any other comments 1 287 2 1 on these various instruments? I don't have any.

2 Jim?

3 DR. WITTER: Can I recue up my question then

4 from earlier in terms of developing new instruments?

5 Dennis is here and he can comment. One of the issues, for

6 example, from IMMPACT is that even though we may not have

7 an instrument, we still want the domain to be measured and

8 that was the same message from the NIH conference that I

9 discussed earlier. So just because we don't have

10 something doesn't mean we don't need something in the long

11 run.

12 So how would you suggest as a part of the

13 discussion that we would encourage and facilitate,

14 whatever the proper term is, to get these endpoints and

15 get them validated and developed for the next generation

16 of sufferers of this condition?

17 DR. FIRESTEIN: I guess you could mandate it.

18 That's what you do.

19 Yes, I mean, as long as it's clear that it

20 will not be used as a club to beat them over the head with

21 later if they don't hit a predetermined mark, then I think

22 it's entirely reasonable to ask for the data to be 1 288 2 1 collected, but it does mean that the primary endpoints are

2 going to probably have to exclude that domain. But on the

3 other hand, pain and patient global is not a bad place to

4 start with fibromyalgia. Really, the question has been in

5 terms of functional indices. We don't really know what to

6 ask yet.

7 DR. KATZ: It sounds like we're all agreeing

8 that ultimately we want to be able to measure the critical

9 components of this syndrome of fibromyalgia in clinical

10 trials, even if we don't necessarily require that one win

11 on all the different components. It seems like the

12 conversation has left off is that while we think that this

13 functional measure might be a good one to throw in there

14 and maybe this fatigue measure might be a good one to

15 throw in there and somehow we'll guess at what might be an

16 appropriate responder index, but the fact is, as you all

17 well know in rheumatology better than I, developing such

18 instruments and such responder indices is an empiric

19 process that requires a concerted and directed effort.

20 It seems reasonable to me that as part of the

21 development process of these medications, the agency is in

22 a reasonable position to require that some sort of 1 289 2 1 responder index be provided which to me seems like it

2 needs to be specifically developed.

3 DR. FIRESTEIN: But again, with the proviso

4 being that it's not going to be used as one of the

5 criteria for having a drug approved because you can't

6 collect the data and then retrospectively validate it and

7 then say that you either hit or miss based on those data.

8 DR. KATZ: Absolutely. It has to be

9 reasonable.

10 DR. STAUD: I also wanted to bring up one

11 point in the discussion that we haven't really done. This

12 is measurements of disease processes that are relevant to

13 the syndrome, and as we know, the process that is relevant

14 is called central sensitization, central sensitization of

15 particularly spinal cord elements as well as probably

16 higher brain centers, and currently the only measure that

17 gets even close to this is tender points that we talked

18 about.

19 I think we have better measures these days

20 that we could request from companies to use as criteria in

21 these trials, even if they don't make the primary

22 criteria, to look at these measures because they have 1 290 2 1 impact most likely on the evaluation of the disease and

2 its course.

3 DR. CUSH: I think it's a good opportunity for

4 the FDA to hear from us who are practicing clinicians what

5 would be valuable and reasonable in the construct of

6 trials and indications, but I also think that a parallel

7 process should go on between the FDA and the NIH as far as

8 developing a consensus group which will involve the

9 experts in the field as to what would be the most

10 discriminate values. And they'll be able to look at

11 ongoing data collection and basically do the same as the

12 way OMERACT has functioned to help rheumatoid arthritis.

13 One of the problems and one of the hindrances

14 of that is that you bring together the best minds in

15 fibromyalgia research who are very biometrically oriented

16 and in the end, you get so far away from real life as far

17 as what you're requiring for outcomes, that it's only good

18 for trials and drug development and it has no utility to

19 what I'm doing in my practice with my patients and the

20 extrapolatability of the information from that new trial

21 with its design to what I'm going to tell my patient and

22 what he or she may expect. 1 291 2 1 So I do think that the input of this body at

2 this point is important. I think we should push forward

3 what we think should happen, whether it's how many

4 domains, which domains, single domains, combinations of

5 domains. I think it's important that you hear, but I also

6 think that another process has to complement this.

7 DR. FIRESTEIN: So we've reached the end of

8 your questions. Never mind. Yes, Wendy?

9 MS. McBRAIR: This isn't a question, just a

10 comment. I work with a lot of fibromyalgia patients and

11 they are looking for some answers and they are looking for

12 some help. So I really commend the FDA on even bringing

13 up this discussion and starting to look for answers and

14 guidance. Along with medication control and learning more

15 about what we can do to help folks, we certainly need to

16 continue to look at what the cause is of fibromyalgia and

17 hopefully some companies will continue to work on that as

18 well as some scientific researchers.

19 It's very frustrating for patients to get the

20 runaround and then also to find out what they have but not

21 to learn that there's some real help out there. So I hope

22 that we continue this conversation. 1 292 2 1 DR. FIRESTEIN: Dr. Simon?

2 DR. SIMON: Yes, we are assuaged. We want to

3 thank everybody here. We tried to construct a committee

4 that was part skeptic, part expert, part experience, and I

5 think we really achieved that. Some people came totally

6 disbelieving there was any reason to have this discussion,

7 I think, and I think that there were good things that were

8 brought up. And most importantly, you really gave us

9 wonderful advice about what we truly are grappling with on

10 a daily basis because in fact there are promising

11 therapies that are in front of us and we just didn't know

12 the kind of questions to ask, and you've helped us to be

13 able to do that.

14 DR. FIRESTEIN: Thank you very much,

15 everybody. This meeting is now adjourned.

16 (Whereupon, at 2:54 p.m., the committee was

17 recessed, to reconvene at 8:00 a.m., Tuesday, June 24,

18 2003.)

19

20

21

22 1 293 2 1

2

3

4

5

6

7

8

9

10

11

12

13

Load more

  293

Copy Link