Monday, July 29, 2002

8:00 a.m.



Holiday Inn Bethesda

Versailles I and II

8120 Wisconsin Avenue

Bethesda, Maryland



Gary S. Firestein, M.D., Chairman

Kathleen Reedy, R.D.H., M.S., Executive Secretary


Jennifer Anderson, Ph.D.

Kenneth D. Brandt, M.D

Leigh F. Callahan, Ph.D.

John J. Cush, M.D.

Ildy M. Katona, M.D., CAPT, MC, USN

Susan M. Manzi, M.D.

Wendy W. McBrair, R.N., M.S., C.H.E.S.

Yvonne S. Sherrer, M.D.



Steven B. Abramson, M.D.

Raymond A. Dionne, D.D.S., Ph.D.

Janet D. Elashoff, Ph.D.

Clifford J. Woolf, M.D.


Michael Ashburn, M.D., M.P.H.

Nathaniel P. Katz, M.D.

Mitchell B. Max, M.D.


Frank F. Davidoff, M.D.

Alastair Wood, M.D.


Charles H. McLeskey, M.D.


David Borenstein, M.D.

John T. Farrar, M.D. MSCE

Vibeke Strand, M.D.




Call to Order and Introductions:

Gary S. Firestein, M.D. 5

Meeting Statement:

Kathleen Reedy 8


Lee S. Simon, M.D. 10


James Witter, M.D., Ph.D. 13

1992 Guidance:

Christina Fang, M.D. 24

Sharon Hertz, M.D. 34

Basic Science:

Clifford J. Woolf, M.D., Ph.D. 40

Discussion Points #1, 2 62

Claim Structure:

Lee S. Simon, M.D. 95

Discussion Points #3, 4 115

Back Pain, Chronic Issues:

David Borenstein, M.D. 142

Discussion Point #5 168

Open Public Hearing

Najib Babul, Pharm.D. 180

Kenneth M. Verburg, Ph.D. 190

Eugene Laska, Ph.D. 200

Mason Diamond, D.D.S. 203

Abraham Sunshine, M.D. 211

Daniel Carr, M.D. 216

Ann Berger, M.D. 227

Thomas J. Schnitzer, Ph.D. 234

Z. Shainhouse, M.D. [Letter] 245

Michael R. Hufford, Ph.D. 247


James Witter, M.D., Ph.D. 257

Tolerance and Toxicity:

Nathaniel P. Katz, M.D. 263




Statistical Issues for Measurements: 298

Laura Lu, Ph.D.

Open Discussion of Points: #1, 2, 3, 4 and 5 306



1 P R O C E E D I N G S

2 Call to Order and Introductions

3 DR. FIRESTEIN: Welcome to everybody to

4 this meeting of the Arthritis Advisory Committee

5 along with a number of esteemed guests.

6 My name is Gary Firestein. I am the chair

7 of the committee. Before we get started with the

8 actual agenda, because there are so many new people

9 here today, it might be valuable to go around and

10 have everybody around the table introduce

11 themselves briefly.

12 As I said, I am Gary Firestein. I am from

13 UC/SD and I am a rheumatologist.

14 Why don't we go around to my left.

15 DR. SHERRER: I am Yvonne Sherrer. I am a

16 rheumatologist. I am from Fort Lauderdale.

17 DR. CUSH: Jack Cush. I am a

18 rheumatologist from Presbyterian Hospital of

19 Dallas.

20 DR. CALLAHAN: Leigh Callahan. I am an

21 epidemiologist from the University of North

22 Carolina in Chapel Hill.

23 DR. WOOD: I am Alastair Wood. I am a

24 clinical pharmacologist from Vanderbilt.

25 DR. DAVIDOFF: I am Frank Davidoff. I am



1 an internist and a recovering journal editor.

2 MS. McBRAIR: Wendy McBrair. I am a nurse

3 and health educator from Virtua Health in New

4 Jersey.

5 DR. WOOLF: Clifford Woolf. I am a

6 biologist from Massachusetts General Hospital and

7 Harvard Medical School.

8 DR. DIONNE: Ray Dionne, clinical

9 pharmacologist, National Institute of Dental and

10 Craniofacial Research.

11 DR. MAX: Mitchell Max, neurologist,

12 National Institute of Dental and Craniofacial

13 Research.

14 DR. WITTER: Jim Witter from the FDA.

15 DR. SIMON: I am Lee Simon, Division

16 Director of 550, FDA.

17 DR. McLESKEY: Charley McLeskey, an

18 anesthesiologist, serving as the industry

19 representative here from Abbott Labs.

20 DR. STRAND: Vibeke Strand. I am a

21 rheumatologist, teach at Stanford, and work as a

22 consultant.

23 DR. BORENSTEIN: David Borenstein,

24 rheumatologist, Clinical Professor at George

25 Washington University.



1 DR. FARRAR: John Farrar. I am a

2 neurologist interested in pain management at the

3 University of Pennsylvania.

4 DR. ELASHOFF: Janet Elashoff,

5 biostatistics, Cedars-Sinai and UCLA.

6 DR. ASHBURN: Michael Ashburn,

7 anesthesiologist, from the University of Utah.

8 DR. ANDERSON: Jennifer Anderson,

9 statistician, from Boston University Medical

10 Center.

11 DR. KATZ: Nathaniel Katz. I am a

12 neurologist at Harvard Medical School.

13 DR. MANZI: Susan Manzi. I am a

14 rheumatologist from the University of Pittsburgh.

15 DR. ABRAMSON: Steve Abramson,

16 rheumatologist, NYU and Hospital for Joint

17 Diseases.

18 DR. KATONA: Ildy Katona, pediatric

19 rheumatologist, from the Uniformed Services

20 University.

21 DR. BRANDT: Ken Brandt. I am a

22 rheumatologist from Indiana University.

23 MS. REEDY: Kathleen Reedy, Food and Drug

24 Administration.

25 DR. FIRESTEIN: As I mentioned, we do have



1 a very full schedule and we have a large number of

2 people in this committee today, so it will be

3 impossible for everybody to take the podium for

4 prolonged presentations, and I would just ask the

5 members of the committee to try to keep comments to

6 the point, so that everybody can have an

7 opportunity.

8 We will begin the meeting with a meeting

9 statement read by Kathleen Reedy.

10 Meeting Statement

11 MS. REEDY: This is the meeting statement

12 for the Arthritis Advisory Committee meeting on

13 July 29th and 30th, 2002.

14 The following announcement addresses the

15 issue of conflict of interest with regard to this

16 meeting and is made a part of the record to

17 preclude even the appearance of such at this

18 meeting.

19 The Food and Drug Administration has

20 approved general matters waivers for the following

21 special government employees which permits them to

22 participate in today's discussions: Gary

23 Firestein, Kenneth Brandt, Ildy Katona, Yvonne

24 Sherrer, Susan Manzi, Jennifer Anderson, John Cush,

25 Alastair Wood, Nathaniel Katz, Michael Ashburn,



1 Janet Elashoff, Mitchell Max, Raymond Dionne,

2 Steven Abramson.

3 A copy of the waiver statements may be

4 obtained by submitting a written request to the

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

6 of the Parklawn Building.

7 In addition, Leigh Callahan, Frank

8 Davidoff, Wendy McBrair do not have any current

9 financial interests in pharmaceutical companies,

10 therefore, they do not require a waiver to

11 participate to today's discussions.

12 We would like to note for the record that

13 Ms. McBrair's employer's interests in two drug

14 companies are exempt under 2640.203(g).

15 The topics of today's meeting are issues

16 of broad applicability unlike issues before a

17 committee in which a particular product is

18 discussed, issues of broad applicability involve

19 man industrial sponsors and academic institutions.

20 The committee participants have been screened for

21 their financial interests as they may apply to the

22 general topics at hand. Because general topics

23 impact so many institutions, it is not prudent to

24 recite all potential conflicts of interest as they

25 apply to each member, consultant, and guest.



1 FDA acknowledges that there may be

2 potential conflicts of interest, but because of the

3 general nature of the discussion before the

4 committee, these potential conflicts are mitigated.

5 We would like to note that Dr. Charles

6 McLeskey is participating in today's meeting as a

7 non-voting industry representative. As such, he

8 has not been screened for conflicts of interest.

9 In the event that the discussions involve

10 any other products or firms not already on the

11 agenda for which FDA participants have a financial

12 interest, the participants involvement and their

13 exclusion will be noted for the record.

14 With respect to all other participants, we

15 ask in the interest of fairness that they address

16 any current or previous financial involvement with

17 any firm whose product they may wish to comment

18 upon.

19 DR. FIRESTEIN: Thank you very much.

20 Now we will move on to the Welcome from

21 Dr. Simon.

22 Welcome

23 DR. SIMON: Thank you, Gary, and I would

24 like to welcome the committee. We are grateful

25 that you are willing to come, take time out of your



1 practice and busy days to join us here in this

2 rather hot and humid land, but nonetheless, the

3 fact that you have been able to take time out

4 Monday and Tuesday, we are quite grateful about.

5 We recognize that much of what you do here

6 is done involuntarily and we recognize that that is

7 a burden and the government appreciates your

8 commitment.

9 Having been recently on the other side of

10 this microphone and having sat around the table

11 with you as a committee member previously, I can

12 appreciate really what it takes to do this, so

13 thank you.

14 I want to make clear that this meeting is

15 the first of many meetings in an iterative way for

16 us in 550, and hopefully other divisions in the

17 future, to participate with you all in discussing

18 issues of pain, which we find a very critical time

19 in the development of new therapies for pain.

20 We have advanced the science of

21 understanding mechanisms and we believe that part

22 of our role at the FDA is to foster new therapeutic

23 development by discussing all different kinds of

24 ways to look at pain indications and how one would

25 approve such drugs. We believe that these kinds of



1 discussions will allow us to further understand

2 better how to create and construct guidances for

3 industry.

4 Much of what we will discuss today will

5 not, and has not, been generally discussed within

6 the entire FDA. I would like to make clear that

7 much of the discussion will inform us in 550, the

8 Analgesics Anti-inflammatory and Ophthalmologic

9 Product Division, about issues that we have been

10 grappling with and have been advising industry

11 about, about the products that we are responsible

12 for.

13 However, much of what we will discuss

14 today will be brought back for further discussions

15 with other divisions, such as 170, Anesthetics and

16 Critical Care, that is particularly interested in

17 this topic since they are responsible for drugs

18 like opioids.

19 So, we feel very strongly that today's

20 discussion, although not directly product oriented,

21 will help us and inform us significantly about

22 where we are going in the future in guidance

23 development.

24 So, again, thank you very much, and I will

25 turn the meeting back to Gary.



1 DR. FIRESTEIN: Thank you, Lee.

2 We will move ahead now with an

3 introduction to the topic from Dr. Witter.

4 Introduction

5 James Witter, MD., Ph.D.

6 DR. WITTER: Good morning. Thank you,

7 Gary, Dr. Simon.

8 I am the clinical team leader in 500 and,

9 as such, I would like to thank the members of the

10 team that have spent a lot of time and energy

11 getting ready for today. I particularly would like

12 to acknowledge the help of Barb Gould and I think

13 you will appreciate some of her work here shortly.

14 [Slide.

15 In case you missed it, we are here to talk

16 about pain, and pain is one of those words that

17 even, standing alone, evokes an emotion out of I

18 think everybody. Maybe, in fact, some of you have

19 some of this right now. It is generally not a good

20 emotion, though.

21 [Slide.

22 Pain is really quite fascinating because

23 it is, in one way, the ultimate symptom and

24 therefore, the target for drug development, which

25 is part of the interest today, but it crosses some



1 magical line and can become a disease, which we

2 talked about at a meeting just down the street a

3 couple of months ago. So, it kind of goes through

4 what we might think of as I guess a phenotypic

5 change.

6 [Slide.

7 The purpose of the meeting really, then,

8 is what we are going to try and do is simplify

9 things down to concepts and really examine two main

10 aspects of pain and its relief. One of those is

11 how have analgesics been studied and labeled to

12 date, and how should analgesics be studied and

13 labeled in the future.

14 The ultimate goal, then, is to inform

15 analgesic labels in a meaningful way for both

16 patients and clinicians. So, a lot of the focus is

17 going to be a discussion of labels.

18 [Slide.

19 Let's starts off with some definitions

20 then. Can we say, then, that since acute pain is

21 generally considered a self-limiting condition,

22 that that should inform us on how the drug should

23 be studied, labeled, and used? Use is what we are

24 particularly concerned about because we know that

25 off-label use has resulted in serious adverse



1 events and death with certain analgesic drugs in

2 the past.

3 [Slide.

4 Can we, on the other hand, say that

5 chronic pain is defined as daily or intermittent

6 pain that occurs either on or off medication and

7 lasts more than 3 months for patients who do not

8 have cancer, but lasts more than 6 weeks for those

9 who have cancer, if what we are trying to do is

10 recruit patients into trials, we don't want to keep

11 them out, particularly those that have cancer.

12 [Slide.

13 So, I am going to ask you to answer a

14 series of questions in your head. Please don't

15 raise your hand unless they apply.

16 But I would like to know: Who has never

17 experienced pain? Who thinks that pain doesn't

18 hurt? Who thinks that pain doesn't interfere with

19 your activities? And who thinks pain doesn't

20 impact your life?

21 I see no hands.

22 [Slide.

23 So, do we then have an agreement,

24 unspoken, that an analgesic should: relieve pain,

25 should improve function, should improve quality of



1 life, and do so in a safe manner?

2 And this is important. The other side of

3 the equation from working is safety, and we are

4 going to talk about that today and tomorrow also,

5 but it is always going to be I think in the back of

6 our minds.

7 [Slide.

8 As I mentioned earlier, we are really

9 going to be focusing on labeling, so if you look in

10 the draft OA or in the RA guidance document, you

11 will see something that states the following:

12 "Although label claims have legal and regulatory

13 uses, their central purpose is to inform

14 prescribers and patients about the documented

15 benefits"--and I have inserted in here (and

16 risk)--"of a product."

17 [Slide.

18 Now, this isn't the first time that we

19 have talked about labels and analgesics. We did so

20 about four years ago. We took only one day, and I

21 think by the end of tomorrow, you will realize that

22 that was not sufficient. We broke it up into a

23 morning and afternoon session, and I think I see

24 some people that were here then.

25 The morning session, we really discussed



1 the onset of pain relief, what we call fondly,

2 internally, the "fast-faster" wars, and we also

3 studied design of Rx prescription/OTC analgesics.

4 In the afternoon, we devoted it to pain

5 claim structures for both acute and chronic pain.

6 [Slide.

7 We asked some questions, as we usually do,

8 of the Advisory Committee. We asked: Should pain

9 claims be categorized as: for acute versus chronic

10 versus unrestricted or I guess general pain claims?

11 Should they be by categories, for example,

12 neuropathic pain, or should they be by

13 subcategories, for example, diabetic neuropathy?

14 [Slide.

15 We also then asked: Of these studies, how

16 many should there be, how long should they be, what

17 kind of pain "models" should we be using to inform

18 such labels, and what is this concept of

19 "clinically meaningful" benefit and how should it

20 be determined in both the setting of acute and

21 chronic pain?

22 [Slide.

23 But we are here to talk about the future,

24 so what we are going to be discussing throughout

25 these two days are some ideas about how to move



1 forward and how to make pain claims for the future,

2 and what we might able to do, for example, is break

3 them up into two basic categories, a clinical and a

4 mechanistic.

5 Clinical is first because, as I mentioned

6 before, pain is the ultimate symptom, so we need to

7 make sure that we address that. Tomorrow, in

8 particular, we are going to be discussing the acute

9 pain setting and, in particular, what we have

10 called the ABC's of doing studies to look at

11 analgesics in the acute situation.

12 Later today, we will be talking more about

13 chronic and what those studies should be, in

14 particular, then labels that should have a specific

15 chronic claim, such as osteoarthritis, which we

16 routine give out in the division, or should we

17 talking about more general claims, replicates of

18 three models, which Dr. Simon will be going into in

19 just a bit, but I think one thing that Dr. Simon is

20 going to stress is that we are trying to set up

21 many ways, particularly for chronic pain, many ways

22 to get approved.

23 Then, I think we are going to be

24 discussing some mechanistic approaches or what we

25 might call some bridging studies, and I will talk



1 about that in a bit.

2 [Slide.

3 So, let's just stop for a moment and think

4 about a mechanistic claim. We don't have such a

5 thing, but we wonder what it might look like if we

6 did have one, would it look like, for example,

7 something that would say prevents neuroplasticity,

8 does that make sense to people, or reducing

9 prostaglandin levels, or reducing substance P in

10 CSF, are those the kinds of things that we would

11 mean by a "mechanistic claim."

12 [Slide.

13 So, mechanisms, I have come up with

14 something here called "Mechanisms of Total Pain

15 Relief," and this is a hypothetical model--and

16 please blame me for anything that is wrong

17 here--but let's just say that we can categorize

18 things in terms simply of we will call them Factor

19 X, which are NSAIDs, and like-related compounds,

20 Cox-2's, for example, and let's take a Factor Z,

21 which are opioids and related compounds, tramadol,

22 for example, and then Factors Y, which are future

23 drugs either in development or still in somebody's

24 mind somewhere.

25 Let's say that these then contribute to



1 this called chronic pain.

2 [Slide.

3 If we do some mathematics on this, can we

4 say that--let's form some hypotheses here. Can we

5 say Hypothesis 1, for example, that if you take any

6 X or any NSAID, and you add that to any Z or any

7 opioid, you will get 100 percent pain relief, is

8 that the correct hypothesis?

9 Or is it, Hypothesis 2, that we take any

10 combination of X and any combination of Z, we have

11 to add in something else, something else that is

12 missing, the Y factor, to really get 100 percent

13 pain relief?

14 [Slide.

15 Now, once we have answered or tried to

16 answer that, then maybe we then have developed a

17 plan for everybody. Plan 1, for example, going

18 back to Hypothesis 1, would be, well, we really

19 have all we need out there. All we need to do is

20 improve the safety of these existing compounds.

21 Or do we say Hypothesis 2 is true, and

22 sure, of course, we want to optimize use of

23 existing drugs, but what we really need to do is

24 develop and improve new drugs.

25 If that doesn't work, we have an



1 alternative plan and we are ready to go here, we

2 have the extra strength pain relief--and thank you,

3 Barb.

4 [Slide.

5 So, I think it is important, the ideas

6 that we discuss today, they sift down, they

7 eventually become drugs. They get into research,

8 both pre- or non-clinical and clinical. If they

9 are lucky, they come to us. If they are lucky

10 again, they get labeled and they get out there for

11 use.

12 [Slide.

13 We are very much a part of this process,

14 and we have become more so thanks to the help of

15 Dr. Meyer Katzburg, who I would like to acknowledge

16 for all his work in setting up what we now have as

17 we are live on the air. The Division has a web page

18 accessible through--go to the CDER web site. You

19 will see there is an announcement of this web page.

20 We are excited about it, it is still growing, and

21 we would love your comments. I can assure you what

22 you send to us, we will all read it, so make it

23 good.

24 [Slide.

25 A couple of months ago I had the pleasure



1 and pain experience to work with Dr. Dionne, who is

2 sitting here today, on the NIH-FDA Analgesic Drug

3 Development Workshop.

4 [Slide.

5 We had some objectives for that workshop.

6 We wanted to define pain in terms of the unmet

7 needs for pain management and where to go for unmet

8 needs in terms of pain research, and we discussed

9 how to harness the emerging technologies and

10 improve the development and ultimate FDA approval

11 of new therapies.

12 [Slide.

13 Of course, we had some outcomes and

14 suggestions from this. There was a concern that

15 this separation of pain into acute and chronic may

16 miss addressing the nervous system "plasticity"

17 that many feel goes on.

18 It was acknowledged that there is no

19 consensus for a pain metric, but that one, in fact,

20 needs to be developed to allow for comparisons and

21 poolings of results across the analgesic trials.

22 There was a lot of discussion as to

23 whether new analgesics need to be evaluated as

24 supplementary medications on existing ones because

25 that represents more accurately the pattern of



1 clinical use.

2 [Slide.

3 We talked about the need for new therapies

4 to treat pain mechanisms and we talked about how to

5 translate these scientific advances into improved

6 pain relief when it comes down it, it is going to

7 really take a cooperative effort between academics

8 and industry and the regulatory agencies, such as

9 us.

10 Then, we talked about the FDA guidance of

11 1992 and how it needs revision. Let me just talk

12 about that. Dr. Fang will be discussing it in much

13 more detail.

14 [Slide.

15 Let me just mention to you, so that we are

16 on the same page, that the document really

17 discusses analgesic approaches in the 1980's, and

18 if you read it, it assumes that revision would be

19 necessary with time, so I think we all are in

20 agreement that we have arrived.

21 Maybe one of the most distressing features

22 is that it encourages "me too" types of drugs

23 rather than encouraging the "me first" types of

24 drugs that I think we all agree we need in the

25 future.



1 So, without further delay, I would like to

2 introduce Dr. Christina Fang from the FDA.

3 I have omitted here, my mistake, I am

4 sorry, Dr. Sharon Hertz, also from FDA, will be

5 discussing the '92 guidance document and some of

6 the positives and negatives from that.

7 We will have Dr. Clifford Woolf from the

8 Mass. General talk to us about the issue of

9 plasticity, our own Lee Simon, who will be

10 discussing the pain claim structure, and Dr.

11 Borenstein will talk to us about what might be one

12 of those new indications in particular lower back

13 pain.

14 Thank you.

15 DR. FIRESTEIN: Thank you very much.

16 As you noted, we are going to move ahead.

17 If the FDA is going to revise the 1992 guidance, it

18 might be useful to first review what they are.

19 So, Dr. Christina Fang and Dr. Sharon

20 Hertz will do that now.

21 1992 Guidelines

22 Christine Fang, M.D.

23 DR. FANG: Good morning. My name is

24 Christina Fang. I am a medical reviewer for the

25 Division of Anti-inflammatory Analgesics and



1 Ophthalmic Drug Products.

2 [Slide.

3 I am going to talk about 1992 analgesic

4 guidance document and the current issues.

5 [Slide.

6 The 1992 Guideline for the Clinical

7 Evaluation of Analgesic Drugs had provided the

8 guidance to analgesic drug development and the

9 research in last 10 years. It was originally

10 developed with the focus on NSAIDs and opioid type

11 drugs.

12 With the emerging new molecular entities

13 and with our growing knowledge about analgesics and

14 analgesia, we see the need to resolve many major

15 issues.

16 [Slide.

17 The major areas for improvement in 1992

18 guidance document will be presented at the

19 subsequent slides. Each will be followed with a

20 brief discussion on major issues.

21 [Slide.

22 The 1992 Guidance document recommended the

23 analgesic indications to be for the management of

24 pain. It is stated that evidence of pain. It is

25 stated that evidence of pain of several different



1 etiologies will justify general purpose analgesic

2 labeling, also the inclusion of specific labeling

3 indications for preoperative medication, for

4 support of anesthesia, for obstetrical analgesics,

5 or the dysmenorrhea requires specific studies.

6 [Slide.

7 How general and how specific the

8 indications should be has always been in debate.

9 The indication recommended should be based on the

10 number of acute and chronic pain model studies.

11 All the analgesics should be studied

12 sufficiently to include representative

13 subpopulations of major types of pain. The purpose

14 is to provide guidance to practitioners and to

15 minimize unsafe and ineffective off-label use.

16 In terms of specific indications, there

17 are some limitations. For example, we are not able

18 to study all of the indications because of the lack

19 of model sensitivity. If a drug only works for

20 very specific indications, it should be

21 demonstrated that the drug has unique

22 pharmacodynamic activities directed only at the

23 specific indication.

24 [Slide.

25 Acute and chronic indications. This topic



1 has always been in debate, as well. We see the

2 need to study the short-term and long-term

3 efficacy, but how much should we have regulatory

4 requirement in terms of models, in terms of

5 replications, we see the same model and the

6 different models, and in terms of length of study.

7 How short-term or the multiple-dose study

8 will help us to study the initial dosing regimen to

9 see if loading dose is necessary and to determine

10 optimal dosing interval.

11 [Slide.

12 In the discussion of chronic studies, the

13 1992 Guidance stated that the focus of the

14 multiple-dose studies of more than 2 to 3 days in

15 duration is to provide documentation of clinical

16 acceptability and the safety of the test drug

17 rather than providing pivotal proof of efficacy.

18 [Slide.

19 Today, we no longer think of studies of 2

20 to 3 days in duration as chronic studies. We need

21 to determine the length for long-term efficacy

22 study. If adequately designed and well controlled,

23 the long-term studies should be able to provide

24 pivotal proof of efficacy.

25 It is especially valuable for drugs with



1 delayed onset. The reason we ask for long-term

2 studies is because we see the problem with

3 off-label use for chronic pain. Also, these

4 long-term studies will provide useful information

5 for product labeling, about long-term benefit-risk

6 ratio and the durability effect.

7 [Slide.

8 In terms of pain models, the 1992 Guidance

9 stated that the selection of pain model depends on

10 the strength of analgesia, route of administration,

11 model sensitivities, active controls, and mechanism

12 of action.

13 Also, the initial Phase II studies should

14 explore a wide enough range of pain models.

15 [Slide.

16 We see the need for more acute and chronic

17 pain models because we only have limited models for

18 study of acute pain and most of which were

19 developed for the development of NSAID type drug

20 and also we have limited models for chronic pain,

21 and most of those to be studied were

22 musculoskeletal in origin.

23 We also see the need for models to study

24 the worst type of pain because of the dosing

25 regimen that could be different for this kind of



1 setting, and maybe there is a need for concomitant

2 and rescue analgesics.

3 [Slide.

4 In terms of dosing, the 1992 Guidance

5 stated that Phase II studies "should explore the

6 entire dose-response curve of the test drug and

7 should be the basis for selecting the dose used in

8 later Phase II and Phase III studies."

9 Phase III studies are "intended to assess

10 the effectiveness of the recommended dosage

11 schedule under conditions of use."

12 [Slide.

13 We see the need for studying both dose

14 levels and dosing intervals at acute and chronic

15 settings. The dosage obtained from acute setting

16 may not apply to chronic use, and the dosing

17 recommendations should be based on optimal

18 benefit-risk ratio rather than dosing many for

19 convenience.

20 We should also differentiate fixed dosing

21 in clinical trials for establishing efficacy from

22 the variable dosing used in clinical practice.

23 [Slide.

24 In terms of efficacy parameters, the 1992

25 Guidance stated that, "The development program for



1 an analgesic should collect data to describe

2 adequately onset of effect, peak effect, and

3 duration of effect. There many ways to collect

4 data on these measures of efficacy."

5 Then, there is a long list of measured and

6 derived parameters in the 1992 Guidance document.

7 [Slide.

8 The choice of efficacy parameters should

9 be based on minimizing bias, demonstrating time

10 course of effect, and providing useful information

11 for dosing recommendations.

12 Pain curves, onset, and the duration

13 should all be studied using valid and reliable

14 tools, and should be studied for both acute and

15 chronic settings.

16 [Slide.

17 For chronic pain evaluations should

18 determine how much the pain-related functional

19 status and the patients global satisfaction should

20 be used for primary or supportive evidence.

21 [Slide.

22 In terms of study controls, the 1992

23 Guidance recommends the placebo and active control

24 for single-dose study, the active control or

25 placebo control with rescue for short-term,



1 multiple-dose study, and active control for

2 long-term or multiple-dose study.

3 [Slide.

4 We see the need for adequate controls in

5 both acute and chronic analgesic studies. The

6 placebo controls should always be considered

7 whenever applicable because of the high placebo

8 response in analgesic trials.

9 The superiority design versus equivalence

10 design should be planned accordingly. There are

11 some special considerations for chronic studies in

12 terms of differential dropout rates and in terms of

13 how to keep blinding intact if there are different

14 safety profiles between the drugs to be compared.

15 [Slide.

16 In terms of effect and sample size, the

17 1992 Guidance stated that the calculation of sample

18 size "depends on the variance, the magnitude of

19 difference to be detected, and the desired power."

20 Special consideration should be given to

21 the "validity and the implications of the clinical

22 significance of the differences or similarities to

23 be detected."

24 [Slide.

25 How do we determine clinically meaningful



1 effect size has been a debate. There is no

2 consensus on how to define up-to-date. There are

3 did approaches. Whichever approaches are used, a

4 wide database should be applied. The sample size

5 determination is closely related to the

6 determination of clinically meaningful effect size.

7 [Slide.

8 In terms of safety, the 1992 Guidance

9 stated that for peripherally acting or NSAID oral

10 analgesics, the study should regular dosing for a

11 least 6 months. For centrally acting oral

12 analgesics, there should be regular dosing for at

13 least 1 month, continuing for at least 3 months if

14 feasible. For oral combination analgesics, the

15 studies should have regular dosing for at least 1

16 month.

17 [Slide.

18 We see the need to study the safety in

19 terms of the relationship between extent of

20 exposure and adverse events. The extent of

21 exposure includes the level of exposure and the

22 length of exposure.

23 We see the need to study the maximum

24 recommended dosing proposed. The ICH guidelines

25 for chronic pain only provides the minimum



1 requirement for minimal number of subjects and the

2 length of exposure.

3 There may be a need to study the

4 representative study population. There may be a

5 need to study the special population with high

6 risks. The large safety trial may be needed if

7 there are serious safety concerns.

8 [Slide.

9 In terms of opioid sparing, we need to

10 determine the clinical relevance of opioid sparing.

11 We need to see the extent of dose sparing that is

12 clinically meaningful.

13 We need to decide if opioid sparing could

14 be discussed in terms of concurrent analgesics or

15 in terms of adjuvant analgesics. For opioid

16 sparing study design to be treated as a concurrent

17 analgesic, there should be consideration of

18 standardization of opioid use and also the data

19 analysis that combines pain data and the rescue

20 medication data, and we need to determine how to

21 evaluate efficacy and safety for this kind of use.

22 [Slide.

23 You can see we have many issues to be

24 resolved. We need a strong need to updating 1992

25 Guidance document. We see the need for proposals



1 for future analgesic research. There is also the

2 need for consensus among researchers, drug

3 sponsors, and the regulatory agency.

4 Here, I am just introducing the general

5 concepts and the details will be discussed by my

6 colleagues in the subsequent presentations.

7 Thank you very much.

8 DR. FIRESTEIN: Thank you very much.

9 Now we will go to the second half of this

10 presentation by Sharon Hertz.

11 Sharon Hertz, M.D.

12 DR. HERTZ: Thank you.

13 [Slide.

14 First of all, I would like to thank Dr.

15 Simon and his division for inviting us to

16 participate in this Advisory Committee. I am from

17 the Division of Anesthetics, Critical Care, and

18 Addiction Drug Products. As many of you may know,

19 we also work with a lot of the analgesic products.

20 I am going to present some highlights from

21 our internal discussions on analgesics development,

22 and there will be some overlap with Dr. Fang's

23 presentation. I think what may came out is that

24 there is tremendous overlap in the Division's

25 concerns and in a lot of our approaches to this



1 process.

2 [Slide.

3 The 1992 Guidance has been in use for over

4 a decade and we know that subsequent advances in

5 pain research and in pain management really are

6 calling for new approaches to analgesics

7 development.

8 The 1992 Guidance places what we feel is

9 an undue emphasis on models rather than on really

10 looking at particular clinical settings of intended

11 use and target populations, and this has led to

12 some ambiguous labeling and perhaps an inadequate

13 exploration of drugs in the context of the actual

14 clinical use.

15 [Slide.

16 We think that the guidance lacks an

17 adequate emphasis on Phase II dose finding and we

18 have seen many development programs that have come

19 through with very abbreviated Phase II programs.

20 [Slide.

21 There is not an adequate addressing of

22 duration of clinical trials, particularly for drugs

23 intended for chronic administration, and study

24 designs that are recommended in the guidance are no

25 longer considered practical and have been shown to



1 lead to somewhat ambiguous results.

2 [Slide.

3 Selection of adequate control groups, as

4 described in the current ICH guidelines, has

5 replaced some of the older thinking represented in

6 the older guidance.

7 [Slide.

8 While the 1992 Guidance makes a

9 distinction between pain due to inflammatory and

10 noninflammatory conditions, it fails to recognize

11 the greater variability in pain etiologies and how

12 this may impact on the response to different

13 analgesics.

14 [Slide.

15 Here are some of the basic development

16 points that we tend to focus on and request when we

17 discuss program development with sponsors.

18 Obviously, for Phase I, we like to see an adequate

19 characterization of the PK profile, but not just

20 for single dose, but also multiple dose studies.

21 We like to see preliminary safety and

22 tolerability over a very broad range of doses

23 potentially anticipating what will be used later

24 on.

25 [Slide.



1 During Phase II, we like to see the

2 product explored in potential target populations.

3 Pain conditions identified as responsive in

4 preclinical trials or experience with drugs of a

5 similar class may help define populations to begin

6 exploring during Phase II.

7 [Slide.

8 Analgesics are rarely used only as a

9 single dose agent, so single dose studies shouldn't

10 be proposed for support of marketing applications.

11 Rather, these should be used more to explore early

12 on, analgesic properties.

13 [Slide.

14 We like to see a wide exploration of

15 dosing during Phase II to help inform what would be

16 appropriate arms in Phase III trials.

17 [Slide.

18 Phase II provides a lot of very important

19 opportunity to explore outcome measures and

20 determine what approach is most likely to

21 demonstrate the best way to demonstrate efficacy of

22 this particular product.

23 [Slide.

24 Is there a subgroup that responds well,

25 suggesting a responder analysis is a better primary



1 analysis? If so, what are the characteristics of

2 that group? Or do most patients exhibit a moderate

3 but important improvement suggesting an analysis of

4 mean scores as most informative?

5 [Slide.

6 Are there products that are already

7 approved that are better than the studied product,

8 so that even though the study drug beats placebo,

9 it doesn't necessarily lend itself to the target

10 population in that study, that there may, in fact,

11 be another, better indication for the product?

12 [Slide.

13 During Phase III, we ask the sponsor to

14 consider ways to prospectively define a clinically

15 meaningful response for the primary pain variables,

16 preferably using validated measures. As Christina

17 mentioned, this is a very difficult thing to do,

18 because we don't necessarily know yet what

19 clinically meaningful represents.

20 We really prefer the use of validated

21 measures particularly for the primary outcomes.

22 [Slide.

23 For a product likely to be used

24 chronically, we request studies of adequate

25 duration. Typically, we request 12 weeks on final



1 titrated dose. This affords an opportunity to

2 assess durability and it is a concept, the 12-week

3 concept is also used for other products in other

4 areas of the Agency.

5 [Slide.

6 Also, for our particular drug groups,

7 particularly the opioids, these 12-week studies can

8 offer an opportunity to provide information

9 concerning tolerance if designed accordingly.

10 [Slide.

11 Efficacy needs to be replicated, not

12 necessarily in an exactly duplicated design, but in

13 a similar population, and these studies are going

14 to provide the basis for informing the label and

15 how the product is to be used.

16 We look forward to getting together with

17 the hosting division to discuss the outcome of this

18 Advisory Committee and to work together on further

19 guidance development and approach to analgesic

20 development.

21 Thank you.

22 DR. FIRESTEIN: Thank you, Dr. Hertz.

23 The next item on the agenda is a

24 discussion of some of the basic science behind pain

25 and analgesia by Dr. Clifford Woolf.



1 Basic Science

2 Clifford J. Woolf, M.D., Ph.D.

3 DR WOOLF: Thank you very much for this

4 opportunity to share a basic science perspective on

5 this very important issue.

6 [Slide.

7 What I would like to try and discuss today

8 is how the advances that have occurred in the last

9 10 years, since the 1992 Guidelines, some of the

10 advances that have been made and the implications

11 for them in looking at analgesia and analgesics,

12 and this issue of labeling.

13 Some of the particular issues I would like

14 to address is whether there is a basis for the

15 differentiation of pain in terms of its chronicity,

16 intensity, and how our understanding of the

17 mechanisms that are responsible for pain can drive

18 and may actually be included in any discussion

19 about indication.

20 [Slide.

21 To begin with, to look at pain chronicity,

22 I think it is important, when we look at the

23 difference between acute and chronic pain, to try

24 and identify whether chronic pain may be the

25 results of the persistence of a mechanism or may be



1 the result of the recruitment of a novel mechanism

2 that is not present in those patients that have

3 acute pain, because these clearly are quite

4 different.

5 [Slide.

6 So, doing a kind of an analysis of those,

7 we can readily appreciate that acute pain

8 characteristically is transient, it may be

9 recurrent, but it is always reversible. That is a

10 key element implicit in our definition of acute

11 pain, whereas, chronic pain, I think we can

12 usefully divide into two very broad categories.

13 There are those patients who have

14 long-lasting pain which is reversible, so that if

15 the driving mechanism responsible for that pain is

16 removed, that pain will tend to disappear, whereas,

17 there are other patients where the pain is truly

18 persistent and we can even say irreversible.

19 I think these are very distinct

20 subcategories and we need to recognize and solve

21 that.

22 [Slide.

23 In terms of looking at pain intensity,

24 again, the issue is whether there is a continuum of

25 pain mechanisms that can generate pain of different



1 intensity divided between mild, moderate, and

2 severe, or whether each of these levels of

3 intensity of pain reflect discrete mechanisms that

4 operate, that are recruited at different levels of

5 disease or as new etiological factors come into

6 play.

7 Another important aspect we need to take

8 into account is when we look at the intensity of

9 pain that is experienced by an individual, whether

10 that reflects an increase in some stimulus, some

11 external driving force, some disease factor, or,

12 indeed, may be an alteration in the responsiveness

13 of the nervous system.

14 Certainly, there is now increasing belief

15 amongst basic scientists that the responsiveness of

16 the nervous system can alter quite profoundly, and

17 an increase in intensity may not necessarily

18 reflect an increase in stimulus.

19 [Slide.

20 The simple underlying approach to pain

21 until quite recently was that multiple etiological

22 factors operating by means of inflammation, tissue

23 damage, nerve lesions, or a number of other ways,

24 could act on a highly specialized sensory apparatus

25 in the nervous system to drive the symptoms and



1 signs that we now collectively call pain, and that

2 there was, if you like, this convergence of

3 etiological factors acting on the nervous system to

4 initiate a set of changes which generated the

5 response that we interpret as pain and that we

6 could then subdivide the pain depending on the

7 etiological factors, the duration, the associated

8 changes into different pain syndromes.

9 What I would like to argue today is that

10 we need to move away from this very simple model,

11 and I would like to show you why it is neither

12 correct nor helpful in defining the approach the

13 analgesics.

14 [Slide.

15 One of the main reasons is that it has

16 become increasingly clear that we are dealing with

17 multiple distinct pain mechanisms. This is an

18 incomplete list. Almost certainly this list is

19 going to change as our understanding of pain

20 improves, but it is clear that there is a distinct

21 mechanism that is responsible for nociception by

22 which I mean the sensory mechanism that is

23 responsible for pain in response to a transient

24 non-damaging, noxious stimulus.

25 There are distinct mechanisms that operate



1 to alter the sensitivity of the high-threshold

2 nociceptive primary afferents that are responsible

3 for nociception, and these changes at the

4 peripheral terminals of these nociceptors are what

5 we call peripheral sensitization and are a major

6 driver of inflammatory pain.

7 In addition, it is increasingly apparent

8 that changes in the processing of sensory

9 information within the central nervous system, that

10 collectively we can call central sensitization,

11 play a major role in the shaping of the pain

12 experience and may in some individuals and in some

13 situations be a major factor responsible for the

14 pain.

15 After nerve damage, we now appreciate

16 there is the development of ectopic excitability,

17 sensory inflow with a sensory stimulus. There are

18 also increasing indications that lack of inhibition

19 and structural alterations in the nervous system

20 may play a major role particularly in chronic pain

21 associated with nerve damage.

22 Today, I am going to stick my discussion

23 to the first three mechanisms and try and

24 illustrate how understanding of them has

25 implications for determining the efficacy of



1 different groups of analgesics.

2 [Slide.

3 In addition to multiple pain mechanisms,

4 we need to recognize that pain is not a monolithic

5 single entity. There are different pain symptoms

6 that may complicate a way to reflect these

7 different mechanisms, and that if we use global

8 pain scores, we may be missing some of the

9 different mechanisms that operate in different

10 conditions, so it is important for us to appreciate

11 that there is spontaneous pain, pain that

12 apparently arises without any peripherals or

13 without any stimulus, and evoked pain, pain that

14 occurs in response to some input.

15 Spontaneous pain itself may be divided

16 between that that appears to derive from the skin,

17 from the superficial structures of the body, and

18 that which is deep. Indeed, there are differences

19 between the pain that is continuous and that which

20 is intermittent, and clinically, we certainly

21 recognize that these are not the same.

22 Evoked pain, again there is enormous

23 difference between pain that is evoked by thermal

24 and mechanical stimuli, and it is important to

25 differentiate pain that occurs in response to a



1 stimulus that normally would not be painful, what

2 we call allodynia, and an exaggeration of the

3 response to a noxious stimulus, that which we call

4 hyperalgesia.

5 What I would like to argue is that each of

6 these different categories reflects different

7 activities in the nervous system and it is

8 essential in performing clinical trials to try and

9 capture as much of this information because it

10 reflects some of the processing that generates the

11 pain experience.

12 [Slide.

13 To illustrate the points that I have made,

14 I am going to look at the COX-2 selective or

15 specific inhibitors and try and identify from our

16 increased knowledge of the mechanisms that operate

17 to produce pain, how there may be elements of pain

18 that are sensitive to these classes of drugs and

19 others that are not, and for that reason, why the

20 discussion of whether it is appropriate to discuss

21 global analgesics or even analgesics that are

22 appropriate for all acute pain or all chronic pain

23 needs to take into consideration some of these

24 factors.

25 [Slide.



1 So, to begin with, to come back to

2 nociception, as I said before, this is the term

3 that we use to describe the capacity of the nervous

4 system to respond to particular intense stimuli,

5 noxious stimuli, those stimuli which have the

6 capacity to damage the body.

7 These stimuli are detected by highly

8 specialized primary sensory neurons, the nociceptor

9 neurons, which respond only to intense, and not to

10 innocuous stimuli, and they feed into particular

11 neurons within the central nervous system that

12 transfers this information to that part of the

13 cortex that eventually results in the sensation or

14 the perception of pain.

15 This, if you like, is the "ouch" pain, the

16 pain we feel in response to a pinprick or touching

17 something that is too hot or too cold, and clearly,

18 it has a major role as a protective mechanism, an

19 early warning device, and that is something we need

20 to appreciate because abolition of no nociception,

21 while appropriate in some conditions, such as

22 during surgical intervention, is not appropriate in

23 the chronic setting.

24 [Slide.

25 How does nociception generate? Well, if



1 we think back to 1992, we had almost no information

2 on how noxious stimuli act on the nervous system to

3 generate nociception, and in the last 10 years, the

4 progress has been extraordinary. Only in the last

5 few months has the receptor, the CRM1 receptor been

6 cloned that converts cold stimuli into cold pain.

7 Heat pain is detected by a number of

8 different receptors. About five years ago, the

9 vanilloid receptor 1 was identified as being a heat

10 transfuser, and only in the last month has another

11 member of the vanilloid family, the TRPV3, the TRP

12 channel V3 been identified.

13 So, we now know the individual ion channel

14 receptors that respond to these noxious stimuli and

15 produce generated potentials. There are also

16 receptors that respond to chemicals released at the

17 time of tissue damage, such as bradykinin, the B1

18 and B2 receptors, and we are at the point of

19 understanding how intense mechanical stimuli are

20 transfused into electrical activity.

21 Now, the point of going through all of

22 these is that you will see there are no

23 prostaglandin receptors, there is no COX-2 here, so

24 that the process by means of which an intense

25 thermal chemical or mechanical stimulus produces



1 nociception is COX-2 insensitive. No amount of

2 COX-2 inhibitors given at anytime will affect the

3 way we respond to pinprick or heat stimulus, so

4 that COX-2 is not appropriate for that indication.

5 [Slide.

6 If we look at the transfer of information

7 from the primary sensory neuron to central

8 neurons--and this is an attempt to cartoon the

9 central terminal of nociceptors and their synaptic

10 interaction with neurons in the spinal cord--we

11 have identified the key transmitters that act to

12 transfer this information.

13 There are both excitatory amino acids,

14 such as glutamate and neuropeptides, such as

15 substance P, and they act on a number of receptors

16 on the postsynaptic neuron, both inotropic

17 receptors and metabotropic receptors, and these can

18 be modulated in different ways by a number of

19 receptors which play a role in inhibitory

20 mechanisms.

21 The GABAergic, particularly the GABA-A

22 receptors, which control presynaptic release of

23 transmitters and a number of other receptors,

24 particularly the opiate receptors, which are

25 expressed both pre- and post-synaptically, and can



1 reduce synaptic transmission.

2 So, opiate receptors and opioids, opiate

3 receptor activation and opioids can certainly

4 modify this transmission process and can reduce

5 nociception, but again, you will see that there is

6 no COX-2 or prostaglandins involved in this, and

7 once again, nociception, both peripherally and

8 centrally, is not COX-2 sensitive.

9 [Slide.

10 That is essentially the conclusion made

11 here.

12 [Slide.

13 If we talk about COX-2 as being an

14 analgesic, we need to take onboard that it is not a

15 global analgesic, it does not reduce all pain in

16 all circumstances, and it certainly will not reduce

17 nociception, which is actually a desirable

18 consequence of all chronic usage as I have

19 indicated.

20 [Slide.

21 We now move on to peripheral

22 sensitization. This is the setting now where we

23 have inflammation in the periphery. The peripheral

24 terminal of nociceptors are exposed to inflammatory

25 mediators, and this changes the peripheral terminal



1 in the way that this terminal can now be activated

2 by stimuli that have a lower intensity, so that

3 both stimuli that would normally not produce pain,

4 and noxious stimuli produce a greater response, and

5 this creates the situation where we have what is

6 called primary hyperalgesia, which is abnormal pain

7 sensitivity in the site of tissue damage, and one

8 of the particular roles that peripheral

9 sensitization has been shown to operate in is

10 primary heat allodynia, the reduction in the heat

11 threshold for producing pain.

12 Normally, we require stimulus of about 42

13 degrees for the conversion of a hot to a painful

14 stimulus, but in the presence of inflammation, this

15 can fall quite substantially.

16 What are the mechanisms involved in

17 generating peripheral sensitization? Well, they

18 are multiple, but the one that I want to highlight

19 today is that as a result of the inflammatory

20 response and the release of cytokines, particularly

21 IL-1 beta and TNF-alpha, there is the induction of

22 changes in cells surrounding the inflamed area of a

23 number of enzymes and growth factors and

24 chemokines, but the one here that I want to

25 emphasize is COX-2, but if COX-2 and phospholipase



1 are induced at the site of peripheral inflammation,

2 that results after action by specific tissue

3 isomerases and the production of prostanoids, such

4 as prostaglandin E2, which can then act on EP

5 receptors, prostaglandin receptors that are

6 expressed on the peripheral terminal of the primary

7 nociceptor.

8 Prostaglandin, when it acts on the

9 peripheral terminal, does not directly produce an

10 activation of the peripheral terminal, it does not

11 itself produce pain. What it does do is alter the

12 excitability of the peripheral terminal, and we now

13 know how that occurs. It is via activation of

14 kinases that are present in the peripheral terminal

15 that phosphorylate either transducive proteins,

16 such as the vanilloid VR1 heat transducer, reducing

17 its threshold of activation or it phosphorylates

18 ion channels that are present in the peripheral

19 terminal making the peripheral terminal

20 hyperexcitable, so that less of a stimulus or less

21 transducer action is required to activate the

22 peripheral terminal.

23 I indicate there is a northern blot on the

24 side showing that in normal skin, there is

25 undetectable COX-2 levels, but within several hours



1 of peripheral inflammation, there is an enormous

2 induction of this enzyme, and the point being that

3 this particular pain is COX-2 sensitive. You

4 cannot have COX-2 action if there is no target

5 COX-2 expressed, but after peripheral information,

6 it begins to be expressed, so this particular

7 mechanism is COX-2 sensitive.

8 There are, in addition to prostanoids,

9 other mechanisms that can drive peripheral

10 sensitization, which means that COX-2 inhibitors

11 may not completely eliminate this process.

12 Bradykinin, amines may also produce these changes,

13 this activation of kinases, which can phosphorylate

14 some of these proteins.

15 Conceivably, drugs may be developed that

16 can block these kinases and even their targets,

17 such as the vanilloid receptor or the ion channels,

18 and may actually totally abolish the changes that

19 are produced by peripheral inflammation.

20 [Slide.

21 I now want to move on to changes that can

22 occur within the central nervous system, changes in

23 the excitability of neurons which alter its

24 responsiveness, and the situation here is that we

25 now recognize that noxious stimuli produced by



1 irritants, tissue damage, inflammation, anything

2 that can activate nociceptors can result in a use

3 or activity-dependent plasticity within the central

4 nervous system, altering the excitability of these

5 central neurons, and this results in a situation

6 whereby these neurons respond to normal inputs in

7 an exaggerated or abnormal way.

8 This generates two broad changes that we

9 can recognize in pain. One is secondary

10 hyperalgesia, which is a change in sensitivity to

11 pain outside of an area of tissue damage or

12 inflammation.

13 Peripheral sensitization contributes to

14 the pain sensitivity at the site of tissue damage,

15 but central sensitization, this abnormal

16 responsiveness of central neurons, contributes to

17 the change in sensitivity that spreads into normal

18 non-damaged or non-inflamed tissue outside the area

19 of tissue damage.

20 One particular mechanism that we now

21 recognize as being driven by central sensitization

22 is tactile or brush-evoked allodynia. This is the

23 pain that can occur by the activation of normal

24 low-threshold mechanoreceptors that would be

25 activated by lightly touching or brushing the skin.



1 After the induction of central sensitization, such

2 stimuli can begin to produce pain, and this is a

3 reflection of this mechanism.

4 [Slide.

5 The reason why central sensitization

6 produces changes in pain is it turns out that the

7 pain projection neurons within the nervous system

8 do not exclusively receive input from nociceptors,

9 the high-threshold sensory fibers.

10 They receive, in addition, an input with

11 weak synaptic input from low-threshold

12 mechanoreceptors. This synaptic is normally too

13 weak to drive the cells, so that activity generated

14 by light touch, movement of a joint will not

15 normally generate an output in the pain projection

16 neurons, but if the excitability of the central

17 neurons is increased, then, this normal input in

18 normal, low-threshold mechanoreceptors can begin to

19 drive these abnormally excitable central pain

20 projection neurons and result in the recruitment of

21 pain in response to this normal input.

22 This is the mechanism for brush-evoked

23 mechanical allodynia.

24 [Slide.

25 What actually produces the increase in



1 excitability of the central neurons and the

2 specific details are not important for the purposes

3 of this discussion, but just to say that it turns

4 out there are two phases to the production of

5 central sensitization.

6 There is an acute phase that occurs within

7 seconds of the activity of nociceptors. If you

8 activate nociceptors intensely, and this can be

9 done by an irritant stimulus or heating the skin or

10 tissue damage, that will result in the release of

11 glutamate and beyond it, if there is enough

12 glutamate released as a result of repetitive

13 activity in nociceptors, that will induce

14 activation of intracellular kinases, cyclic

15 AMP-dependent protein kinase A, and

16 calcium-sensitive protein kinase C, which will

17 phosphorylate the receptors and ion channels on the

18 postsynaptic membrane, altering their

19 responsiveness.

20 So, there is an activity-dependent change

21 in the excitability of the postsynaptic membrane

22 due to the synaptic release. Again, you can see

23 that while there are multiple players invoked in

24 here, COX-2 is not a feature. So, this component of

25 central sensitization, the acute component that is



1 switched on almost immediately by intense

2 nociceptor activity is not COX-2 sensitive.

3 [Slide.

4 However, it turns out that peripheral

5 inflammation, in addition to inducing COX-2 in the

6 site of tissue damage, as I have indicated, also

7 induces COX-2 within the central nervous system, in

8 the spinal cord, and this occurs after several

9 hours.

10 The question is does this have any role in

11 central sensitization.

12 [Slide.

13 Well, there are two things to first

14 recognize, is that the central induction of COX-2

15 occurs only in response to peripheral inflammation,

16 and not in response to peripheral nerve damage, so

17 again, we need to differentiate when we are looking

18 at this mechanism the way it operates after tissue

19 damage and inflammation is quite distinct from what

20 happens after peripheral nerve injury.

21 It turns out that the late phase of

22 central sensitization, that phase that occurs hours

23 and days after tissue damage does involve COX-2,

24 because COX-2 begins to be induced in neurons

25 within the central nervous system, produces



1 prostaglandins which have multiple actions,

2 increasing transmitter release, increasing the

3 excitability of postsynaptic receptors, as well as

4 blocking some inhibitory actions.

5 The net result is that the increase in

6 excitability of central neurons acutely is not

7 COX-2 sensitive, but that which occurs some hours

8 after tissue damage begins to have a component that

9 is COX-2 sensitive.

10 [Slide.

11 So, the conclusions I would like to make

12 from this is that there are COX-2 sensitive

13 peripheral and central components of inflammatory

14 pain, but not necessarily of the pain associated

15 with peripheral nerve injury, that COX-2

16 inhibitors, as an example, can only act when their

17 target is expressed. It needs to be induced. This

18 takes a finite amount of time.

19 The cytokines IL-1 needs to produce, it

20 needs to act on cells, which then switch on

21 transcription factors, such NF kappa B, which then

22 switch on the COX-2 gene, the messenger RNA has to

23 be made, translated into protein, and this needs to

24 be transported to the appropriate place in the

25 cell.



1 This takes several hours, so that after

2 peripheral inflammation, you only get a COX-2

3 sensitive component when the COX-2 is expressed and

4 there.

5 There are also non-prostanoid contributors

6 to inflammatory pain, and this may explain why

7 COX-2 selective or sensitive inhibitors cannot

8 produce a complete relief of pain. Other

9 mechanisms continue to operate. So, that may

10 contribute to the ceiling effect of these class of

11 drugs.

12 I have already mentioned that peripheral

13 nerve injury may not be present.

14 [Slide.

15 So, I think we need to consider then what

16 are the models that are appropriate for looking at

17 the relationship between etiology and the symptom

18 that we call pain.

19 Well, one possibility may be that

20 different etiologies may act on the nervous system

21 to produce different distinct mechanisms that may

22 produce particular symptoms. If you need to treat

23 the particular kind of pain associated with a

24 particular etiology, you can target the individual

25 mechanism.



1 Unfortunately, the reality as far as we

2 can judge is more like this, that a single

3 etiological factor can operate on the nervous

4 system to operate multiple mechanisms. Peripheral

5 sensitization and central sensitization are not

6 independent, both can be switched on by peripheral

7 inflammation.

8 Peripheral nerve injury can produce both

9 ectopic excitability and central sensitization, and

10 part of the challenge that we have is to try and

11 identify the links between different etiological

12 factors and the mechanisms they operate, as well as

13 how the different mechanisms can change, produce

14 the symptoms that the patient complains of.

15 [Slide.

16 What I would like to try and suggest is

17 that we need to differentiate between analgesic

18 drugs, drugs where the implication is a global

19 relief of pain, and drugs where there is a

20 reduction of the abnormal sensitivity of the

21 nervous system, and that this is a useful

22 distinction.

23 I hope I have indicated to you that both

24 the temporal and intensity characteristics of pain

25 do not, by themselves, reflect mechanisms, that



1 they are different mechanisms that can operate to

2 produce both acute and chronic pain, and that for

3 this reason they may not, by themselves, be useful

4 predictors of analgesic action.

5 I would like to argue that as we begin to

6 understand more about pain mechanisms and the very

7 particular mechanisms that individual drugs have,

8 that it is this combination that is going to

9 provide the most useful input for determining

10 indication and efficacy.

11 [Slide.

12 In order to make progress, we need to move

13 away from using exclusively global pain scores as

14 our outcome measures. We need outcome measures

15 that are sensitive or specific to particular

16 mechanisms, and that is a big challenge.

17 We need clinical trials that can validate

18 mechanistic hypotheses and that are designed

19 specifically to address the issue of which drugs

20 acting on which mechanisms can alter the symptoms

21 in particular groups of patients.

22 We need to consider labeling claims and

23 the like to the action of drugs, with the

24 interaction of the drugs with specific pain

25 mechanisms, as well as the more traditional



1 approach, which has been empirical trials looking

2 for efficacy.

3 My final conclusion is that I think--and

4 this overlaps to some extent with the comments made

5 by Jim Witter--are there going to be global

6 analgesics. I think this is unlikely.

7 Pain has too many different mechanisms

8 operating that it is very unlikely that a single

9 drug is going to affect all of them and that the

10 challenge we have is to try and optimize the way to

11 detect which particular mechanisms an individual

12 drug is operating to see the utility of blocking

13 that mechanism for particular groups of trials and

14 let that drive the labeling of the drugs.

15 Thank you.

16 DR. FIRESTEIN: Thank you very much for an

17 excellent discussion.

18 Discussion Points #1 and 2

19 DR. FIRESTEIN: At this point, we can move

20 into some of the discussion issues that were raised

21 by Dr. Simon and the Agency. I believe that we

22 were going to discuss Points No. 1 and 2. I will

23 just read the first one and then open it to the

24 group for comment.

25 1. A revised analgesic guidance may



1 include indications intended to inform labels for

2 the management of acute versus chronic pain, rather

3 than a general pain claim. Please comment on the

4 clinical relevance of this distinction in terms of

5 efficacy and safety.

6 if there is anybody who would like to get

7 the ball rolling here? I suppose that then becomes

8 the Chair's prerogative to comment and then have

9 everybody disagree with me.

10 I think that the discussion that we have

11 already had, defining the distinct mechanisms of

12 pain, raised some of the issues about separate

13 labels for acute versus chronic pain as opposed to

14 a general pain claim versus a specific claim that

15 is mechanism based.

16 I think in particular, one of the things

17 that was discussed earlier was the question of

18 whether chronic pain in some cases merely

19 represents persistence of acute pain mechanisms,

20 and how can one distinguish that in a chronic pain

21 labeling is going to be quite difficult.

22 I don't know, Dr. Woolf, you might want to

23 comment on that particular aspect.

24 DR. WOOLF: The point I was trying to make

25 using the COX-2 inhibitors would be, to get down to



1 specifics, that although they may have an

2 indication for chronic pain based on a number of

3 replicate trials showing efficacy in chronic pain,

4 the evidence indicating that there is no COX-2

5 induction of peripheral nerve injury, which may

6 certainly produce chronic pain, would indicate that

7 most patients with neuropathic pain may not respond

8 to COX-2 inhibitors, so that an indication of

9 chronic pain by itself is incomplete and may lead

10 to inappropriate use of analgesics, which may not

11 have efficacy in certain particular groups of

12 patients.

13 So, the issue then is does chronic pain,

14 by itself, have a meaning. I think we have just

15 got to be a little cautious of that.

16 DR. FIRESTEIN: I guess on the other hand,

17 it might at least bring us a little closer to

18 reality as opposed to a more global pain

19 indication, in other words, although there are

20 clearly limitations between acute versus chronic

21 pain, that is less problematic than trying to have

22 a global pain indication that would cover all

23 aspects of all pain indications.

24 DR. MAX: Gary, you have already in your

25 question, you already indicated that this



1 distinction is mechanistically insufficient,

2 because you said chronic back pain can have acute

3 inflammation on top of it. I think it is clear

4 from Clifford's talk that this does not do very

5 much for us with mechanisms.

6 However, just from a practical clinical

7 setting point of view, I think it is clear that

8 when we talk about acute pain, we are talking about

9 a specific clinical orientation of the patient.

10 They have sudden bad pain and they are willing to

11 do anything they can for a few days to handle it,

12 and a little bit of impairment of work might be

13 okay.

14 On the other hand, in chronic pain, we

15 really need evidence from day-in, day-out living,

16 not just the single dose trial, that the patient

17 has got to be able to live with the analgesic

18 regimen and the way of evaluating it is going to be

19 much different.

20 So, I think the main argument for this

21 division being important is the practical

22 considerations, the clinical setting, are so much

23 different that they really imply completely

24 different clinical trial designs.

25 I mean once we take each, then, we can



1 bring in some of the mechanistic considerations

2 that will be hard.

3 DR. FIRESTEIN: Dr. Brandt, did you have a

4 comment?

5 DR. BRANDT: Yes. I think, Dr. Woolf,

6 that was really a beautifully lucid and useful

7 dissection of mechanisms. To bring it to

8 osteoarthritis pain, I would like to ask whether it

9 suggests a research approach.

10 Nonsteroidals for patients with

11 osteoarthritis improve pain on average, on visual

12 analog scales, 20, 25 percent. Some patients get

13 terrific relief, some patients get worse, but on

14 average, 20, 25 percent.

15 If you add acetaminophen to a

16 nonsteroidal, you get a further increment, but

17 there still is a significant amount of residual

18 pain. Based on what you said, presumably, there is

19 another mechanism that is driving it, how does one

20 get at that, how does one study that to know what

21 sort of drug might be useful or might be reasonably

22 tested to get at that residual pain.

23 DR. WOOLF: Chronic osteoarthritis is a

24 very interesting disease from a basic science point

25 of view. The problem we have is that there are



1 very poor preclinical models that it is very

2 difficult to test in the preclinical setting what

3 the mechanisms are.

4 The fact that there is a response, even

5 though modest, to standard NSAIDs when in most

6 patients there is not ongoing inflammation, raises

7 the issue of where is the COX-2 that presumably

8 they are acting on, so I think the first research

9 question is, is this a disease of the periphery in

10 terms of COX-2 mechanisms or is the COX-2 induced

11 in the central nervous system.

12 The fact that there is an additional

13 contribution of acetaminophen would imply that that

14 is likely to be the case.

15 The ceiling effect of NSAIDs is as you

16 indicate, and the fact now with the

17 second-generation COX-2's, where the doses can be

18 pushed to a level where all conceivable COX-2 is

19 likely to be inhibited certainly indicates that

20 there is a residual mechanism that is not COX-2

21 sensitive.

22 What it is, is obviously the big

23 challenge, and I could speculate, but I think this

24 is where new drugs with new targets are coming onto

25 the market. Some of them may be useful by



1 themselves, but I think in clinical practice, we

2 know already that polypharmacy is a standard way in

3 which patients are treated.

4 So, it is very likely that these new

5 drugs, acting on different independent targets,

6 will have a role, sometimes by themselves, but

7 often in combination with existing therapy.

8 DR. FARRAR: Understanding that even in

9 the realm of arthritis, it is very often difficult

10 to identify in any given patient the primary cause

11 for their discomfort, I wanted to ask Dr. Woolf

12 whether, if we were able to identify a subset of

13 arthritic patients who had, in fact, a very similar

14 peripheral mechanism, whether that nice

15 pathophysiology slide you showed with all the

16 various mechanisms, whether all of those mechanisms

17 would apply in every patient or whether, in fact,

18 there would be within even a mechanistic approach,

19 differences in the way that a particular patient

20 responds to both the pain and the underlying

21 treatment based on the fact that some may have a

22 predominance of one kind of receptor over another

23 or a predominance of one response over another.

24 DR. WOOLF: I think it is even more

25 complicated than that. I think it is not only the



1 problem that individual patients within a

2 particular group or clinical entity, a particular

3 form of arthritis may have different mechanisms,

4 but an individual patient over the evolution of

5 their disease will almost certainly have different

6 levels of contributions of the different

7 mechanisms.

8 The challenge is how to identify them, and

9 the fact, the comment that was made that some

10 patients may respond extremely well to NSAIDs than

11 others, I think that gives part of the clue. I

12 think one of the tools that we are going to have to

13 use are drugs to try and identify mechanisms.

14 Those patients who respond very well to

15 COX-2 inhibitors, by definition, we are defining at

16 least one component of their pain is COX-2

17 sensitive, whereas, those patients that don't,

18 assuming the drug, the notions of bioavailability

19 or PK, we can conclude that in those individual

20 patients, there is not a COX-2 component.

21 So, I think we are going to have to use a

22 combination of trying to link up symptoms with

23 mechanisms, which is difficult, but not impossible,

24 as well as the responsiveness of the patient to

25 very specific forms of therapy.



1 DR. SHERRER: A question as it relates to

2 chronic pain, because it was mentioned earlier by

3 Dr. Witter, and it is certainly true clinically,

4 that there are two types of chronic pain. There is

5 the chronic persistent pain, and there is the

6 chronic acute intermittent pain or intermittent

7 pain at least.

8 Do those patients represent people with

9 repetitive acute pain mechanisms even though it is

10 one disease, such as the osteoarthritis patient who

11 flares every few weeks or with a weather change or

12 with activity, or, in fact, is that a different

13 mechanism of chronic pain?

14 DR. WOOLF: I gave an example just to try

15 and differentiate in the most global sense, but

16 there will again be patients, such as those with

17 trigeminal neuralgia, who will also have

18 intermittent pain where the mechanism will be

19 completely different from an OA patient with flare,

20 so I hope I didn't give the impression that that

21 represents two distinct mechanisms.

22 There may be again multiple mechanisms

23 that operate between those two classes, but I think

24 we are all aware of patients who have OA of the

25 hip, when the hip is replaced, can do extremely



1 well with minimal recurrence of pain, where there

2 are patients with peripheral neuropathic pain where

3 the neuroma is removed, and they have a transient

4 response and the pain comes back, so the point

5 being that in some cases, removing the etiology,

6 the cause, the hip, can actually remove the pain,

7 whereas, in other patients, it appears as if the

8 mechanisms have now been hard wired, if you like,

9 and are resistant to, are no longer driven by the

10 initial disease process.

11 DR. FIRESTEIN: Let's come back to one of

12 the issues raised here, and that is whether or not

13 there is utility to differentiating between acute

14 versus chronic pain as compared with a general pain

15 claim and, in particular, issues that relate not

16 only to efficacy but safety.

17 One example of that would be for the

18 selective COX-2 inhibitors where one dose might be

19 approved for the treatment of acute pain and has

20 had either a dosage creep that has then at least in

21 the clinic led to use of some of these higher doses

22 for chronic treatment, and some of the safety

23 issues may not have been addressed in the clinical

24 trials because of that.

25 Does anybody have a comment? Yes.



1 DR. ELASHOFF: What I wanted to ask is in

2 the first day or so of pain, if you are labeling

3 things for acute or for chronic, does one know in

4 the beginning whether you ought to be using the

5 ones labeled for acute, because you don't know

6 whether it might turn out to be chronic or not, or

7 might you have the knowledge to say you ought to be

8 starting in with chronic, so would one always start

9 with acute things and then switch, or does one

10 potentially have the knowledge at the beginning

11 that you might start out with chronic things.

12 So, it seems to me that the issue of the

13 labeling has to also say, well, practically

14 speaking, how would you know in any given situation

15 which ones you are going to be using.

16 DR. FARRAR: I think we need to very

17 carefully differentiate between how we use the

18 medicine and what we are treating. The question

19 you are asking really relates to whether the

20 medicine is used over a long period of time or

21 whether it is used over a short period of time.

22 I think the issue is not answerable from

23 an acute or chronic perspective. If you take

24 migraine headache, there are medicines that are

25 used to prevent it, that are used regularly over a



1 long period of time, and then there are medicines

2 that are used to treat it, which may be used over a

3 very short period of time.

4 I think we need to differentiate between

5 whether it is used over a long or short period,

6 which can be done in a label, to say this drug can

7 only be used for, it has only been shown to be safe

8 for six weeks versus saying whether you are

9 treating acute or chronic pain. I think those two

10 are very different.

11 DR. CUSH: But aren't you just saying the

12 same thing? I mean it is acute, a short period,

13 and chronic if it's long term. We know that based

14 on what the etiology of the pain is, the problem,

15 whether it's postsurgical or dysmenorrhea or

16 migraine, what our goals are as far as short term

17 or long term.

18 But the terms of acute therapy and chronic

19 therapy are useful. They dictate how we use these

20 drugs. They dictate our expectations for these

21 drugs. To go with a more general pain claim is too

22 vague and not applicable to many patients that we

23 use.

24 DR. FARRAR: But don't confuse acute

25 treatment and chronic treatment with acute pain and



1 chronic pain. As was said here, you don't know

2 when you start necessarily whether it is going to

3 be a 2-day treatment or a 10-day treatment.

4 DR. CUSH: I think most physicians do know

5 when they start out with managing pain what the

6 goals are for pain management. Now, it is not to

7 say that patients who start out with a migraine

8 don't have a migraine that might be extending out

9 beyond a few days, and acute therapies may not

10 work, but I think that there are goals when you

11 make a diagnosis and see a patient as far as

12 whether it is going to be short-term therapy or

13 long-term therapy.

14 DR. WOOD: I also found the last talk very

15 interesting, but it seems to me the question that

16 we need to debate is where the science is with this

17 and whether the science is mature enough to

18 actually make decisions on this.

19 I mean I would characterize this as being

20 a bit like, say, leukemia. Leukemia is

21 characterized by an increased white count, and

22 clearly the management of leukemia depends on

23 knowing a lot more than just that the number of

24 white blood cells is increased.

25 You need to know the etiology, you need to



1 know the subset of patients, the subset this

2 patient belongs to in order to define an

3 appropriate therapy.

4 So, my question I think is the following -

5 is the science mature enough or likely to become

6 mature enough in the foreseeable future to divide

7 patients into subsets based on the kind of

8 divisions that Dr. Woolf described, and are we or

9 will we be at a stage in the near future when we

10 could make treatment decisions based on such

11 subdivisions, or alternatively, is this solely at a

12 stage where this should guide or direct drug

13 development, and are you proposing this, not as a

14 treatment decision paradigm, but one that would

15 allow us to identify potential new targets for drug

16 development, which--and this is important for this

17 discussion--which we would then need to define in

18 some way, a way in which we would approve the drug,

19 because it is improbable that the approval will be

20 based on some surrogate for the subsets you are

21 talking about.

22 Does that make sense?

23 DR. WOOLF: Yes, I think so. The

24 situation we are at currently has been based on the

25 experience with both NSAIDs and opiates, and we now



1 have a sense of which patients are likely to

2 respond, the kinds of outcome measures that are

3 sensitive to that.

4 My concern is that the basic science is

5 now revealing new targets which industry are

6 developing new molecules, and the current models

7 that the 1992 Guidelines reflect are not

8 appropriate for that, that if we use these models,

9 there may be heterogeneity of mechanisms in the

10 patient groups that we study that will dilute the

11 outcome measures to a point where it may look as if

12 there is no efficacy globally, whereas, in fact, in

13 the subgroups that do have the particular

14 mechanisms, you would get very high efficacy, and

15 that was a point that was raised by Dr. Fang

16 earlier, that the responder rate may reflect the

17 different incidences of mechanisms.

18 We are at a transition point where it is

19 difficult to predict exactly how useful clinically

20 the identification of mechanisms is likely to be,

21 but I think equally, there is now enough evidence

22 from the COX-2's where we are defining exactly how

23 they produce the effects and efficacy to recognize

24 that we can divide patients into COX-2 sensitive

25 and COX-2 insensitive groups.



1 With that knowledge, we can identify some

2 of the best ways to identify efficacy, as well as

3 clinical utility.

4 DR. WOOD: But presumably, the COX-2

5 insensitive group includes all of the above, I mean

6 everything that is not prostanoids mediated, so the

7 heterogeneity in that group is probably at least as

8 large as the heterogeneity in the total group. It

9 is just lacking the prostanoids insensitive group.

10 So, how would you guide either therapeutic

11 decisions on the basis of that, or alternatively,

12 and more importantly I guess for this group, how

13 would you guide the definition of patients to

14 include in the trial that would demonstrate such

15 efficacy, that is not just an exclusion?

16 DR. WOOD: Well, in terms of COX-2's, for

17 example, that if the COX-2's have a label for acute

18 pain, I think that would be too generous in the

19 sense that procedural pain, pain associated with

20 minor acute procedures that would generate

21 nociceptor pain, would not be sensitive to COX-2's,

22 and therefore, that would be an inappropriate

23 usage.

24 Equally, there is minimal clinical data

25 available, but if there were, I think it is likely



1 that postherpetic neuralgia and diabetic neuropathy

2 are going to turn out not to be COX-2 sensitive, so

3 that a chronic pain indication, a global chronic

4 pain indication for COX-2's again would be

5 inappropriate.

6 There would be some patients where that

7 would not be likely to produce efficacy. The

8 problem is there is still heterogeneity in the

9 other groups, I accept that, and that is what makes

10 it very difficult.

11 DR. FIRESTEIN: Dr. Ashburn, any comment?

12 DR. ASHBURN: One thing I wanted to point

13 out is that we have been talking about several

14 different definitions of acute versus chronic.

15 Dr. Hertz talked about that the 1992

16 advisory on analgesic drug approval discussed the

17 concept of acute pain as being pain that existed

18 very early on, had a fairly sudden onset and a

19 short duration of action, and chronic pain was pain

20 that had persisted for six weeks in a cancer

21 patient, although I have cancer patients who would

22 say that if it persists for two day, it is chronic,

23 and chronic pain, for people who are not dying of

24 cancer, has to last six months before it meets the

25 definition.



1 Dr. Woolf gave what I believe is a more

2 appropriate definition regarding the expected

3 impact on the body and the expected reversibility

4 of the pain.

5 On the other hand, some of the other

6 speakers have really alluded to something which may

7 be more important with regard to drug review, and

8 that is, the duration of therapy, which is much

9 more different, if the expected therapy is of short

10 duration rather for long-term, chronic delivery.

11 I want to just point out that one issue

12 has to do with regard to safety and durability of

13 effect, which I think are very important factors

14 that need to be investigated when a medication is

15 being looked at for outcome. The other one has to

16 do with defining different disease states with

17 which to do studies. That had to with appropriate

18 labeling with regard to dosing interval.

19 DR. FIRESTEIN: That actually begins to

20 bring us towards the second question. We have a

21 couple of other comments that people wanted to

22 make, and then we will move on. But I think most

23 people here seem to be in agreement that a general

24 pain claim is rather vague and it is going to be

25 difficult to approach from a mechanistic or even a



1 clinical perspective.

2 I think one of the things that we might

3 want to consider, after hearing the elegant

4 discussion on pain mechanisms, is in addition to

5 acute and chronic, whether or not there might be a

6 place for a third category, such as acute

7 persistent, where patients that have acute

8 mechanisms of pain, that are persistent and

9 reversible, but need to take the medication for a

10 prolonged period of time, might have even different

11 criteria than other chronic indications.

12 Dr. Cush was next, then, we will get a

13 couple of other comments, and then we will move on.

14 DR. CUSH: My comment is to Dr. Woolf. I

15 think that many of us would like to see pain

16 defined mechanistically in an effort to better

17 control pain, maybe use complementary regimens to

18 get more total control, if that were possible, a

19 disease, such as osteoarthritis, but at this point,

20 would you not say that we can maybe define

21 mechanistically how certain drugs may work, and

22 that might well go into some of the preclinical

23 work that would go into maybe how a drug is defined

24 as far as its mechanism of action, but we do not

25 yet have the tools to define mechanistically how



1 these drugs work in clinical trial meaning that we

2 don't have the tools for different diseases to say

3 that this going to be a peripheral sensitizing drug

4 or central, and whatnot.

5 DR. WOOLF: If we conduct clinical trials

6 the way they have been at the moment, then, the

7 answer is yes, because global pain scores are not

8 going to identify mechanisms.

9 The big issue there is if we can gather

10 more information, for example, I indicated the

11 peripheral sensitization had a particular property,

12 which is abnormal heat sensitivity in the site of

13 inflammation, whereas, central sensitization was

14 associated with tactile allodynia.

15 Now, if that inflammation were collected

16 as part of secondary outcome measures, maybe we

17 could get an indication whether new forms of

18 therapy acted on those particular mechanisms in

19 addition to whatever global effect they had on pain

20 scores.

21 So, I think we need to move from seeing

22 pain as this monolithic entity with a single

23 expression, which is what the patient feels, to try

24 and collect more data, in the same way that if we

25 look at heart failure, we would make a number of



1 measurements - peripheral edema, hypertension,

2 cardiac output, and treat those specifically.

3 I think we need to do the same with pain.

4 The trouble is we are not exactly sure of the

5 durability of these different components and their

6 reflection to mechanisms, but I would argue global

7 pain scores, by themselves, are too insensitive to

8 pick up these individual mechanisms, and therefore,

9 some drugs with some utility may be lost.

10 DR. FIRESTEIN: Two other quick comments.

11 Dr. Davidoff, did you have a comment to make, and

12 then Dr. Abramson, and then we will move to the

13 second issue.

14 DR. DAVIDOFF: Yes, I would also like to

15 add my appreciation for the discussion, which I

16 think was very lucid. But in thinking about that

17 and some of the other comments, it occurs to me

18 that there might be another spectrum in which to

19 make useful distinctions, perhaps even in terms of

20 labeling.

21 That is, there appear to be certain

22 clinical situations which are analogous to some of

23 the, as you put it, preclinical models where the

24 mechanism is relatively pure, and the models are

25 chosen to be able to study a particular type of



1 pain.

2 There are others, mostly clinical

3 situations, where it seems pretty obvious that the

4 mechanisms are mixed, and the difficulty is trying

5 to sort them out on some clinical basis whether it

6 is from subtle clinical cues, maybe the development

7 of testing that would allow you to identify the

8 mechanism, or the therapeutic trial.

9 The power of a therapeutic trial, as

10 Alastair has suggested, may actually reemerge as

11 something very powerful, just the way the treatment

12 of hypertension has evolved, so that it is not

13 clear.

14 There are certain relatively pure forms of

15 hypertension, like a pheo or primary aldosteronism,

16 where the treatment is highly specific and narrowly

17 defined, whereas, with most hypertension, it is

18 much more difficult, and, in fact, patients are put

19 on one drug and then a second drug, and a third

20 drug, and nowadays, frequently four drugs, and the

21 therapeutic response is really the way the

22 diagnosis is made, if you were smart enough to know

23 what each of those drugs was doing.

24 So, I wonder if it might be useful to add

25 sort of a dimension of purity versus--how should I



1 say--pure versus mixed mechanisms as being one way

2 to consider approaching the labeling.

3 DR. FIRESTEIN: Dr. Abramson.

4 DR. ABRAMSON: I think I had a related

5 comment because it seems that the issue is less

6 whether we should have an acute versus a chronic

7 label, which I think we should because of the

8 different clinical syndromes, but the issue is the

9 heterogeneity of what we are going to be calling

10 indications for clinical pain, and having to

11 grapple with, it that too broad a concept.

12 I mean you are describing different pain

13 mechanisms, and whether we will have a broad-based

14 label is something I think is going to be difficult

15 to grapple with.

16 I am a little concerned in that context,

17 therefore, that to try and dichotomize mechanisms

18 may be premature, in other words, many of these

19 syndromes have to be mixed, as was just said, and

20 some of the science is early and some of the

21 observations don't take into account perhaps the

22 kinetic changes over time.

23 So, I guess the question again for Dr.

24 Woolf is how advanced are the preclinical models in

25 terms of the expression of the different molecules



1 in the central and peripheral system and how might

2 we think about, when we do clinical trials in

3 chronic pain, differentiating these different

4 mechanisms based on tissue expression of some of

5 these molecules.

6 DR. WOOLF: I think your point is well

7 made. We are certainly at a point where I think it

8 is appropriate to discuss it and to try and build

9 in our view of the way in which pain is generated

10 to take into account mechanisms, but this is early.

11 This is a point where the kinetics I agree

12 are poorly defined particularly in patients.

13 Unfortunately, many of the changes, the expression

14 of different molecules occur within the nervous

15 system, so access in patients to tissue to actually

16 determine them is extremely difficult.

17 The reliability of animal models for

18 clinical diseases is a separate issue, which is

19 obviously complicated, but I think we just need to

20 try and include this as part of our operating

21 definition of what pain is, and not just ignore the

22 mechanism, particularly since we are at a point

23 where we are about to get new forms of analgesics

24 that have actions that are different NSAIDs and

25 opiates, and as a consequence, may need different



1 outcome measures reflecting the action of a

2 particular mechanism.

3 So, we are not there yet, but I think we

4 are a point where, as new trials have been

5 designed, we may need new approaches to them.

6 DR. FIRESTEIN: Actually, we have been

7 migrating slowly towards Discussion Point 2, which

8 specifically asks about mechanistic approaches

9 versus clinical approaches, and maybe we can steer

10 for the final five or 10 minutes of the session,

11 the conversation towards the utility of those two

12 approaches, whether scientifically we are at the

13 point where we should be focusing strictly on

14 mechanistic targets or whether or not the gold

15 standard will be the patient's clinical syndrome.

16 DR. MAX: Let me follow up on Dr. Wood's

17 question on where are we with the science of

18 clinical analgesia. I think it is pretty primitive

19 compared to the animal models because pain is a new

20 enough field, with so few clinical investigators,

21 mostly doing single center trials, that we haven't

22 had the size of the clinical trials combined with

23 the rigor to answer these questions.

24 I think we agree that we are mammals, and

25 if Clifford can demonstrate all these different



1 mechanisms in rats, we can in people, and there are

2 a number of examples in the laboratory with humans

3 where we can do, say, a selective nerve block and

4 knock out one kind of pain.

5 We expect that if we looked hard enough

6 with the right tools and the large cohorts in many

7 industry trials, we might find some interesting

8 correlations to learn how to use the drugs better.

9 That is why better tools, if we could

10 develop the equivalent of the arthritis trial

11 groups' scales, we might find things, and I think

12 Clifford's group is working on this, but we are

13 quite primitive, like we have just done a trial

14 with Hopkins looking at a crossover trial of

15 placebo tricyclics and opioids in postherpetic

16 neuralgia in 70 patients, and we find that one

17 group responds to opioids, and an independent group

18 responds to tricyclics, but to really prove that,

19 you would need to replicate, you would need to give

20 the patient back the same drug.

21 We haven't separated that from the

22 possibility of random variation. So, I think the

23 problem for this committee is to provide enough of

24 an incentive for industry trials to try to look for

25 mechanistically based advantages.



1 I don't think we can count on that coming

2 out, but I think if we look a little harder, they

3 are going to emerge.


5 DR. BRANDT: I don't think that Question 2

6 is necessarily an either/or proposition. Coming to

7 responsibilities of safety and efficacy and looking

8 at drugs, if we come back to a way guidelines for

9 management of OA both by the ACR and by ULAR,

10 basically recommends starting with acetaminophen,

11 and if that doesn't work, moving on basically on

12 NSAIDs, and so on.

13 It occurs to me in thinking about Dr.

14 Woolf's comments, we don't know how patients who

15 fail acetaminophen respond to an NSAID. We assume

16 that they are NSAID responsive and they will do

17 better. We don't know that, and it might be useful

18 in terms of this dissection, admittedly at a very

19 crude level and admittedly with the caveat we don't

20 have a clue how acetaminophen works, to get that

21 sort of information in and see whether

22 acetaminophen failures, how frequently they respond

23 to NSAIDs and to agents that perform differently

24 than COX-2 inhibition.

25 I think there is a place to start in this,



1 taking a disease that is understood to some extent.

2 DR. FIRESTEIN: But is it more useful to

3 have a musculoskeletal approach or a mechanistic

4 approach for these drugs, for instance, do we need

5 to have separate rheumatoid arthritis and

6 osteoarthritis indications?

7 In spite of what has been said, there

8 actually is a fairly prominent inflammatory

9 component, for instance, do we want inflammatory

10 pain versus non-inflammatory pain, for instance, in

11 musculoskeletal diseases.

12 DR. BRANDT: Well, I think the issue is

13 that there are a number of origins of pain beyond

14 inflammation. There is not any disagreement that

15 OA has an inflammatory component, but, for example,

16 I think that bone pain may be significant in

17 osteoarthritis because of the alterations in bone

18 hemodynamics.

19 That might evoke interest in a whole

20 different class of drugs that would be relevant to

21 OA pain, vaso-active types of medications, that it

22 provides an opportunity by considering the

23 pathophysiology of the disease, and I think you

24 would agree there are differences between RA and OA

25 in a broad sense, not just with regard to pain or



1 inflammation.

2 That might provide opportunities to

3 explore different approaches to developing disease,

4 perhaps specific analgesics.

5 DR. KATONA: My question is for Dr. Woolf.

6 Do you have any idea on the developmental aspects

7 of the different pain mechanisms? Just working

8 along with children and adults, it is very obvious

9 that in any inflammatory disease children, who have

10 somewhat less pain, it is easier to be controlled,

11 as well as acute situations don't get chronic as

12 often as adults.

13 I am just wondering if you have ever

14 looked at or whether you have any data on it.

15 DR. WOOLF: There certainly is a major

16 interest in the developmental aspects of pain, and

17 this is an area that I, myself, do not work on, but

18 it appears as if the very early interventions in

19 neonates may have consequences, long-term

20 consequences that are quite different from a

21 similar intervention in children and adults. That

22 is one aspect that needs to be looked at, and then

23 the separate aspect of the responsiveness of

24 children themselves.

25 That raises the whole issue of what are



1 the mechanisms that operate or are responsible for

2 the conversion of acute pain to chronic pain. We

3 have heard discussion earlier of when you are

4 giving an analgesic acutely, you may not know

5 whether the patient is going to require that for a

6 long time.

7 Our knowledge of why some patients go on

8 to develop chronic pain, and others do not, is

9 quite poor, and the difference between children and

10 adults in that is certainly an important issue.

11 DR. FARRAR: I think the discussion point

12 asks the question of whether a mechanistic approach

13 or a clinical approach has a rationale, and I think

14 that what we are hearing from Dr. Woolf and Dr.

15 Brandt, and others, is that both of them are

16 clearly applicable to the appropriate use of any

17 medication.

18 It seems to me, though, that the point

19 before the FDA is that we are not yet at the point

20 to be able to mechanistically identify each and

21 every patient that comes to see us. We are also,

22 frankly, not even able to clinically identify at

23 the beginning, the underlying clinical reason for a

24 patient's disease process the first time they come

25 to see us.



1 Understanding that the nature of the

2 science of medicine is still very nascent, it is

3 still very much at the beginning, that it is

4 appropriate to consider the way in which a drug is

5 labeled, to consider the way in which patients

6 present and the way in which physicians will then

7 treat them.

8 I am a neurologist. I would love to know

9 what the underlying mechanism is of half the

10 patients that I see who come to me for pain. In

11 fact, I can't do that, even in patients with the

12 same disease process, we cannot identify,

13 necessarily identify their response.

14 In thinking about how a drug company

15 therefore must perform tests to look and see

16 whether the drug is working, I think it needs to

17 focus on the way in which patients present, so that

18 if we can develop a mechanism, Dr. Max was

19 suggesting, a mechanism to be able to actually

20 identify certain subgroups, then, it makes sense to

21 perform trials in those particular subgroups.

22 Until that science catches up, we are left

23 with treating patients with osteoarthritis.

24 Treating patients with osteoarthritis means testing

25 in osteoarthritis and understanding that the



1 underlying mechanisms may be very different in that

2 same patient.

3 Where that leads to is again the issue of

4 differentiating between the long-term use of a

5 medication and treating a long-term process,

6 because the two are very different, and I think we

7 need to stick with the way in which medicines are

8 likely to be used for the time being.

9 DR. FIRESTEIN: You have made some very

10 cogent points. I think that while the science has

11 progressed considerably with regard to mechanisms,

12 in the end right now we are faced with patients

13 that come into the clinic that may have multiple

14 mechanisms for a particular clinical syndrome that

15 we are going to be treating.

16 It is likely that at least for now, we

17 need to focus on the clinical presentation for many

18 patients.

19 Lee, I know that there is lots of people

20 that had additional comments, but we need to move

21 on. Are there any additional points that we need

22 to address for this section?

23 DR. SIMON: Not right now except Dr.

24 Goldkind has one more bit of information to add and

25 a question to ask.



1 DR. GOLDKIND: Some of this has been

2 addressed by Dr. Firestein. We need to remember

3 that ultimately, the common pathway for approving

4 an analgesic relates to the experience of pain, and

5 so it may be worth discussing whether an indication

6 that is mechanistic in development, but ultimately

7 relates to a metric that is somewhat global, might

8 not be the hybrid, you know, is allodynia

9 associated with a condition, that could be a

10 mechanistically driven indication, but it would

11 still have to ultimately be reflected in the

12 patient's experience.

13 I think we need to remember that the

14 patient ultimately needs to be impacted in a

15 meaningful way, and if it drives development to

16 allow more detail and description in the label or

17 some creativity in an indication, if there is an

18 important benefit to be accrued.

19 DR. FIRESTEIN: There is probably general

20 agreement with that.

21 I think we will end this session here. We

22 will take a 10-minute break, so that we can get

23 back on track. We will see you in a few minutes.

24 [Break.]

25 DR. FIRESTEIN: The next speaker is going



1 to be Dr. Lee Simon, the Division Director, and he

2 is going to talk to us about chronic pain and the

3 claim structure.

4 Claim Structure

5 Lee S. Simon, M.D.

6 DR. SIMON: Thank you, Dr. Firestein. I

7 would like to thank again the members of the

8 committee. I would like to take a moment and thank

9 the Divisions of OTC and 170 Anesthetics and

10 Critical Care, for lending us members of their

11 committee to join with the Arthritis Advisory

12 Committee given the fact that pain is such a broad

13 and extraordinary large indication, it affects so

14 many different syndromes and diseases, and much of

15 what you can see our discussion relates to, do you

16 do models or do you do diseases, and ultimately

17 end, as Dr. Witter had suggested, how we do that

18 depends on what we are trying to inform patients,

19 are we trying to inform patients about the

20 syndromes and diseases they suffer from and what

21 kinds of drugs then interfere with them, or are we

22 trying to think about ways that will do also

23 driving new drug development.

24 I think much of these next several

25 discussions that will be presented to you will have



1 a lot to do with that.

2 I would also like to just take a second to

3 acknowledge my entire division that has spent weeks

4 in putting these talks together. They have really

5 done a spectacular job, and I would like to

6 acknowledge the fact that this has been one of Dr.

7 Jim Witter's pet projects over the years, even

8 prior to my arrival, and is the culmination of a

9 lot of work for Jim, and I think he has done a

10 terrific job.

11 I would like to thank all of the guest

12 speakers, some of which you have not yet heard, but

13 given Dr. Woolf's superlative presentation, you can

14 imagine the level of conversations we will have and

15 presentations we will have.

16 In the context of chronic pain, let me

17 remind you I am talking now about things that our

18 division in 550, Analgesics, Anti-inflammatory and

19 Ophthalmologic Drug Products, have grappled with

20 and some of the advice that we have been providing

21 some of you sponsors in the audience so far as it

22 relates to the identity of chronic pain.

23 I think that it has been a really

24 informative discussion to think about chronic pain,

25 not just in the context of its chronicity, but also



1 in the context of how one uses a drug and how one

2 then thinks about the safety, thus, how one would

3 design a clinical trial to inform you about chronic

4 pain.

5 [Slide.

6 So, pain is always a subjective

7 experience. Some people are quite stoic. My wife

8 never seems to need any kind of anesthesia to get

9 her teeth worked on, whereas, I have to put to

10 sleep to get my teeth cleaned.

11 So, I think that the subjective experience

12 really defines a lot of what we are trying to

13 target here, and that is very important although

14 Dr. Woolf has mentioned that the patient global

15 response is not necessarily going to tell us much

16 about mechanisms, but don't forget the subjective

17 experience, it is important to know what the

18 patient feels about the therapeutic response and

19 whether they are adequately treated.

20 Everyone learns the meaning of pain

21 through experiences usually related to following

22 off your bike or falling around when you are trying

23 to be a toddler and trying to reach that breakable

24 thing on the chair or table above you.

25 As an unpleasant sensation, it becomes an



1 emotional experience over time, and it is clearly

2 not only a physical stress, but an emotional

3 stress, as well.

4 [Slide.

5 I have had a really interesting

6 opportunity. I was given the Merck Manual from

7 1899 as a gift when I participated as an author in

8 the Merck Manual of 1999, so it allowed me to look

9 back on pain and the therapy of pain in 1899 versus

10 what we think about in 1999, and what the changes

11 have been.

12 So, in one hundred years, as you heard

13 from Dr. Woolf's talk, there has been clear

14 progress in the field of understanding of pain,

15 defining painful disease states and syndromes,

16 along with delineating appropriate therapy.

17 [Slide.

18 That is shown by this comparison between

19 the original 1899 and now, 1999. So, this, in

20 fact, is the original page from the index of

21 indications from the 1899 Merck Manual,

22 demonstrating pain and the definitions of pain.

23 You will notice that hepatalgia is a very

24 important syndrome of pain in 1899, as was

25 odontalgia, otalgia, ovarian neuralgia, very



1 specific definitions as you can see, clearly

2 delineating the way we do today about different

3 kinds of pain.

4 Furthermore, this is the entire list of

5 available pain medications in 1899 that were

6 suggested. Yellow are some of the things that have

7 fallen out of favor, such as iodine or potassium

8 cyanide, something that would not be readily

9 available today for us to use.

10 On the other hand, the white actually

11 demonstrate the drugs that were available in 1899,

12 belladonna, chloral hydrate, codeine, morphine,

13 menthol, some of which may be similar to the kinds

14 of things we use today, like Arthritis-Eze, which

15 is always advertised on the TV about the use of

16 menthol, phenacetin, the parent product for

17 acetaminophen, and sulpyrine was what they referred

18 to as aspirin in those days. I actually didn't

19 know that.

20 [Slide.

21 So, looking now in 1999, this is just one

22 of the pages of the index on pain. As you can see,

23 we have clearly moved forward about categorizing

24 pain in various different ways, both by some of the

25 things you have heard about from Dr. Woolf, as well



1 as descriptors, such as after tooth extraction or

2 bladder pain, abdominal pain, psychogenic pain,

3 carpal tunnel syndrome, and this then actually goes

4 on for three pages.

5 [Slide.

6 What also interested us, the separate

7 Analgesics Index, which, in fact, goes on for

8 multiple pages, describes pain relief in terms of

9 acute postoperative pain, or in cancer pain

10 syndromes, or non-opiate drugs for pain,

11 nonsteroidals, opiate drugs, so, in fact, it is

12 really quite interesting how we have come along,

13 where we have been, and where we are today.

14 [Slide.

15 So, we have actually furthered our

16 description of pain, but even 100 years ago, we

17 fundamentally are using today the same fundamental

18 drugs that they were using then - opioids, morphine

19 and codeine, for example, nonsteroidals, as

20 evidenced by salaparendi [ph], "effective aspirin,"

21 it was called in those days, forms of sedatives

22 like chloral hydrate.

23 Well, we don't usually use chloral hydrate

24 today for pain relief, but we certainly use other

25 kinds of things that help people tolerate pain. We



1 don't really know how they work, for example, the

2 tricyclic antidepressants, and then muscle

3 relaxants.

4 So, I am not sure that we have come a long

5 way in the analgesic development area. One of the

6 reasons for that has to do with the issue of

7 various descriptors of pain.

8 [Slide.

9 This is an archaic way of actually

10 bringing this about, and I thought that we would

11 start here with this. Dr. Cush actually jokingly

12 referred to this kind of archaic description prior

13 to beginning this session.

14 Somatic pain, visceral pain, and

15 neuropathic pain, not that neuropathic is archaic,

16 but this issue of somatic and visceral are, so

17 somatic pain - caused by the activation of pain

18 receptors in either the cutaneous body surface or

19 deeper tissues, such as musculoskeletal tissues,

20 whereas, visceral pain, pain that is caused by

21 activation of pain receptors, gee, a really similar

22 kind of description, not exactly the way Dr. Woolf

23 would have necessarily described the various

24 different effector agents of somatic or visceral

25 pain.



1 So, pain receptors from infiltration,

2 compression, extension or stretching of the

3 thoracic, abdominal, or pelvic viscera, such as

4 chest, stomach, and pelvic areas.

5 What has actually survived this archaic

6 descriptors is the neuropathic pain - caused by

7 injury to the nervous system either as a result of

8 a tumor compressing nerves or the spinal cord, or

9 cancer actually infiltrating the nerves or spinal

10 cord, but unfortunately, this now definition

11 removes or leaves out the issue of inflammation to

12 the nerve root as part of the causal relationship

13 of neuropathic pain.

14 [Slide.

15 Then, we move to something we have already

16 talked about, not just the sense of where it is in

17 the body, but, in fact, the descriptors of how

18 severe it is, so mild, moderate to severe. They

19 are very useful as descriptions. Patients

20 understand severe pain versus mild pain, but to any

21 one patient, that might be very different, so for

22 me, I think walking into the dentist office is

23 severe pain without even having them do anything.

24 So, it does not provide any rigor.

25 Perhaps these should be used to modify the



1 definitions of acute and chronic pain indications,

2 which perhaps might allow patients to understand

3 more about how to use, but what measure do you

4 apply for mild, moderate, severe, and ultimately,

5 that measure, either defined by the sponsor or by

6 the agency in evaluating that measure, ultimately,

7 it is the bias of the agency, investigators, and

8 sponsors to suggest which is really which, which is

9 mild, which is severe, which then brings us up to

10 acute versus chronic pain.

11 [Slide.

12 I would like to remind you when we think

13 about this, I think the discussion that was ensuing

14 right before we took the break was really a

15 critical one. It is both a temporal sequence, as

16 well as the idea that the mechanisms are separate.

17 It shouldn't necessarily mean that we are defining

18 them absolutely. This is an area that is

19 iterative, it is still in development.

20 We don't have a clue about all the

21 aspects, as you have already heard, and, in fact, I

22 expect that in 10 years from now, we will know a

23 lot more than we do today.

24 So, acute pain - short-lasting, so

25 temporal component, manifesting in objective ways,



1 perhaps that is mechanistic. It can be easily

2 described and observed.

3 It may be clinically associated with

4 diaphoresis and tachycardia, so there are clinical

5 events that take place associated with the

6 transient events, the transient stimulus that leads

7 to the acute pain.

8 Maybe only lasting several days,

9 increasing intensity over time, which might lead to

10 this issue of that bridge between acute and

11 chronic, the subacute pain. It can occur

12 intermittently, episodic or intermittent pain. Dr.

13 Sherrer referred to an OA flare superimposed on top

14 of a more chronic event.

15 Usually related to a discrete event for

16 onset, such as postoperative, post-trauma,

17 fracture.

18 And then there is chronic pain -

19 long-term, typically defined if it lasts for

20 greater than three months, in the context of cancer

21 pain, perhaps less based on survival issues. More

22 subjective and not as easily clinically

23 characterized as acute pain, and has a more

24 psychological overlay.

25 I don't mean to suggest that we are



1 incapable of understanding and identifying chronic

2 pain, but tachycardia and diaphoresis is not

3 necessarily associated with the onset of chronic

4 pain. This kind of pain usually affects a person's

5 life, changing personality, and their ability to

6 function, as well as their overall lifestyle.

7 [Slide.

8 That brings us to a discussion that Dr.

9 Firestein led just before - what about the general

10 descriptor of pain, why can't we just label these

11 things for pain and let the marketplace decide, why

12 can't we just say it works in this kind of pain,

13 and you could try it in something else, and if it

14 doesn't work, you try something else.

15 That might be helpful and useful, but it

16 is not particularly informative to patients,

17 particularly with what we know today. The general

18 pain definition has been broadly used in the past,

19 however, acute and chronic indications use

20 different models, may be mechanistically different,

21 and have different safety issues.

22 Furthermore, the psychological component

23 clearly separates acute pain from chronic pain, and

24 that may have very important implications for

25 therapeutic intervention, patient response, and



1 patient safety claims.

2 [Slide.

3 Unfortunately, one of the major proponents

4 of this kind of meeting was not able to make it

5 today, and I wanted to allow Dr. Lipman to seem

6 like he is actually in the audience by bringing up

7 some of the things that he has referred to in the

8 past, one of which is this particular statement

9 from a paper in Cancer Nursing, which is that

10 chronic pain has a psycho-social component that

11 must be dealt with before depression becomes a part

12 of the clinical picture. Chronic pain should be

13 recognized as a multi-factorial disease state. So

14 it is a state that is responding to something, but

15 nonetheless, may be an independent disease state

16 requiring intervention at many levels.

17 [Slide.

18 This diagram actually reflects these many

19 levels and demonstrates the interaction that over

20 time basically, whatever the pathologic process is,

21 associated with the interaction with physical

22 factors, leads to anxiety, depression, and

23 psychological factors overlying each of these

24 events, so that in the right circumstance and in

25 the right patient, there could be issues of



1 isolation and loneliness, totally informing the

2 patient leading to increasing anxiety and

3 depression, the issues of hostility, why me, why is

4 this happening to me, why can't I deal with this,

5 and then the issues of social factors, which lead

6 to the increasing loneliness and anger associated

7 with this increasing isolation, thus suggesting a

8 time period that we are liable for being able to

9 intervene, to be able to allow this cascade of

10 events perhaps not to progress.

11 [Slide.

12 So, in thinking about trial design from

13 the regulatory point of view, we have to think

14 about again how Dr. Witter suggested, what are the

15 issues regarding how to inform patients about their

16 use of these particular therapeutic interventions.

17 So, look for trial designs that will allow

18 us to see the result of how to translate the use to

19 the patient, so as Dr. Hertz suggested before, we

20 are becoming much more interested in disease states

21 to be studied than models to be studied.

22 At the time, we didn't have a lot of

23 understanding of the diseases. It seemed

24 reasonable to try to look at models, but is

25 alveolar bone pain in dental extraction the same as



1 bunionectomy, is dysmenorrhea, which actually has a

2 clear mechanism of understanding of why there is

3 cramping and abdominal discomfort, is that actually

4 extrapolatable in a general way to other forms of

5 pain.

6 So, some of the models that we were

7 looking at are disease states that we have been

8 looking at, have been osteoarthritis, chronic low

9 back pain, which has been a big debate, some of

10 which we will be informed in a little bit by Dr.

11 Borenstein, fibromyalgia, an area of great and

12 intense investigation, which has some very

13 interesting aspects to the psychological overlay of

14 how people deal with their pain, and perhaps

15 genetics, about who selects out the individual

16 response to an inciting event, and then who goes on

17 to develop a chronic pain syndrome without further

18 inciting episodes.

19 Neuropathic pain, and there are many of

20 those, I just selected out two - diabetic

21 neuropathy and amyotrophy, cancer pain and the old

22 issues associated with that, that are quite unique.

23 Temporomandibular joint pain, peripheral vascular

24 disease perhaps, and then not only the disease

25 states or models, but what about mechanistic



1 approaches.

2 [Slide.

3 I am going to present three different

4 possibilities for your consideration. I almost

5 feel like Rod Serling in creating the Twilight

6 Zone. These are all just for your consideration.

7 We would like to throw out the possibility that we

8 want to engender drug development.

9 We think this might be a good way to go,

10 but now that I am on the light side rather than the

11 other side, perhaps I don't have the right

12 perspective that other people have about what is

13 necessary, so we have to think about this together

14 as whether or not these are the right ways to do

15 things.

16 So, possible indications of one disease or

17 model, one could even add in mechanism perhaps, an

18 example, signs and symptoms of osteoarthritis. Not

19 everybody knows that OA is osteoarthritis but us

20 rheumatologists do. So, an example, signs and

21 symptoms of OA, two replicate randomized and

22 controlled trials, three co-primary outcomes in

23 which each must win, so it would be pain, function,

24 and a patient-determined global. And why would we

25 want that latter one is again it is important for



1 us to know how the patient feels, not unimportant

2 in labeling and allowing other patients to know

3 what that means. There yet may be other measures

4 that become important as we will talk about in a

5 second.

6 There needs to be superiority to placebo

7 or perhaps superiority to an active comparator.

8 There could even be discussions, although it is not

9 on this slide, about non-inferiority to an active

10 comparator, but, in fact, that would have to be

11 defined based on some issues as shown in the

12 appended paper from Ellenberg and Temple about

13 placebo responses and things like that.

14 [Slide.

15 There is also the possibility of thinking

16 about a whole organ system indication, such as

17 musculoskeletal disease, and then one might think

18 about, for example, improvement in the pain of

19 musculoskeletal disease.

20 Three models of diseases, though, might be

21 required to achieve this, all within the rubric of

22 musculoskeletal disease, so low back pain perhaps

23 in association with studies in osteoarthritis, and

24 then perhaps also in fibromyalgia, all of which

25 affect the musculoskeletal system, we believe, and



1 perhaps inform us somewhat about the use in a

2 general way in musculoskeletal disease.

3 You will need two replicate randomized,

4 controlled trials for each model or disease state.

5 There need to be three co-primary outcomes, each of

6 which have to be won on, of pain, function, and

7 patient-determined global, and it could be

8 superiority to placebo or superiority to active

9 comparator, or maybe in the right circumstance

10 non-inferiority that we could discuss.

11 The important aspect of this would be that

12 the label would reflect, not just the idea of

13 musculoskeletal disease, but reflect the approval

14 of all the disease or models that had been studied,

15 so therefore, you would get the approval for

16 musculoskeletal disease in osteoarthritis and

17 fibromyalgia and chronic low back pain, which would

18 be actually in the label, as well as in the

19 Clinical Studies Section, to inform people about

20 the responses.

21 Furthermore, we would be even interested

22 in discussing the issue of, well, gee, in

23 fibromyalgia, maybe wind-up, the concept of wind-up

24 pain is really critical, and perhaps, in fact, if

25 you could interfere with that, in drugs that are



1 quite unique, that have nothing to do with what we

2 have thought about pain before, such as an NMDA

3 inhibitor, perhaps that might be the right way to

4 go and achieve that for fibromyalgia.

5 [Slide.

6 Then, the big discussion point that a lot

7 of people have heard before and we have informed

8 people about is the idea of a general chronic pain

9 indication. Now, this seems to be quite a high

10 bar, however, just think about how high a bar it

11 reflects, meaning it could be suggesting that drugs

12 could be used in any form of chronic pain.

13 Now, this leads us to a discussion of

14 lumping and splitting, and some of the discussion

15 we have had to date would suggest that it is going

16 to be impossible as we learn more mechanisms to

17 actually get a drug that would be appropriate for

18 chronic pain totally, and that may well be true.

19 Thus, I would take you through this

20 argument, suggesting that replicate trials in each

21 model should be in disparate diseases, so you would

22 have to study one aspect of musculoskeletal

23 disease, one aspect of cancer pain, and perhaps one

24 aspect of neuropathic pain, and that product,

25 whatever that product might be, would have to win



1 in all three areas.

2 However, this is not to limit the possible

3 areas. It may be that you could figure out

4 something else besides neuropathic pain to study

5 and thus get the same rubric - must measure pain,

6 patient global, and some functional outcomes are

7 the co-primaries, and again win, must be superior

8 to placebo in all three and superior to the active

9 comparator, and again, I point out that the label

10 reflect two issues.

11 One would be the approval for the broad

12 category, limited specifically by safety

13 considerations, and the label will also, based on

14 the data accumulated to achieve this, would

15 demonstrate that the therapy is approved for the

16 indication of chronic pain, but also the three

17 diseases or models or mechanisms that had been

18 studied, so therefore, it is kind of four things.

19 You get all three areas, perhaps other

20 areas that you were also studied in, so if you did

21 musculoskeletal disease into two different areas of

22 osteoarthritis and chronic low back pain, they also

23 would be referenced in the label and in the

24 Clinical Trial section as thought appropriate for

25 patients information and clinician information.



1 [Slide.

2 Yet, there is still yet another approach,

3 which we certainly want to encourage, although we

4 are not entirely sure how to go about doing it, I

5 don't know if you are, is the mechanistic approach.

6 We don't yet know how to do it, we don't really

7 know the models, but possible examples, as Dr.

8 Witter alluded to, perhaps alteration of wind-up by

9 inhibition of NUDA receptors in fibromyalgia,

10 alteration of brain plasticity or neuroplasticity,

11 alteration of early markers that might predict

12 specific and verified clinical outcomes, thus

13 giving a broad opportunity to really drive the

14 science and improve drug development.

15 [Slide.

16 All of this has to be remembered in the

17 context that we, at the Agency, have to label

18 things in the context of benefit to risk. So, as

19 this cartoon suggests, as this unfortunate person

20 sitting at this particular cafe selecting out which

21 food to choose, and seeing the risks and benefits

22 that are listed up on each one, it would not be

23 dissimilar from a physician, patient, or clinician

24 choosing particular drugs to choose based on their

25 benefits to risk, as listed within documentation



1 that had been accumulated in trial development.

2 Thank you very much.

3 DR. FIRESTEIN: Thank you, Lee.

4 Discussion Points #3 and 4

5 DR. FIRESTEIN: At this point, we have

6 been asked to discuss Points 3 and 4 here. Yes?

7 DR. MAX: I would like to comment to Lee.

8 As I have said to you before, I really like one

9 thing you said, and I am really profoundly worried

10 and I really hate another thing you said.

11 What I really like is that your primary

12 goal is to advance the science by encouraging many

13 clinical trials in many diseases, and I have

14 written a review article in Anesthesiology last

15 July with Clifford, where we conclude that the best

16 way to learn about mechanisms in human is from

17 clinical trials in many diseases, and your approach

18 does that.

19 The one thing--and I think it is a detail

20 that I am very concerned with--is your stipulation

21 that each trial needs to demonstrate, at the same

22 time, a win for not only pain, pain scores over

23 placebo, but in addition, a global outcome, global

24 patient preference, and quality of life.

25 I would argue that if you look at large



1 databases of opioid trials and malignant and

2 nonmalignant pain, as my colleagues in the

3 Anesthetic Division have, and in my experience

4 looked at chronic neuropathic pain and chronic back

5 pain in other trials, it is unusual that one shows

6 all three at once, and maybe we are behind you in

7 OA, and I am afraid if you tell industry that you

8 need to have a win in all three for each positive

9 trial, that it's a why study pain, let's give that

10 up, it's an impossible thing to meet.

11 I would propose the alternative, that you

12 show pain is reduced more than a placebo by

13 statistically significant outcomes, and at least

14 you show evidence that you are not intoxicating the

15 patient, there is no deterioration in the global or

16 in the patient preference, and perhaps as an

17 additional tier, you can get additional claim to

18 give the incentive to develop better quality of

19 life. That's my counterproposal.

20 DR. SIMON: I would just like to point out

21 that, and I am delighted that I have stimulated

22 this kind of discussion, that the quality of life

23 measures are not necessarily the same thing as

24 function, and what we are relating to are

25 functional measures, not necessarily requiring the



1 bar of achieving an improvement in quality of life,

2 although that is very important to us and certainly

3 would be a secondary outcome that we would be

4 looking for.

5 It is unfortunate that a lot of the

6 definitions of health-related quality of life

7 measures have been assumed to be measures of

8 function. It is not necessarily clear that all

9 are measures of function, and I am not yet sure

10 that we have all the measures that we need to

11 achieve this particular proposal.

12 It may well be that measures of function

13 yet need to be developed in cancer, for example,

14 that will allow us, to inform us in the relative

15 short term of study, that patients with cancer

16 whose pain is improved would benefit from function,

17 as well.

18 This is a suggestion of not just the

19 development of new drugs, but new outcome measures

20 that is critical, and I think Dr. Strand will be

21 discussing some of the issues about the tiered

22 nature of how to look at that question.

23 DR. FIRESTEIN: Dr. Strand.

24 DR. STRAND: I just wanted to comment back

25 to you, Mitch, that, in fact, we know from



1 certainly musculoskeletal diseases, OA and RA, that

2 when you improve pain, and even if that is the most

3 that you seem to improve in terms of the disease,

4 such as the COX-2's in, say, rheumatoid arthritis,

5 you are still getting responder analyses, you are

6 still showing improvement in physical function, and

7 improvement in health-related quality of life.

8 So, in fact, these domains are affected

9 very significantly by pain and they are improved by

10 pain, so I think that perhaps the bar is not as

11 high as you might think.

12 Obviously, we have to look at it in terms

13 of what disease states or what mechanisms of pain

14 we are trying to treat, but it goes to show that

15 with the multiple ways pain affects people in their

16 day-to-day lives, if we are improving that, we

17 should see it in these other aspects.

18 DR. FIRESTEIN: I guess the other issue is

19 whether pain and these other outcome variables,

20 especially quality of life, are independent. I

21 think we have had a lot of these discussions with

22 regard to rheumatoid arthritis and osteoarthritis

23 where quality of life is a dependent variable on

24 pain, as well as other aspects of joint

25 destruction.



1 So, it is not clear to me that you gain a

2 lot from a measure of quality of life if you don't

3 get a win because of statistical vagaries or an

4 inaccurate instrument for measuring that when the

5 patient is subjectively better based on other

6 criteria for pain.

7 Yes, and then Dr. Katz.

8 DR. ELASHOFF: Yes, the whole issue of

9 exactly what the correlation is between these

10 measurements across patients or across studies is

11 an empirical one. I suspect that they are never

12 completely independent, but that the correlation in

13 some cases might be low and in other cases it might

14 be high.

15 I think one needs to think conceptually of

16 what one might expect in any given situation and

17 why you might expect them to be less correlated or

18 more correlated, but this is an empirical question

19 on which a lot of light could be thrown by proper

20 analysis of older studies.

21 Typically, there isn't enough in-depth

22 analysis of exactly what the relationships are

23 among various outcome measurements, and I would

24 like to encourage that not only new studies be

25 asked to really look in detail at the relationships



1 between these outcome variables, but that older

2 studies could be re-analyzed to address that

3 question.

4 DR. KATZ: I would like to caution against

5 a "one size fits all" strategy with regard to what

6 domains one might require to say that a trial is

7 successful or not successful, and I would also like

8 to caution against an overly enthusiastic

9 generalization from the rheumatic diseases to other

10 types of pain in that regard.

11 For example, it is clear that if somebody

12 is on their death bed with cancer pain, you know,

13 one's obligation is to relieve pain and its

14 associated suffering, and the opioids are a

15 miraculous and time-proven strategy for that.

16 To then require that that patient get out

17 of bed and walk down the block, or do some other,

18 you know, or improve functionally in some way would

19 be a big mistake and would prevent us from really

20 achieving our primary goals in that situation.

21 Certainly, one could design a functional

22 measure heavily weighted towards pain that might

23 show function, but that is, you know, just a

24 remeasurement trick that doesn't really accomplish

25 anything I don't think.



1 Similarly, in the patient, a 75-year-old

2 with postherpetic neuralgia, with a 4 out of 10

3 pain, they might be pretty much doing what they

4 need to do every day anyway, and that doesn't meant

5 that relieving their pain is not an accomplishment

6 even though it would be very tricky to design a

7 functional or quality of life measure that would

8 show dramatic improvement.

9 Lastly, you have got some really bad power

10 calculation issues in terms of powering a trial to

11 improve an SF-36 or something like that. It really

12 sets a very high financial and feasibility

13 threshold when, in many cases, relieving pain is

14 really the primary goal.

15 Although in osteoarthritis, I can

16 certainly accept that function is an intrinsic part

17 of what we are trying to improve there, and in that

18 context, it may make more sense, so I think we need

19 to think carefully about each individual situation.

20 DR. FIRESTEIN: Dr. Callahan and then Dr.

21 Cush.

22 DR. CALLAHAN: First, I would like to

23 agree probably in musculoskeletal diseases, they

24 are very different, but I do agree with Dr. Strand

25 in terms of pain and function are highly



1 correlated.

2 My question was for Lee. When you say

3 pain based on our discussions this morning, are you

4 talking about a global pain or talking about

5 various types of pain to get a global pain, as well

6 as specific pain that would get at more of what was

7 presented by Dr. Woolf?

8 DR. SIMON: Dr. Firestein, can I answer

9 that?

10 DR. FIRESTEIN: Of course.

11 DR. SIMON: Thank you.

12 DR. FIRESTEIN: The Chair appreciates your

13 request.

14 DR. SIMON: I learn from previous

15 experience.

16 I think that your question really relates

17 to the lack of development of the area. If this

18 was five years hence, and Dr. Woolf's scenario was

19 translated to a specific new receptor inhibitor, we

20 would likely be thinking exactly in the terms that

21 you have just said.

22 Our problem is, is that we are not yet

23 there. I could envision three different receptor

24 inhibitors demonstrating improvement and perhaps

25 even getting a moniker chronic pain indication



1 depending on whether or not they are broad enough

2 to warrant that, again going back to the lumping

3 and splitting concept.

4 Yes, I believe in the splitting concept

5 because I think that, and I think much of our

6 division does, many in our division do, because I

7 think the reasons for that are very logical and

8 disease-specific and mechanistic understood.

9 For example, in acute pain, I can't

10 imagine that a drug that necessarily works in

11 dysmenorrhea will necessarily work in bunionectomy,

12 and just because it works in dysmenorrhea and is a

13 good model to study for that particular event, and

14 it tells you something about one day of use,

15 doesn't mean it is translatable to other forms of

16 pain, but I think we are limited.

17 We don't have all of that information yet.

18 I would like to believe that what I have proposed

19 or what we have proposed may actually lead us in

20 the way to develop more, not less.

21 DR. CUSH: My comments are directed at Lee

22 and Jim, that I think given the comments of Dr. Max

23 and Dr. Katz, I think that to consider a pain

24 indication is reasonable and then to define that,

25 that the indication here is pain, but there is also



1 improvement, not only in pain, but in quality of

2 life or function or in a patient global, that could

3 be in the indication as determined by the research

4 that is done, might be very useful to users and to

5 patients and whatnot.

6 To get to your suggestions regarding

7 indications, I like the idea of disease-specific,

8 organ-specific, and then global indications, I

9 think that that sets sort of sequentially more

10 difficult tasks, but greater implications to the

11 populace, and I think that the design you laid out

12 would be very useful.

13 DR. FIRESTEIN: Dr. Abramson and then Dr.

14 Ashburn.

15 DR. ABRAMSON: Lee, I would just like

16 address the splitters versus lumpers question and

17 make a case for splitting.

18 Even in the realm, the domain of

19 musculoskeletal disease, because fibromyalgia, OA,

20 and low back pain are obviously going at different

21 mechanisms perhaps, and I think we are at a moment

22 now where we can hypothesis test some of the

23 mechanistic concepts, and we can do it using

24 clinical studies.

25 I think if we look at fibromyalgia



1 differently, if we lump them, we may lose the

2 opportunity to looking at different

3 mechanistic-based pain pathways. So, I would argue

4 for splitting largely as a way to do clinical

5 trials to test these different potential mechanisms

6 neatly and cleanly.

7 DR. ASHBURN: I found your presentation to

8 be quite interesting and I think that many of your

9 aspects were starting to be well thought out, but I

10 have the same sort of love-hate relationship that

11 Dr. Max presented before, because one of the things

12 that you alluded to even when you were talking

13 about your experience in the dentist and your

14 wife's experience in dentists, is that pain is many

15 things.

16 Pain is not purely nociception, which many

17 physicians think of it, but rather, pain is a

18 global area, and it is best treated using a

19 bio-psycho-social model of care including

20 interdisciplinary care of which medical management

21 is only one part of the care.

22 When one is talking about taking care of

23 patients with complex disease, even I think of

24 headache as complex, maybe my neurology colleagues

25 don't think of it, but those patients are fairly



1 complex. Medical management is only one part.

2 The NIH Consensus Conference was done

3 almost a decade ago now, presented that

4 self-management techniques were equally efficacious

5 to the medical interventions that we frequently

6 focus on.

7 So, one of the issues is that setting

8 study and outcome measurements in those patients is

9 a good start, but is fairly difficult to do. There

10 are disease-specific measures of health that Dr.

11 Carr may talk about that are under development with

12 regard to the care of individuals who have complex

13 pain problems, but they are in their infancy.

14 They frequently look at function, they

15 look at physical function, as well as mental

16 function, and they usually have several different

17 scores enveloped into one area, and then the

18 question would be, drilling down, is improvement in

19 one functional score adequate, is improvement in

20 many adequate, does it matter.

21 Those are the sort of issues that make me

22 nervous, and the concern that I have is, is that

23 while it is an excellent idea to integrate

24 measurement of outcomes amongst a wide variety of

25 fields as a requirement to looking at new



1 medications, requiring that positive benefit be

2 shown may be a barrier to care and may actually

3 decrease interest in the development of new

4 medications for the treatment of these patients.

5 DR. FARRAR: I have to say that I really

6 enjoy coming to these meetings because I get to sit

7 in a room with a group of real experts and hear

8 them disagree vehemently about things that we are

9 all talking about, and yet with the same common

10 goal, which is to strive to make patients' lives

11 better, which is ultimately what medicine is about.

12 I think, in part, I won't comment on what

13 I loved and hated about Dr. Simon's presentation,

14 but one of the things that he said that certainly

15 is applicable to this, is that things are going to

16 change and that we are not targeted today or we are

17 not charged today with coming up with the final and

18 ultimate answer, that we are charged with coming up

19 with what makes the most sense for right now.

20 It made me think about the fact that we

21 really have to be honest with ourselves. If we had

22 a drug that was absolutely spectacular in the

23 treatment of pain, in the way that penicillin was

24 with pneumococcal pneumonia, you wouldn't need a

25 randomized trial and you could use any measure you



1 care to use, and you would come up with a positive

2 result.

3 What comes to mind in pain management is

4 hip replacement in an old patient who has a broken

5 hip that is amenable to that treatment. I mean any

6 way you look at that, the patient is better. The

7 patient's pain is better, they can walk again, they

8 can get out of bed. Any measure you care to use

9 would work.

10 The unfortunate part is that in

11 medications, we are not yet at that step. It seems

12 to me, therefore, that what we are charged with

13 really is providing enough information to the

14 people who are going to be using these medications

15 to allow them to make reasonable choices about how

16 they treat their patients.

17 I agree that, you know, the clinician on

18 the front line is faced with a whole bunch of

19 different choices, and if we can figure out the

20 mechanism and figure out a test that will give them

21 the mechanism, then, by all means, a mechanistic

22 approach makes sense.

23 If can figure out whether we know this

24 patient is going to develop an allergic reaction

25 and this one is not, then, we should choose



1 obviously only the group that has the allergic

2 reaction.

3 It occurs to me that we are not there yet,

4 and that really, in many ways, what the label needs

5 to reflect--and I keep coming back to the label

6 because ultimately, that is what gets out to the

7 public and then obviously clinical trials on top of

8 that, but what the label needs to reflect is what

9 is it that we know about this drug, do we know that

10 it is safe given in three doses, do we know that it

11 is safe given in 1,000 or in 500 milligrams, do we

12 know that it is safe in terms of kids or adults or

13 pregnant and not.

14 In terms of efficacy, do we know that it

15 works when given in a single dose--that is

16 important--do we know that it works when it is

17 given over a long-term period of time.

18 With that kind of information in hand, I

19 think it is possible to practice medicine, and that

20 is really what we are targeted at doing today.

21 Clearly, one size does not fit all, and every drug

22 is going to have a different set of underlying

23 things that we need to know about it.

24 That makes the job very, very complicated,

25 which is clearly indicated by the amount of



1 disagreement that we have, but I think we need to

2 focus on that.

3 DR. FIRESTEIN: Thank you, although I

4 don't think the sham surgery for hip replacement

5 protocol has been completed yet.

6 DR. STRAND: I just wanted to say that

7 neither should we be trying to shove responder

8 analyses based on other diseases into the pain

9 field, and the fact that RA and OA have actually

10 been addressed very differently from that point of

11 view, but that we should really be thinking about

12 these things as domains, domains of physical

13 function or function period domains of

14 health-related quality of life, and not pick the

15 instrument.

16 We have lots of disease-specific

17 instruments for various kinds of diseases, we have

18 ones for cancer pain, et cetera, so that we don't

19 have to shove the idea into a situation where it is

20 not clinically appropriate.

21 DR. McLESKEY: Well, Lee, you certainly

22 stimulated the discussion. As the industry

23 representative, I would probably be negligent in my

24 duty here if I didn't have at least some response

25 at this stage.



1 I would like to echo Dr. Farrar's comment

2 of a minute ago that obviously our entire goal for

3 being here, your agency, and the various roles of

4 the folks in this room is to advance the practice

5 of medicine, to advance the options available to

6 treat patients.

7 I hope we keep that foremost in our minds

8 as we discuss all of these various issues, what

9 will optimize that result, what will optimize the

10 advance of the practice of medicine and how can we

11 safely achieve that goal with advances in the

12 medications available to our patient public.

13 The pushback that I have heard you receive

14 already or your comments receive already from a

15 couple of the members of the committee on this side

16 of the table specifically, I think probably is

17 representative of the novel concept that you have

18 approached, the innovative concept that you have

19 approached, and expected kind of a result from

20 that, understanding our current knowledge base of

21 disease models, and so forth, and how to measure

22 accurately the effectiveness, and so forth, of

23 various medications.

24 The concept that you mentioned especially

25 for a general claim of three disease states and



1 having to hit on all three of the aspects of pain,

2 function, and global, to me seems like a pretty

3 high bar, and I wonder if the industry colleagues

4 of mine in the room would not feel similarly, and

5 yet, on the other hand, we don't want to act like

6 antagonists and pull back and push back and oppose

7 advances as the advances in the understanding of

8 the mechanisms of pain have been discussed earlier

9 today.

10 So, I would just suggest that we don't

11 want to make the hurdle so high that, in fact, it

12 will stifle innovation and move exactly in the

13 direction we don't want to go. We want to

14 stimulate innovation and advance and move forward.

15 So, again, I hope I am not coming across

16 as somebody who is antagonistic to advance, I am

17 not, but I think to accurately represent industry,

18 we would like in the future to work closely with

19 the regulatory authorities and with the

20 academicians, and so forth, to come up with some

21 kind of a compromise approach that is reasonable,

22 that provides a hurdle that we think we can get

23 over and accomplish the eventual mission of pushing

24 medicine forward.

25 DR. FIRESTEIN: On the other hand, maybe



1 the bar for a global pain indication needs to be

2 high because a drug that really is or a therapeutic

3 that really is appropriate for all pain

4 indications, as a global pain indication would

5 suggest, is not really practical at least with the

6 current state of knowledge.

7 There are so many mechanisms of pain, it

8 is actually unlikely that we would find something

9 that is effective for wind-up pain and fibromyalgia

10 and osteoarthritis and cancer pain, and the

11 question is whether or not, under those

12 circumstances, the graded approach that has been

13 suggested, in particular a disease-oriented

14 approach followed by an organ-oriented approach,

15 followed by a global pain indication is reasonable

16 because the final Holy Grail of global pain is, in

17 practical terms, not really approachable based on

18 the science that we have heard today and has been

19 written about over the past several years.

20 DR. McLESKEY: Perhaps so, but on the

21 other hand, the comments that I have heard from Dr.

22 Farrar and others indicate that maybe we are not

23 quite there yet, and are we trying to run a little

24 bit too soon before we have perfected the issue of

25 walking.



1 But, nevertheless, as you have said, that

2 in order to achieve a global claim, which would

3 obviously be attractive to industry, and I would

4 argue would be attractive to clinicians to some

5 degree, as well, to offer them flexibility, and so

6 forth, if we are to hit on three separate

7 indications or diseases and to perform those

8 indications in replicate, and on each of those hit

9 on the three issues of pain, function, and global,

10 that implies to me that the sponsor would have to

11 perform a substantial number of pivotal trials in

12 order to achieve that mission, which again makes

13 the hurdle extremely high.

14 DR. BRANDT: Just a question for

15 clarification based on what you just said, Gary.

16 You referred to global pain. My understanding of a

17 patient global, for example, is a little different

18 from that, and one of the problems is there are

19 many, many, many globals, it depends on how you ask

20 the question.

21 For example, taking all things into

22 account, how is your arthritis or how is your

23 disease doing, which takes into account side

24 effects, it takes into account other joints than

25 the index joint and so on.



1 Perhaps Lee could clarify what he meant by

2 his global.

3 DR. FIRESTEIN: Well, my understanding is

4 that global means all pain, all indications.

5 DR. SIMON: Actually, let's be very clear.

6 A patients global response is very different than a

7 global indication, and so we would ask for patients

8 to tell us how they feel, as Dr. Brandt has

9 suggested, but Dr. Firestein, I think--I don't mean

10 to put words in your mouth although I am delighted

11 about what you said--was referring to the concept

12 that this high bar would likely stimulate further

13 development because, in fact, it would allow us to

14 look at a therapeutic that would be active in very

15 different disease states, thus, a global chronic

16 pain indication. A very different use of the

17 "global."

18 DR. WOOLF: I think this issue has

19 implications for the preclinical development of

20 analgesics which we haven't really spoken about,

21 but the information that can be derived in terms of

22 global action across a matrix of pain models is

23 essential.

24 I think that as the development plan for

25 any given analgesic is entered into, we need to



1 have as good an evidence as possible of the action

2 of the particular drug, its specific action in

3 terms of which targets it is interacting and its

4 relative efficacy in a broad range of different

5 models, models that are maybe more sophisticated

6 than some of the ones that are being currently

7 used.

8 DR. MAX: Let me put forth what I hear is

9 the consensus around the table and see if it really

10 is. I think we may be suggesting to you that there

11 is no objection to having a general pain claim that

12 requires two studies in each of three different

13 disease categories.

14 We could learn a lot from all the

15 different studies that will come in, and I just

16 hear some objection to making the lowest level

17 general pain claim have each of the six trials get

18 all three endpoints, and the counterproposal is

19 that general pain can be six trials, 3 times 2,

20 each getting pain, is reduced significantly, but to

21 get statistically significant global patients and

22 function would be incentivized by a higher level

23 reward, just like the rheumatoid arthritis claims

24 do that, and I think I agree with Vibeke and others

25 that it is important to have an incentive to



1 develop better measures because there are real

2 issue, should we be spending for COX-2's, should we

3 be giving opioids chronically.

4 Function makes a difference in these

5 questions, and we need to know more about it, but I

6 think we are suggesting to you that there be an

7 additional carrot for this.

8 Does that capture what you are saying,

9 Charles?

10 DR. McLESKEY: I am not sure, Mitchell, I

11 am not sure that there is universal unanimous

12 agreement that there would be three separate

13 disease states studied in order to achieve a

14 general claim.

15 I am one guy representing, obviously,

16 trying to represent industry, but I work for one

17 company, and I would suggest that before such a

18 generalization or a statement like that of general

19 acceptance were achieved, that there be some kind

20 of working group formed where there would be

21 representatives from several of the major players

22 in this area to make sure we have consensus of that

23 kind of an approach.

24 DR. FIRESTEIN: But it is important to

25 remember that whether the number is three, you



1 know, three disease areas, or four, or two, or five

2 or six or more, that the global pain indication

3 should, by necessity, be a very high standard,

4 because it needs to cross all mechanisms.

5 The question is whether it serves the

6 clinicians well to have a global pain indication

7 for a drug that does not work well in neuropathic

8 pain, for instance, if you have done one or two

9 other diseases or organ systems.

10 I think the bar is, by necessity, going to

11 be high for global pain because that is in essence

12 all pain under all conditions. It seems to me

13 based on what I have heard today that there are

14 lesser labeling criteria that still are very broad

15 and still would be probably more reachable than we

16 are today with current technology.

17 So, asking for all pain under all

18 conditions when it hasn't been demonstrated is

19 perhaps asking for something that is not really

20 appropriate at this point.

21 DR. McLESKEY: I appreciate your comments.

22 My only retort to that is that we need to balance

23 incentives in order to advance the field versus the

24 hurdles that are placed in order to achieve those

25 goals, and that kind of a consensus development at



1 this stage, I would suggest needs input from some

2 others who perhaps are not at this table.

3 DR. WOOD: Just to respond to this, I

4 think it is important. I don't think we have

5 consensus, at least certainly not from me, that the

6 global pain indication would be required for

7 approval.

8 So, I would visualize that a drug would

9 come to the Agency and get approved perhaps with a

10 more restricted label and could progress

11 incrementally up that scale as experience, and so

12 on, increased.

13 It would seem improbable to me that a

14 company would go for a global pain indication as

15 its first step. That would be an awfully high-risk

16 strategy and one that would seem to me

17 counterintuitive anyway.

18 So, I would be less concerned I think that

19 you are, Charles, at the dangers of that, because

20 you would only be going for a global pain

21 indication once you had received approval for

22 probably multiple other indications and had

23 reasonable level of experience.

24 So, I think we are sort of arguing about

25 something that is not likely to be even an early



1 step in drug development. Maybe I am wrong.

2 DR. FIRESTEIN: Why don't you go ahead and

3 respond, and then Dr. Ashburn, and then we will

4 probably move on.

5 DR. McLESKEY: Well, that is certainly a

6 presumption that you have made, and there is

7 actually a history, a recent history that global

8 claims have been achieved, maybe with hurdles not

9 quite so high, and again, obviously, the broader

10 the claim can be, the greater the incentive there

11 is for innovation from the sponsors.

12 All I am saying is that if we make the

13 hurdle quite high or, as you say, if we have to

14 incrementally approach it, the costs go up with

15 that approach, and the resistance to innovation

16 then may rise, which obviously, we don't want to

17 see happen, as well. We want to encourage

18 innovation.

19 DR. ASHBURN: I think the point that you

20 make is something that one needs to bring out,

21 flesh out a little bit more, and that is, is that

22 if you make a global claim too difficult, then

23 companies I think tend to go for a very narrow

24 focus or very narrow indication to get a product on

25 market with the expectation that that product for



1 pain will be used in a wider range of patients, so

2 as an off-label use, and that has a double-edged

3 sword, that if you make the bar too high, people go

4 for a narrow indication. Then, the medication will

5 be released, and then it will be used in patients

6 in whom it has not been studied.

7 Not only is that a problem with regard to

8 lack of good outcome data to guide clinical

9 judgment, but also has a problem with regard to

10 safety. That is one of the issues, trying to

11 strike a balance, so that you encourage people who

12 are developing products to widely study them the

13 medication, but not make the barrier so high that

14 they go for a narrow indication and actually

15 increase the risk of harm to patients once a drug

16 is released.

17 I also want to just re-flesh on the

18 outcome measurement, is that I think it is a

19 wonderful idea to include outcome measurement as a

20 part of the clinical trials for these products.

21 The concern that I have is that it is sending the

22 voice that positive benefit in all those different

23 fields are a requirement.

24 So, I think that tracking outcome

25 measurement can be a vital important required part,



1 but I visualize that data being used to guide the

2 development of the label rather than being a

3 primary indicator for approvability.

4 DR. FIRESTEIN: Well, now that we have

5 resolved this problem, I don't know that we

6 answered the questions that you raised in No. 3

7 here by providing you with a list of appropriate

8 models, but we did discuss No. 4 in some detail.

9 Again, just to reiterate, the notion is

10 that there are still very broad claims that would

11 still be available without a global pain

12 indication, is that correct?

13 DR. SIMON: Correct.

14 DR. FIRESTEIN: At this point, we will

15 move on to a discussion of back pain by Dr.

16 Borenstein.

17 Back Pain - Chronic Issues

18 David Borenstein, M.D.

19 DR. BORENSTEIN: I wanted to thank the

20 Advisory Committee and Lee Simon for asking me to

21 speak today. He said I should make it practical,

22 and I try to be a practical person, so hopefully,

23 what I will speak to you today about in regards to

24 back pain will, in fact, be practical.

25 It was one of the things I did want to



1 raise my hand and speak, but having the option of

2 actually being able to speak and having the

3 microphone allowed me to use it at this time.

4 [Slide.

5 I just wanted to give you a little

6 background about myself for those who may not know

7 me. I am from the George Washington University

8 Medical Center, not the other one across town. So,

9 if you want to find me, that is where you will find

10 me. I have been involved with low back pain in its

11 various forms, both on clinical trials and from the

12 standpoint of taking care of patients, I guess now

13 about 24 years, so I think I have some experience

14 at least in regards to low back pain.

15 [Slide.

16 When the Advisory Committee and Lee asked

17 me to speak, there were some issues that they

18 wanted me to discuss, so I thought I would sort of

19 put them out and say what they were in one form,

20 but what they also truly meant, and that was to

21 find the forms of chronic low back pain and its

22 prevalence.

23 What does that really mean? Is it

24 frequent enough and important enough to study? If

25 we have it, it's a problem that everyone talks



1 about, but is it really big enough a problem for

2 which it is worthwhile to actually look at?

3 Will patient selection including etiology

4 and severity influence the performance of drugs in

5 development? That means is it possible to identify

6 and separate the individuals who have back pain.

7 This may be all moot if we can't really

8 separate them out, they are just going to be one

9 group of people, then, we may just need to discuss

10 back pain, but there may be subgroups that we

11 really want to identify.

12 Which are the appropriate outcome

13 measures? That is, can improvements in back pain

14 be related to therapy, in other words, can it be

15 determined? If we have back pain patients and we

16 treat them, can we actually tell whether we do

17 anything for them?

18 [Slide.

19 4. Will a general indication be useful

20 for different labeling claims? I know Lee beat

21 this up already, somatic versus neuropathic versus

22 chronic headache. So, if you have someone who has

23 pain, it's in the low back, will it, in fact,

24 translate to them as far as their headache is

25 concerned, will there be some applicability?



1 Finally, with chronic low back pain, will

2 it serve as a measure for efficacy for a general

3 chronic pain indication, or should it remain

4 independent for a specific disease, exactly what we

5 have been discussing this morning?

6 I don't know if I have all the answers for

7 it, but I figured I would be discussing them and at

8 least I will give you my point of view.

9 [Slide.

10 So, what is chronic low back pain, what

11 does that mean, and what is its prevalence? How

12 often does it occur?

13 [Slide.

14 Well, in a lot of different studies, low

15 back pain is described as the pain that occurs in

16 the area with boundaries between the lowest and the

17 crease of the buttocks. So, when we talk about low

18 back pain, we are really not talking about leg

19 pain, we are not talking about sciatica, although

20 that is part of what we see with low back pain, so

21 depending upon how you define it, one can have a

22 wide variety of people.

23 If you just define chronic low back pain,

24 this would be the anatomic area that you might want

25 to study. That doesn't mean you wouldn't



1 necessarily study individuals with sciatica, but

2 that might be a special group.

3 [Slide.

4 What is chronic low back pain? It has a

5 duration. Duration may be as defined previously up

6 to three months, that is, up three months there is

7 this opportunity of having a repair, being in this

8 acute nociceptive stage, so that the body may heal

9 itself and then go back to its baseline state.

10 However, after possibly three months,

11 maybe sooner, this neuroplasticity has occurred and

12 thereby you are in a state where the nervous system

13 has had a response to this injury and you are now

14 in a chronic pain state.

15 Others have described chronic pain as pain

16 that persists longer than the expected period of

17 time for healing, so some people have described

18 chronic pain occurring within two days or two

19 weeks, not even waiting two months to be in a more

20 chronic stage because it is no longer in this acute

21 healing phase.

22 So, once again, these are at least two

23 different definitions that one might want to

24 describe in regard to chronic low back pain.

25 [Slide.



1 What is its epidemiology? Is it

2 worthwhile to study? Is it frequent enough, will

3 you find people who would want to be in clinical

4 trials because of this problem?

5 Well, 20 percent of the U.S. population

6 develops back pain yearly, so 1 out of 5 is a

7 potential candidate for a clinical trial. That

8 doesn't mean all of them have chronic low back

9 pain, but certainly 1 out of 5 do develop it.

10 Back pain is the second most common cause

11 of disability in the United States, and it is the

12 most common among men, accounting for 16.5 percent

13 total disabilities in individuals greater than 18

14 years of age in 1999. So, I propose that it is an

15 important problem. Not only does it cause pain,

16 but it also causes disability, and it's expensive.

17 If you look at Workers' Compensation

18 claims, which is far from all the individuals with

19 low back pain, from 1986 to 1996, during this

20 one-year period of time, 8.8 percent of the claims

21 were for back pain, but was up to almost 85 percent

22 of the costs.

23 So, having better therapies for low back

24 pain is important. Not only it a frequent problem,

25 but it also is potentially disabling and



1 significantly expensive.

2 [Slide.

3 So, there are at least reasons for which

4 having better therapies would result in betterment

5 to the individuals with it and society in general.

6 Is there a fiction as regards to how low

7 back pain does over time? In other words, the

8 usual story has been that most patients get better

9 within a two-month period, so we don't have very

10 many going on to a chronic phase.

11 [Slide.

12 Well, this study was done and reported in

13 the Annals of Rheumatic Disease back in 1998. This

14 was done in the Netherlands where they had

15 individuals who were a bit younger, those

16 individuals who we might want to think about being

17 involved with low back pain. They had about 450

18 individuals where they sent out postal

19 questionnaires over a 12-month period and followed

20 them over time to see what happened.

21 Most people, in fact, got better. The

22 median was about 7 weeks. However, still, at 3

23 months, 1 out of 3 still had back pain. You say,

24 well, they still might get better. If you want to

25 know whether these individuals will still be there



1 one year later, this study would suggest 1 out of

2 10.

3 So, with the individuals who have low back

4 pain, 1 out of 10 in general will still be having

5 it one year later. So, we do, in fact, have

6 individuals who are available to be studied. You

7 have, if you think of at least 2 percent, let's

8 say, of the U.S. population each year going into

9 the chronic back pain category.

10 [Slide.

11 Now, it's very funny to me, when people

12 ask me what is back pain, having written a 700-page

13 book on it, it is very difficult for me to answer,

14 and so when I hear people saying chronic back pain,

15 I just go twirling around saying which one do you

16 mean.

17 In my book that I wrote on this, we had 60

18 different reasons for developing the symptom, the

19 symptom of low back pain. Now, it takes a little

20 time to figure which disease is causing that, and

21 we will talk about whether we are good at that or

22 not, but this is one of the ways one might look at

23 the various categories with low back pain, whether

24 it's mechanical, rheumatologic, infectious,

25 psychiatric, so there are a wide variety of



1 disorders which can be associated with this

2 problem.

3 [Slide.

4 Now, let's simplify it a little bit. What

5 turns out to be the case is that the systemic, the

6 rheumatologic, the endocrinologic, the psychiatric

7 types of illness associated with low back pain are,

8 in fact, relatively few.

9 This is probably being generous on the low

10 side. Probably mechanical pain may be more like 90

11 or 95 percent of all the individuals looking at a

12 large enough population of individuals. So,

13 mechanical low back pain can be defined as one of

14 these various problems.

15 It can be associated with disorders

16 dealing with the muscle, ligaments, or tendons

17 which have been injured. It can be discogenic, it

18 can be the intervertebral disk which has been

19 affected, and that is a whole separate topic of

20 whether that causes pain or not, but can be

21 associated with a herniated disc which may also

22 result in a radiculopathy or sciatica.

23 There is also apophyseal joint disease,

24 and I am sure that Dr. Brandt would agree that

25 osteoarthritis affects the lumbar spine, so there



1 is some osteoarthritis there, as well. There is

2 spinal stenosis, spondylolysis, and

3 spondylolisthesis, which is an instability of the

4 spine, and then scoliosis can, in fact, be

5 associated with chronic low back pain.

6 These can all occur acutely. Some are

7 more associated with a more chronic situation. So,

8 you can have some that are acute and some, then,

9 that will go on to the chronic phase.

10 [Slide.

11 I would certainly like to hear what Dr.

12 Woolf has to say about my sources of pain as

13 regards to the lumbar spine. My suggestion is it

14 is once again complicated as to which structures

15 are being affected.

16 Superficial somatic, I love when comes in

17 as far as the back is concerned. I can pick up

18 herpes zoster and cellulitis pretty easily, and

19 that is easy to do. It gets more complicated the

20 deeper in the body you go, and that is why this is

21 so complicated because we are very good at

22 osteoarthritis of the fingers, but it becomes much

23 more difficult when it is osteoarthritis of the

24 zygo-apophyseal joints, because we can't get our

25 fingers around them. It becomes much more



1 difficult to diagnose.

2 So, deep somatic structures, such as the

3 muscles, the joints, the bursa, and fascia, also

4 have a characteristic kind of pain, which I would

5 propose is different than superficial somatic pain

6 in its character, in its clinical symptoms.

7 The same for radicular pain associated

8 with nerve root difficulties compared to visceral

9 referred pain mediated through sympathetic

10 afferents versus neurogenic pain, which may be more

11 of this diabetic neuropathy or amyotrophy,

12 psychogenic pain, which exists totally in the

13 cerebral cortex.

14 So, when you deal with low back pain,

15 depending upon which structures may be affected,

16 and which nerves may be affected, you can get a

17 different character of pain. I truly believe that

18 I can tell the difference between somatic and

19 radicular.

20 [Slide.

21 It was also suggested that we have

22 difficulty in deciding what pain intensity is, and

23 I was always quite interested in knowing what

24 minimal, mild, moderate, and severe was. Dr.

25 Simon's definition was he gets it as soon as he



1 even gets close to the dentist's office.

2 Well, this is the way I decide about it

3 because we don't have any specific machine that

4 measures it specifically. I do it on the basis of

5 function, and this is what I do in the office every

6 day.

7 Minimal is mentioned in passing and its

8 normal function. The person came in because they

9 had knee pain, but when you go through your total

10 review of systems, they mention that their back

11 bothered them once in a while.

12 Mild is a component of symptoms with mild

13 dysfunction. They are concerned that they are not

14 running as far as they used to because their back

15 bothers them. That is starting to concern them.

16 It doesn't bother them with the rest of their

17 activities, it is their recreational activities.

18 Moderate, it is getting in the way of what

19 they do with their work, it is becoming an impact

20 upon how they do their daily lives, and severe, the

21 point that Dr. Simon didn't tell you, is that he

22 brings his wife with him when he goes to the

23 dentist because he will need someone to help him

24 put on his clothes after he gets done.

25 That is the equivalent when I have someone



1 with severe back pain who comes to me, they come

2 with someone else, because they can't function to

3 put on their clothes to get in the office or to get

4 out of it.

5 So, there are ways of differentiating

6 among the various types of discomfort these

7 individuals experience.

8 [Slide.

9 The diagnosis of back pain is nonspecific

10 in 80 percent of patients. This is a dictum which

11 is repeated again and again and again, and it is

12 based upon some studies which been in the

13 literature for quite a long period of time, really

14 before there was an MRI or CT scan.

15 It is easier to just repeat it as to go

16 out and really find out if it's true or not, so it

17 is repeated and said most of the time you really

18 can't tell what is going on with these individuals.

19 That might be a problem if you were going to base a

20 whole indication on an entity which you really

21 couldn't diagnose, and I could understand why that

22 might be a problem.

23 [Slide.

24 Is that truly what happens? There was

25 just a very interesting paper, set of papers, which



1 appeared in the Archives of Internal Medicine just

2 in the last month. It came perfectly on time in

3 regard to this meeting.

4 Basically, it was a pro and con situation.

5 What the authors were saying is specific diagnosis

6 is possible or specific diagnosis is impossible.

7 On one side there was this physician, Dr.

8 Abraham, who raised the point that, in fact,

9 specific diagnoses are possible, that there are

10 clinical symptoms and signs associated with

11 differentiation of muscle, joint, and ligamentous

12 structures, that it is possible to, in fact,

13 differentiate mechanical versus systemic disorders,

14 that you can categorize these clinical symptoms,

15 that can be done, and that subtyping these

16 individuals does have the possibility of improving

17 therapy, that is, if you can separate the specific

18 mechanisms either or pain generators or the nerves

19 that are mediating it, might it be possible to get

20 a better therapy because you could identify them.

21 [Slide.

22 On the other side was Rich Deyo, and he

23 has been long known for being of the school that

24 you really can't make diagnoses. His point,

25 however, his not hidden agenda, quite clear agenda,



1 he is concerned about individuals utilizing health

2 services to make diagnoses, which don't really make

3 a difference, so people doing MRI's and x-rays, and

4 all this.

5 His point is specific diagnosis is

6 impossible. You can find anatomic abnormalities

7 in asymptomatic individuals. This will result in

8 overutilization of imaging techniques. There is

9 inconsistency with physical findings. In general,

10 if we look at it, nonspecific therapy works,

11 nonsteroidals can work in a wide variety of things,

12 so if they do, why bother to try and find the

13 specific pain generator, they work in general.

14 My point is probably a mixture of both. I

15 think both have points to be made for their side.

16 I think it is possible to separate these

17 individuals a bit better, and I think even Dr. Deyo

18 in his response said yes, it probably is

19 recognizing that his concern was about utilization,

20 and not the fact that you couldn't diagnose some of

21 these more specific problems.

22 So, I do think it is possible, but until

23 we categorize and study a bit more specifically, we

24 may not be able to come up with better therapies,

25 and that is part of what this group needs to



1 decide, is that worthwhile, and that is what the

2 committee will have to sort of deal with.

3 [Slide.

4 Also, is it possible to differentiate

5 among these various types of problems, can you do

6 the difference between somatic, neuropathic, and

7 radicular pains? Yes, they can be differentiated,

8 and specific pain generators are difficult to

9 identify, but localization is not essential for

10 effective therapy.

11 So, my point would be this, that it is

12 possible to categorize some of these individuals

13 with chronic low back pain, you can put them in

14 broad categories, and then you can study them to

15 see, in fact, they are responsive to different

16 types of therapies.

17 I think it is important to try and

18 separate somatic versus radicular, but that doesn't

19 mean they should be mutually exclusive, and some

20 therapies may, in fact, work in both areas.

21 [Slide.

22 Now, as my third point, are there pain

23 outcome measures or low back pain measures which

24 have been shown to be effective in picking up

25 differences? Now, Dr. Strand is I am sure going to



1 do an excellent job talking about this tomorrow,

2 and I am not stealing any of her thunder at all,

3 because I am just going to go into this for a

4 minute or two, because I don't want to tread too

5 far afield.

6 But I do believe, at least as part of our

7 discussion, do we have these outcome measures, do

8 we have back-specific function measures, do we have

9 pain measures, and do we have patient global

10 satisfaction measures that make a difference?

11 [Slide.

12 Well, back-specific function measures do

13 exist, and these have been tested for a long period

14 of time. They are the Roland Morris Disability

15 Questionnaire and the Oswestry Disability Index.

16 [Slide.

17 For those who may not be aware of them, I

18 am just going to take one minute to just describe

19 them to show you that they do, in fact, exist, they

20 do function assessments as a means of telling how

21 back pain patients are functioning and how they are

22 doing.

23 There are 24 items from the Sickness

24 Impact Profile. The functions that they pulled out

25 affect back pain that day. The scores are added,



1 and this has been a validated and reproducible

2 instrument for a number of years since it first

3 came out in 1983, and has been associated with

4 picking up differences and improvements in patients

5 with low back pain on a function basis.

6 [Slide.

7 Then, we have individuals who have been

8 measured with the Oswestry Disability Index, and

9 this is also a pain and function assessment. There

10 are 10 sections on various functions with 6 levels

11 of assessment in each.

12 They measure physical and social functions

13 that day. They can once again be added up to 100,

14 and have been validated and are reproducible

15 instruments, as well. So, from the standpoint of

16 function, we certainly have capabilities.

17 [Slide.

18 In regards to pain assessments, I will

19 leave it once again to others to describe whether

20 these are the appropriate ones or whether there are

21 others that are better in describing specific

22 different types of pain.

23 One may have a general type of pain

24 assessment tool, and if you have a specific

25 character of pain, a neuropathic pain, or another



1 type of pain, one might use that specific tool, as

2 well, in that specific circumstance.

3 [Slide.

4 Then, in regards to global satisfaction, I

5 would ask this group to strongly believe that a

6 question to the patient asking how are you doing

7 and are you doing better is a worthwhile outcome,

8 and should always be, period, case closed.

9 It doesn't take too long to ask, it takes

10 very little time to circle, but that is what I ask

11 every day, and you can do it with smiley faces, you

12 can do whichever which way you want, but that is

13 what the patient cares around, do I feel better all

14 over, and what was said in regards to toxicities

15 and frequency of dosing and everything else all

16 gets wrapped up into the way the patient feels.

17 So, I think whether they are satisfied

18 with their therapy, very much, a little, mixed

19 reviews, or I really hate it, really does get to a

20 significant outcome as far as these studies are

21 concerned, and I think it is a very simple question

22 to ask, but a very important piece of information

23 to know.

24 [Slide.

25 Then, of course, optional measures are



1 also possible depending upon whether you think

2 there is depression associated with these

3 individuals with chronic pain. There is the

4 general health status circumstance with SF-36 and

5 various depression scales, I just picked out one.

6 This could be optional if you think

7 depression is playing a significant role in regards

8 to these chronic back pain patients.

9 [Slide.

10 So, I do believe there are instruments

11 that exist that measure the effect of drug

12 interventions on chronic pain for function, pain,

13 global satisfaction, and for general health status.

14 [Slide.

15 Now, what was mentioned also is quite

16 clear, that is, chronic pain therapy is

17 multimodality. Depending upon how long it has been

18 present, one may use one drug, two drugs, three

19 drugs, four drugs. One may use a variety of other

20 physical modalities, physical therapy, exercises, a

21 wide range of things in order to take care of back

22 pain.

23 I am not sure how one wants to deal with

24 that in saying they need to be additive or have a

25 baseline state and then take one aspect away and



1 seeing if substitution makes a difference, either

2 making the patient go back to their baseline state

3 or, in fact, improve upon their baseline state.

4 So, these are some of the therapies that

5 are available as far as back pain is concerned.

6 [Slide.

7 These are the therapies, the drug

8 therapies associated with low back pain. I want

9 you to know that I looked in the PDR to see if one

10 had an indication for chronic low back pain. None.

11 So every day that I work in the office, I have no

12 indication for any of the drugs that I am using.

13 I feel comfort with that, but uneasy. I

14 have to tell my patient if they are smart enough or

15 willing enough to ask me is this indicated for

16 this, the answer is not specifically, but I think

17 you have a problem that will respond to this.

18 So, here is a wide range. This isn't my

19 list, this is culled from a number of different

20 papers and studies looking at what has been

21 effective as far as chronic low back pain occurred.

22 This has been nonsteroidals, muscle relaxants,

23 analgesics, antidepressants, anticonvulsants,

24 alpha-2 adrenergic agonists, and a miscellaneous

25 group including the NUDA receptor antagonists.



1 [Slide.

2 I am not going to go through all of these.

3 Certainly many of you know them already. There are

4 the nonsteroidals. This was recently reviewed in

5 Spine in 2000, suggesting that these medications,

6 in fact, do have benefits as far as chronic low

7 back pain is concerned.

8 The ones that are short-lived, have short

9 half-lifes, they can be used for the acute

10 exacerbations that Dr. Sherrer was talking about,

11 that if you have someone who has a baseline state,

12 but has an acute exacerbation, one can use a short

13 half-life nonsteroidal, long, sustained effects for

14 long half-life medications, and certainly from the

15 standpoint of COX-2 inhibitors, decreased toxicity

16 because the people will be on drugs for extended

17 periods of time is certainly an important

18 indication and concern, that it may be good for a

19 week or two, but when you are talking about one or

20 two years, it is still going to be safe.

21 I am not suggesting that one needs to

22 study it that long a period of time, but there are

23 patients who are on these drugs for extended

24 periods of time, so toxicity is something I am

25 concerned about when I start these patients, but I



1 don't really know how long they are going to end up

2 on them, but if they work, I keep using them.

3 [Slide.

4 Then, there are, of course, the muscle

5 relaxants as they have been described previously,

6 and these are important adjuncts to therapy. If

7 you wanted to see the effect of any one of these

8 for longer than six months, I couldn't show you a

9 study that really did that on any regular basis.

10 [Slide.

11 Non-narcotic and narcotic medicines are

12 all used in patients who have chronic low back pain

13 depending upon their status.

14 [Slide.

15 I am almost out of time, but I wanted to

16 be practical. We have been very much talking about

17 mechanisms and all. I deal with patients just like

18 many of you, and I thought what I would do to end

19 up my discussion today is live my life.

20 You have a few patients with chronic low

21 back pain. This is what they are getting. This is

22 a 52-year-old person who had a work-related

23 myofascial injury in the lumbar spine. It is mild

24 to moderate, she is still able to function. We

25 changed her nonsteroidal to a diclofenac product.



1 She remained on her muscle relaxant when she has an

2 acute exacerbation, so she can stay at work. She

3 knows that she can dose with an extra short form of

4 the medicine, and she knows that she is supposed to

5 be on her exercise program in order to maintain her

6 function.

7 [Slide.

8 There is a 67-year-old person who has

9 facet joint disease, has basically osteoarthritis

10 as part of their chronic low back pain. This

11 individual is treated with a COX-2 inhibitor and a

12 muscle relaxant, and has been on this regimen for

13 an extended period of time.

14 This, I would say was the mild to moderate

15 chronic somatic type of pain.

16 [Slide.

17 Then, I have another individual who has

18 had a laminectomy, some of these are post-surgical

19 individuals, who happens to have a fractured screw

20 in his back, but he doesn't really want to get it

21 taken out.

22 So, this individual, over time, and I have

23 been taking care of him over 10 years, has gone

24 through a variety of therapies now where he is now

25 currently on a COX-2 inhibitor nortriptyline, a



1 fentanyl patch, and a short-acting narcotic when he

2 has his acute exacerbations.

3 [Slide.

4 Then, finally, for the individual who has

5 moderate to severe neuropathic pain, who is still

6 in this chronic back pain situation since he has a

7 component of pain, he has had a traumatic

8 neuropathy to the sciatic nerve.

9 He is on a long-acting nonsteroidal,

10 gabapentin, oxycodone, long acting, and short-term

11 narcotic for when he has an exacerbation.

12 That is what chronic low back pain therapy

13 can be depending upon who you are seeing and what

14 kind of status they are in. I do believe it is

15 possible to separate these individuals out. Many

16 of these individuals have been on a variety of

17 therapies for an extended period of time.

18 [Slide.

19 So, I would like to conclude with this and

20 hopefully have answered some of these questions,

21 but probably have raised more. I do think that

22 chronic low back pain is a model for chronic pain.

23 I think it is an important problem.

24 I think there are enough people in the

25 society for which it is worthy of being



1 investigated. There are outcome tools available I

2 think at this time that can at least give us a

3 handle as to how to measure it, but certainly

4 others, as they are developed, would be useful.

5 Somatic pain is identifiable, that is,

6 pain related to musculoskeletal disorders, and for

7 terms if you don't like somatic, but prefer

8 musculoskeletal system, would be where I would put

9 that, are identifiable and can be seen and studied.

10 The degree of pain and effect of study

11 design I think is also possibly differentiated.

12 For those who have mild to moderate pain, it might

13 be possible to do a single drug versus placebo with

14 an active comparator, however, when you have these

15 individuals who have more severe pain where there

16 may be more mechanisms involved, there, you may

17 have individuals who may be on a stable multidrug,

18 multimodality therapy, but there, take the drug

19 away, have them flare, and then replace it with the

20 study agent and thereby be able to determine

21 whether they did better or worse from their

22 baseline state.

23 That is where I will conclude. Thank you

24 very much for your attention.

25 DR. FIRESTEIN: Thank you very much. We



1 have about 10 minutes to discuss Point No. 5, which

2 is to comment on the value of chronic low back pain

3 as a separate labeled indication versus part of a

4 broader claim.

5 Discussion Point #5

6 DR. MAX: A question for Dr. Borenstein.

7 One big distinction that seems to come out of your

8 talk is the distinction between people who have low

9 back pain every day for a year or two years and

10 those who are having clear-cut, new injury, where

11 perhaps the disc is getting another little tear,

12 and all the studies, like the postcard study you

13 show, had people with new relapses.

14 Do you think it would be appropriate in

15 clinical trials to make some sort of distinction

16 between these people who probably have some acute

17 inflammatory pain on top of it, which might respond

18 to different drugs and how would you do it?

19 DR. BORENSTEIN: Well, I do think it is

20 possible to separate these individuals out. Some

21 people have a chronic ongoing back pain, which it

22 may vary a little bit, but is essentially there for

23 extended periods of time. We are talking months

24 and months and months.

25 There are other individuals who have



1 exacerbations of their pain, they wax and wane.

2 Those individuals do have a different kind of

3 story. Some of those may think it is the weather

4 that bothers them or certain activities that will

5 have an effect upon their pain.

6 So, I do think it is possible through the

7 appropriate questions at the start of such a study

8 to differentiate from these individuals who has a

9 chronic stable type of pain versus those who are

10 having acute exacerbations, which may have more an

11 inflammatory component.

12 DR. MAX: Has the methodology been

13 developed yet in any of the published clinical

14 trials of back pain to distinguish these two

15 classes?

16 DR. BORENSTEIN: Well, as I tried to show,

17 there is great debate about whether one can define

18 or describe low back pain, and this has just been

19 written about last month. I think if people do take

20 care of back pain patients, you can separate these

21 individuals out.

22 There are a certain criteria where one

23 might say their level of pain has remained at a

24 certain level for a period of time. So, I do

25 believe that it is possible to separate them out,



1 but has it been studied specifically as to which

2 group this may be, whether it is osteoarthritis

3 with more a flare component? No, that hasn't been

4 done.

5 DR. FIRESTEIN: Dr. Sherrer.

6 DR. SHERRER: I think Dr. Borenstein has

7 shown that low back pain has all the general

8 problems that chronic pain has in general, and I

9 don't think it is going to offer us anything

10 specific.

11 You pointed out that you have

12 osteoarthritis affecting the low back, you have

13 inflammatory joint disease affecting the low back,

14 you have soft tissue pain affecting the low back,

15 and I think we see that clinically.

16 Then, you have the chronic persistent

17 pain, the chronic intermittent pain. It is the

18 same thing we see with chronic pain elsewhere. So,

19 I don't see that separating low back pain out per

20 se is going to be beneficial unless we are going to

21 be able to separate out inflammatory low back pain

22 or osteoarthritic low back pain.

23 DR. BORENSTEIN: My suggestion would be

24 that we could. If you have a sed rate greater than

25 20, you have an inflammatory process which



1 separates out most, I do think it is possible to

2 separate out those individuals who have

3 inflammatory back pain.

4 I think we can separate out the

5 spondyloarthropathies. Those people have

6 infections, and all those. I would not suggest

7 that it is so difficult to do. I think it is

8 clearly possible to identify those individuals who

9 have mechanical pain.

10 Now, if you want to separate out those who

11 have it solely on muscle discomfort versus joint

12 discomfort, it may become a bit more difficult, but

13 from the standpoint of an inflammatory versus

14 non-inflammatory standpoint, I think that is not a

15 difficult process to undergo.

16 DR. GOLDKIND: I would like to ask Dr.

17 Borenstein what evidentiary base are you familiar

18 with that speaks to the polypharmacy, not

19 surprising at all, but striking how patients with

20 chronic low back pain, and that is probably going

21 to be true in other chronic pain situations, are on

22 polypharmacy, but is it fully anecdotal or do you

23 see studies that incorporate that aspect.

24 DR. BORENSTEIN: Most of them are

25 anecdotal. I mean it becomes most of the way drug



1 studies are done for the most part except in

2 rheumatoid arthritis, and they haven't necessarily

3 been transposed into chronic low back pain, is that

4 you have a stable therapy, which can be on a wide

5 variety of drugs, and then you take one drug away.

6 This, I do not believe has been

7 specifically done in chronic back pain patients who

8 are on more than one drug. That is the problem that

9 we face. If this was thought to be a good

10 process, then, in fact, that could be done, but

11 that is the way some of these patients with chronic

12 back pain need to be treated.

13 Some, in fact, can be treated with one or

14 two drugs. Others with more severe pain are

15 treated with multiple drugs.

16 DR. GOLDKIND: Do you think there would be

17 any value in studying specifically combinations,

18 how we put drugs together, or does the current

19 clinical trial design where there is background

20 that includes the remainder suffice for clinical

21 practice?

22 DR. BORENSTEIN: Well, getting back to

23 what Dr. Woolf was talking about before, this may

24 be one of the ways of trying, in fact, to identify

25 those individuals. Just hypothetically, you have a



1 group of people who are on a nonsteroidal, muscle

2 relaxant, a tricyclic. You have three drugs.

3 You come along and find out that you

4 intervened with one, you take one of those out and

5 intervene and find a subgroup of people who have a

6 specific response, this might be interesting in

7 identifying those individuals who have a response

8 to that specific group, because it is going to be

9 very hard to find these people who have chronic

10 back pain, who are going to be on placebo versus

11 the active comparator, and nothing else.

12 So, I think this may be one of the ways of

13 getting those drug trials done and also identifying

14 those individuals who may be doing subgroup

15 analysis to see how they may have responded above

16 and beyond what the mean might have been otherwise

17 to get at some of these mechanism problems.

18 DR. FIRESTEIN: Dr. Cush.

19 DR. CUSH: I think from Dr. Borenstein's

20 comments we should be very concerned that despite

21 the prevalence of the condition, the number of

22 agents which have targeted back pain for an

23 indication are very few, and that is surprising and

24 disappointing.

25 I think that the FDA should make an effort



1 to try to make this an indication if, on one hand,

2 to spur and excite research in this area as an

3 indication, but obviously, this was always out

4 there and people could have gone after it, and

5 companies may have stayed clear of low back pain as

6 an indication for a variety of reasons, maybe the

7 difficulty in studying patients, the outcome

8 measures, and whatnot, but this is an inherent

9 problem in there and maybe the FDA can look forward

10 to try to develop ways of pushing people in this

11 direction as far as research and clinical trials.

12 One way might be for that global

13 indication that we argued about in the last

14 session, maybe one of the defining diseases under

15 that heading might be low back pain.

16 MS. McBRAIR: As the consumer rep, I just

17 wanted to thank Dr. Borenstein for supporting the

18 idea of studying patient function, their patient

19 global assessment, and possibly quality of life.

20 People can have a lot of pain medication

21 and pain control, and not be able to function very

22 well, as oftentimes noticed by employers and

23 families and others, and I think we need to take a

24 clear look at what we are doing to people when we

25 offer them all these medications.



1 DR. FIRESTEIN: Dr. Brandt.

2 DR. BRANDT: Polypharmacy is not unique to

3 low back pain. It may be a general phenomenon in

4 patients who have chronic pain. In osteoarthritis,

5 those people who are given a prescription NSAID, a

6 very significant proportion are taking also an

7 over-the-counter NSAID and acetaminophen and

8 glucosamine. So, it is not unique to low back.

9 DR. BORENSTEIN: If I could just comment

10 on that. Once again, although ideally from a

11 scientific basis, it is nice to think of nice

12 straight lines as the only way things happen, but

13 dealing with human beings, they always find ways of

14 making the lines curve.

15 I have never seen a straight one yet, and

16 there is always a little bit of everything, and the

17 trouble that we have is trying to identify those

18 people and how they verge away from this line, this

19 straight line, where the curves come in.

20 So, that is why I was saying polypharmacy,

21 yes, there may be this peripheral sensitization and

22 other things playing a role, as well as

23 nociception. Some people may have some of both,

24 and that even though it may be what we would

25 expect, where a COX-2 or a nonsteroidal may have no



1 effect, in certain circumstances, they do seem to,

2 and so we are always surprised, we are always happy

3 it happens, but I can't really always explain it.

4 So, though knowing the basic science is

5 clearly essential, and the better we get at it, the

6 better we will be able to have therapies. At this

7 point, I still think that we still have to use a

8 little bit more leeway in the way we actually use

9 these drugs to try and maximize the effect in our

10 patients.

11 That is once again the basic goal is to

12 make the patients better. The science will catch

13 up with the human beings as they tell us how they

14 are doing.

15 DR. FIRESTEIN: One of the problems with

16 looking at low back pain as a single entity is that

17 it becomes difficult to manage them with an

18 individual agent for diseases, that has multiple

19 etiologies, just as we don't have a single

20 indication for heart disease, for instance, but we

21 wouldn't necessarily even desire a single

22 indication for low back pain, which is in part

23 caused by osteoarthritis or other mechanical

24 derangements, and the like, or neuropathic

25 diseases.



1 I wonder if we would be doing the patients

2 a service or a disservice by lumping all those

3 patients together rather than trying to be more

4 specific in targeting our approaches.

5 For instance, you already mentioned that

6 90 percent of the patients have mechanical issues,

7 and that might be one way of at least getting one's

8 arms around the indication rather than just trying

9 to include all back pain.

10 DR. BORENSTEIN: My response with that

11 would be exactly that. I think you can separate

12 out these individuals who have musculoskeletal

13 versus the systemic illnesses, and make a

14 difference for those individuals.

15 It becomes difficult to say that it is

16 only joint, and not muscle, because you can get

17 referred pain, as well, so if you are able to deal

18 with that process and make a difference, even

19 though it may be muscle first and joint second, or

20 joint first or and muscle second, you can still

21 make an impact in this musculoskeletal arena.

22 DR. FIRESTEIN: Dr. Katz, and then we will

23 finish up.

24 DR. KATZ: I would like to come down on

25 the side of an entity of chronic low back pain.



1 Again, as Dr. Borenstein did, we are talking about

2 non-neuropathic low back pain, we are talking about

3 eliminating systemic diseases, but I would be in

4 favor of that being an indication unto itself and

5 also that being a disease model that could be used

6 to work towards a musculoskeletal claim.

7 All of these diseases can be split

8 infinitely into different subgroups that may

9 respond more or less well. We just heard earlier

10 that hypertension is actually a number of different

11 diseases that respond differently, but nobody is

12 bothered by the idea of having a drug for

13 hypertension, diabetic neuropathy, it is the same.

14 Postherpetic neuralgia, it doesn't bother

15 us to approve a drug that works at best in a third

16 or 40 percent of patients, knowing that our

17 approval only applies to a subgroup, but knowing

18 equally well that because we don't know how to

19 segregate out that subgroup, we need to provide a

20 physician a reason to use the medication.

21 We also know that much more harm has been

22 done by under-recognition and undertreatment of

23 chronic pain than by overtreatment, so if we had to

24 come down on which side we would want to occur, I

25 would prefer to err on the side of seducing



1 physicians into treating their patients.

2 The fact that the chronic low back pain,

3 even musculoskeletal pain is somewhat

4 heterogeneous, I think is a strength in the sense

5 that if you can show in a good trial that your

6 medication works for this admittedly heterogeneous

7 group of disorders, then, all the more it should be

8 applicable to a broader musculoskeletal pain

9 diagnosis where its heterogeneity is actually a

10 strength, and not a weakness.

11 DR. FIRESTEIN: I would agree with that as

12 long as we are primarily discussing mechanical back

13 pain.

14 DR. KATZ: Yes, as Dr. Borenstein defined

15 it.

16 DR. FIRESTEIN: That brings us to the end

17 of this morning's session and we will reassemble at

18 1 o'clock. Thank you.

19 [Whereupon, at 12:02 p.m., the proceedings

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



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

2 [1:05 p.m.]

3 DR. FIRESTEIN: The next segment is the

4 open public hearing, which involved a number of

5 individuals who will make short presentations from

6 5 to 10 minutes.

7 For those individuals that will have

8 PowerPoint slides, I would ask you to make your

9 presentation from up here if you already have them

10 loaded onto the computer, and if you haven't

11 already done that, then, you will not be making

12 slide presentations unless you are very fast.

13 Again, the various individuals have

14 already been apprised of the time limitations and

15 while we don't have a gong up here to cut them off,

16 I would ask them, please, to try to adhere to them

17 as closely as possible.

18 The first is Dr. Najib Babul, Chief

19 Scientific Officer of TheraQuest Biosciences.

20 Open Public Hearing

21 DR. BABUL: Good afternoon. I want to

22 thank the Advisory Committee Chair and the Division

23 Director for allowing me to speak at this meeting.

24 I am particularly pleased to speak at this meeting

25 because I think the briefing document raises a



1 number of important issues both to regulators and

2 to drug development scientists.

3 [Slide.

4 Let me just introduce myself briefly. My

5 name is Najib Babul. I am Chief Scientific Officer

6 for TheraQuest Biosciences, a Philadelphia,

7 Pennsylvania based company, consulting in the area

8 of analgesia rheumatology drug development.

9 [Slide.

10 This is my conflict of interest statement,

11 pharmaceutical sponsors that I work with, have

12 submissions or pending submissions before Division

13 550 or Division 170, and the views that I express

14 are solely those of TheraQuest Biosciences.

15 [Slide.

16 Much has been said earlier today about the

17 regulatory framework for approval of drugs and what

18 is lacking in the existing guidelines. Certainly I

19 can tell you as somebody who has been using the

20 1992 Analgesic Guidelines that before we throw the

21 baby away with the bathwater, these guidelines are

22 fairly robust and certainly help those of us who

23 are in the trenches and developing drugs for acute

24 pain, these guidelines have been exceedingly useful

25 and continue to be useful.



1 That is not to say that we don't presently

2 have challenges in drug development. In addition

3 to these FDA guidelines, there is the CPMP

4 document, draft document, which also provides

5 additional guidance to those of us who are doing

6 international clinical trials in analgesia.

7 Of course, we have rather well put

8 together OA guidance document from the FDA and from

9 the CPMP, which can provide a bit of a foundation

10 for going forward if a decision is made to put

11 together additional guidance documents.

12 [Slide.

13 Now, having said that, there are certainly

14 gaps in the regulatory framework for development of

15 analgesics. This is a short list of some of the

16 gaps as I see them, and the include multi-dose

17 evaluation in acute pain, evaluation of drugs with

18 slow onset of effect in acute pain, and there are

19 clearly some drugs, including drugs that have a

20 depot effect, that provide sustained analgesia in

21 the perioperative period, for instance, that would

22 fit into that category.

23 Drugs for neuropathic pain, which was the

24 subject of a separate Advisory Committee meeting in

25 May, drugs for cancer pain, which perhaps fit in



1 the mandate of this Advisory Committee, and, of

2 course, the possibility of putting together

3 guidance documents for low back pain, for

4 fibromyalgia, and for myofascial pain, then,

5 broadly speaking, looking at chronic pain as an

6 indication.

7 [Slide.

8 This is a brief list of some of the models

9 of chronic pain. One can categorize chronic pain

10 in a number of different ways - mechanistically, by

11 diagnosis, etiology, et cetera, and this is an

12 attempt at categorizing some of the models,

13 myofascial pain, low back pain, osteoarthritis,

14 fibromyalgia, some have argued and actually

15 demonstrated successfully that mixed model

16 populations with chronic non-cancer pain can be

17 successfully evaluated as a heterogeneous

18 population, and then, of course, neuropathic

19 chronic pain and cancer pain.

20 [Slide.

21 Now, there are some compelling reasons why

22 we have lagged behind in chronic pain in contrast

23 to acute pain in developing guidelines and in

24 developing drugs and getting a label claim. I

25 should note that there is a bit of a divergence in



1 terms of the labeling history for opioids,

2 particularly sustained release opioids in the

3 Division of Anesthetic Critical Care, Addiction

4 Drug Products, where there has been a de facto

5 chronic pain indication without stating chronic

6 pain, and in the Anti-inflammatory, Ophthalmic,

7 Analgesics Group where, in fact, that indication I

8 don't believe has broadly existed although clearly

9 there are some drugs historically that have been

10 approved for the treatment of moderate to severe

11 pain implying acute and chronic.

12 Now, some of the challenges that drug

13 developers like myself find in developing drugs for

14 chronic pain is that the etiology is rather

15 diverse. Dr. Borenstein earlier talked about I

16 think 60 or 70 potential etiologies for low back

17 pain alone, so certainly even with a heterogeneous,

18 a seemingly identical "diagnosis," broadly

19 speaking, or presenting a complaint like low back

20 pain, you can have a rather heterogeneous

21 population.

22 Having said that, perhaps much more is

23 made of that than we ought to. A substantial

24 number of patients, as Dr. Borenstein noted, have

25 mechanical low back pain, and while there is some



1 disagreement, many have argued that as many as 90

2 percent of patients with low back pain have

3 idiopathic low back pain, and there is now

4 pharmacologic evidence from work that has been done

5 demonstrating that that group, whether it is

6 homogenous or heterogeneous, in fact, is a

7 worthwhile group to evaluate analgesics in, and we

8 have certainly been able to separate active from

9 placebo.

10 In addition, these patients have

11 considerable amount of psychological overlay which

12 varies a great deal from patients who may have some

13 myofascial pain post-motor vehicle accidents to

14 patients with osteoarthritis who may have

15 considerably less access to diagnosis.

16 We also have a situation that is

17 confounded by disability payments and litigation

18 and secondary gain issues which make it very

19 difficult for us to look at issues of function, for

20 instance, in this population.

21 I think, finally, there are unrealistic

22 outcome expectations. There are a number of

23 stakeholders in this debate, not just drug

24 developers and regulators. In fact, insurance

25 companies and other third parties sometimes view a



1 successful outcome not as relief of pain per see,

2 but a return to work situation, which of course

3 means that their exposure to liability, financial

4 liability is significantly reduced.

5 [Slide.

6 Recently, Division 550 has suggested that

7 replicate evidence in three chronic pain states or

8 chronic pain models are necessary for a chronic

9 pain indication. While I appreciate that the brief

10 document suggests to the committee that this is

11 subject to consideration and some debate, and that

12 it is not cast in stone, I think, Dr. Simon, you

13 referred to this as an iterative process, there are

14 some potential implications that I think we need to

15 consider.

16 [Slide.

17 I think the first issue that concerns me

18 is that there may be an absence of established

19 models to provide evidence in three chronic pain

20 states. While one can throw fibromyalgia into this

21 chronic pain basket, some would argue that, in

22 fact, it is a rather distinct entity and that it

23 may not respond to many of the agents that other

24 drugs perhaps respond to in chronic pain.

25 I think certainly the suggestion contained



1 in the briefing document and indeed at the NIH-FDA

2 Workshop, that replicate evidence for a specific

3 sub-indication would be a basis for approval is

4 reasonable. I think that very few would disagree

5 that at least in a 505(b)(1)/ new chemical entity

6 approval strategy, that if you are going to go for

7 a specific sub-indication, that perhaps some degree

8 of replication is necessary.

9 However, I would suggest to the division

10 and to the committee that replication across three

11 models, models, which we have yet to fully

12 establish and validate, might be too onerous a

13 requirement to put on the pharmaceutical sponsors,

14 and that perhaps, and this is a suggestion for

15 potential discussion by the committee and by the

16 division, that perhaps replication in two models of

17 chronic pain or perhaps robust and internally

18 consistent evidence in single trials in three

19 models might be sufficient to provide a broad

20 indication of chronic pain with the proviso that

21 the Clinical Pharmacology Section of the package

22 insert would speak to the specific evidence that is

23 available on that drug.

24 One concern that a number of us interested

25 in chronic pain have is that if the burden is too



1 high for a broad indication, we may end up people

2 being expeditious, and there was some reference to

3 this earlier, people just taking the quick and

4 dirty route out, just getting a specific narrow

5 sub-indication with the potential for substantial

6 off-label use and orphaning of other indications

7 for evaluation purposes.

8 [Slide.

9 There are a number of additional issues

10 which I would like to just very briefly address.

11 In the briefing document, there is reference to the

12 use of co-primary endpoints. Indeed, pain function

13 and patient global are important endpoints. There

14 is little debate on this issue, and I believe Dr.

15 Strand at the NIH-FDA Workshop led a breakout

16 session on this particular issue, and there was

17 general consensus that these are important

18 endpoints.

19 There is indeed some precedents at least

20 at the division in terms of for OA, in terms of

21 having a win on three co-primaries, however, it

22 does increase the statistical burden required for

23 approval, and I think that for function, function

24 the way it is viewed through self-reports, we need

25 to be careful that we define function carefully



1 because function, the way it is viewed, say, in OA,

2 using WOMAC as an instrument, is very different

3 than the way function is viewed by pain physicians.

4 So, before talking about function as a

5 self-report, perhaps that may be achievable,

6 although I am not certain about that, in all

7 chronic pain states. Certainly, we don't ask that

8 in depression, we don't ask that in migraine in

9 terms of return to work or restoration of function

10 per se, and that it may be too unrealistic a

11 pharmacologic expectation to put on what is really

12 a complex disorder, and I would ask the Division

13 and the Advisory Board to consider this.

14 DR. FIRESTEIN: Dr. Babul, could you wrap

15 up, please.

16 DR. BABUL: I am pleased to note the

17 Division was prepared to consider placebo versus

18 active control, that have some assay sensitivity.

19 I would urge the Division to consider some

20 clinometric flexibility, so that we don't have

21 ossification of trial design methodology. Finally,

22 I would suggest that we need some degree of

23 harmonization to the extent we can between Division

24 170 and Division 550 as we go forward in terms of

25 approaches that are acceptable for opioids and for



1 non-opioid analgesics.

2 Thank you.

3 DR. FIRESTEIN: Thank you.

4 The next speaker is Dr. Kenneth Verburg,

5 Vice President, Clinical Research, Pharmacia.

6 DR. VERBURG: Good afternoon. My name is

7 Ken Verburg. I am here representing Pharmacia

8 Corporation today. We appreciate the opportunity

9 to contribute to the meeting.

10 [Slide.

11 I would like to limit my comments and my

12 brief presentation today to just some general

13 observations about the development of new

14 guidelines for analgesics or drugs intended for the

15 treatment of pain, and then focus on some

16 observations specifically directed towards chronic

17 pain and acute pain.

18 [Slide.

19 As we heard this morning, it makes at

20 least some sense based on the information we have

21 at hand to set up and use a mechanistic basis as a

22 framework at least for the indications or the way

23 that we think the indications should be laid out.

24 This would lead to using this particular

25 mind-set, an easy separation if you will, of



1 nociceptive and neuropathic pain, but a subdivision

2 of nociceptic pain into somatic and visceral pain

3 is not quite so clear with both being acute and

4 chronic, and substantial overlap between the two

5 conditions.

6 Also, we could use a mechanistic basis, as

7 we have heard this morning, about the chronicity of

8 pain, separating out acute and chronic pain into

9 separate indications, and not necessarily having to

10 have or having to demonstrate acute pain a priori

11 before getting an indication for chronic pain.

12 We could also use mechanisms to gauge pain

13 severity. Particularly here, I think, we are most

14 interested in the differences across models and how

15 that might translate to effective regimens, and

16 finally, in terms of just general overall

17 considerations, a notion or a realization that

18 there are different classes of analgesics that may

19 be effective as either monotherapy or multimodal

20 therapy under certain conditions in the particular

21 sites of action.

22 [Slide.

23 We would also encourage that the

24 development programs expedite therapies to meet the

25 clear unmet medical need in this particular area,



1 that efficient programs are set up that provide the

2 information that is needed for registration, cut

3 down on the white space with the gray area that us,

4 as sponsors, sometimes confront, and also that we

5 consider conditions of clinical practice, that

6 being preoperative administration or preemptive

7 administration and/or postoperative administration,

8 multimodal analgesic regimens for certain

9 conditions, and also differences in the treatment

10 of acute and chronic pain.

11 [Slide.

12 Some comments now about chronic pain

13 specifically as the previous presenter outlined.

14 These are the models that we have the most

15 experience in, but limited in terms of their

16 duration in 12 weeks or longer, primarily to the

17 arthritides or osteoarthritis and rheumatoid

18 arthritis. You find very rare cases or even

19 nonexistent, that the other conditions have been

20 studied beyond one or two weeks.

21 [Slide.

22 In terms of the approach to the

23 determination of efficacy, we have used

24 successfully the three-domain approach in both

25 osteo and rheumatoid arthritis, which would include



1 pain intensity, a global assessment and functional

2 or disability assessments, and are pushing forward

3 into chronic low back pain using specific

4 instruments for those conditions, but again using

5 the three-domain approach.

6 As was mentioned this morning, however,

7 this approach may not be applicable to all

8 conditions. Our experience in cancer pain, albeit

9 limited, we have experienced difficulty in showing

10 functional improvement in combination with improved

11 global or pain severity scores.

12 As I mentioned before, on the previous

13 slide, there is a limited number of models, at

14 least in our hands, that would appear to be

15 suitable for the study of three months, and even

16 those that may be approachable for this duration of

17 time, you are always left with the dilemma of what

18 to do with patients on extended placebo treatment,

19 how to handle that both in the clinical trial, as

20 well as the statistical imputation that results.

21 Also, we would like to propose that

22 serious consideration be given to models of chronic

23 intermittent pain, what particular endpoints might

24 be useful, the duration of treatment, and/or the

25 numbers of cycles that would be needed to be



1 treated.

2 Finally, we need to clearly outline as Dr.

3 Witter mentioned this morning, the safety

4 requirements for chronic pain in much more detail

5 than the current guidelines now described.

6 [Slide.

7 Due to the heterogeneous nature of chronic

8 pain conditions, as we have heard this morning, we

9 have also proposed a tiered approach slightly

10 different than Dr. Simon had outlined this morning,

11 but we would also agree that a separate indication

12 for each condition with replicate studies would

13 seem to be of benefit.

14 An indication for chronic musculoskeletal

15 pain, we would propose could be achieved with a

16 single study in three chronic musculoskeletal

17 conditions, in a sense, a replication would be

18 achieved, as well as spreading out the

19 observations, if you will, across a number of

20 musculoskeletal conditions.

21 Finally, we would propose that a way

22 forward for a general chronic pain indication would

23 be a single study in two chronic musculoskeletal

24 models and/or cancer pain, and a single study in

25 two neuropathic models, again tracing back t the



1 differences in the mechanisms at least as we best

2 have them identified now. This would seem to fit

3 very well with that particular model and the

4 limitations.

5 I just want to make a couple simple points

6 here. One model does not achieve all necessary

7 objectives, in particular, demonstrating acute

8 onset of analgesia is difficult in some of these

9 models due to the high placebo response and the

10 self-limiting nature of the pain often confounds

11 demonstration of effective regimens, particularly

12 on the days 2 and beyond.

13 It is also very variable as to what an

14 effective regimen might be depending on the model

15 that is selected, so we would advocate that studies

16 with multiple doses over a number of days be

17 conducted in both musculoskeletal conditions, as

18 well as post-surgical conditions.

19 Finally, one additional comment

20 particularly related to primary dysmenorrhea. This

21 is sort of an orphan here. It is a stand-alone

22 indication, however, data from this particular

23 model has been used in many cases to support an

24 overall acute pain claim, particularly with respect

25 to onset of action.



1 [Slide.

2 While the current guidelines provide

3 adequate criteria in our view to evaluate

4 single-dose analgesic efficacy, it is traditionally

5 understood that replicate studies in dental pain

6 and post-surgical pain are required.

7 There are well-defined efficacy measures

8 assessing onset, extent, and the duration of

9 analgesia. Again, it is generally understood that

10 the time to onset of analgesia should be

11 demonstrated to be less than one hour in replicate

12 trials, and that the time to rescue medication from

13 single-dose studies is used to support the dose

14 regimen on day one and subsequent days.

15 [Slide.

16 The criteria to demonstrate multiple-dose

17 efficacy, i.e., an effective regimen, are less well

18 defined by the current guidelines, however, and

19 that is where significant work I think needs to be

20 focused.

21 Also, while we are doing this, study

22 design and study conduct considerations are also

23 important to bring into the mix, and that includes,

24 as I mentioned before, the self-limiting nature of

25 the pain in some models and also that the severity



1 of the initial pain in other models may not be

2 controlled by monotherapy alone.

3 [Slide.

4 Just to give you a little example of the

5 self-limiting nature of pain, this is data from a

6 thinly disguised COX-2 specific inhibitor trial in

7 laparoscopic cholecystectomy looking at the percent

8 of patients with moderate to severe pain plotted on

9 the Y axis versus the days post-surgery on the X

10 axis.

11 Here, you can see significant treatment

12 effects on days 2 and 3, but overall by day 4, and

13 particularly by day 5 and beyond, you can see that

14 the numbers of patients experiencing moderate to

15 severe pain even in the placebo group is quite

16 small and does not allow adequate assay sensitivity

17 to see a drug effect.

18 [Slide.

19 Finally, just a comment about multimodal

20 analgesia, obviously, the premise here is to obtain

21 additional clinical benefit by controlling pain

22 with agents from two to more classes. Ideally,

23 these would be operating through different

24 mechanisms or at least different sites, and the

25 efficacy measures versus monotherapy would be



1 reduced medication requirements, improved analgesia

2 over monotherapy, a reduction in adverse effects,

3 and improved patients global assessments.

4 [Slide.

5 Again, just to give you a little taste of

6 what that looks like, this is from a total knee

7 arthroplasty study looking at morphine alone here

8 in the white line down at the bottom, and then two

9 doses of a COX-2 specific inhibitor in the blue

10 line at the full therapeutic dose, and in the

11 yellow line, at half-maximal therapeutic dose.

12 You see that there are significant

13 improved analgesia scores in terms of reduction in

14 pain intensity with both doses versus morphine

15 alone.

16 [Slide.

17 One acute pain model does not fill all

18 criteria for determination of a single dose and

19 multiple dose efficacy, and we would propose that

20 new guidelines specify in more detail which models

21 are best to define onset, peak effect, and

22 duration, specify compartmental approaches perhaps

23 for pain studies, for example, single dose,

24 multiple dose studies on day one and subsequent

25 days, and then propose models best for monotherapy



1 versus combination therapy.

2 [Slide.

3 Finally, specify what acute pain models

4 are needed to obtain a broad acute pain indication

5 by severity and/or etiology. We have spoken about

6 that in the context of chronic pain today, and I

7 suspect some of the same conversation will surface

8 tomorrow.

9 Specify how many models and whether

10 replication is needed in each. If models are of

11 similar etiology, we would propose that really only

12 one model should need replication in that

13 particular instance.

14 Finally, as was my comment with chronic

15 pain, we need to more carefully define the safety

16 requirements for acute pain with a new agent,

17 either when studied alone and/or in combination

18 with pursuit of a chronic pain indication.

19 Thank you.

20 DR. FIRESTEIN: Thank you. Could you

21 clarify just one point, and that is, for the

22 chronic pain indication, the alternative proposal,

23 two studies and three models is one study and four

24 models?

25 DR. VERBURG: Yes, I was proposing one



1 study across four different models.

2 DR. FIRESTEIN: So, there would be fewer

3 studies for each individual indication, but an

4 increase in the number of total indications

5 examined for the chronic pain?


7 DR. FIRESTEIN: Thank you.

8 The next speaker is Eugene Laska, Director

9 of Statistical Sciences Division, Nathan Kline

10 Institute for Psychiatric Research, sponsored by

11 Merck Research Laboratories.

12 DR. LASKA: The business of doing clinical

13 trials in the context of randomized, double-blinded

14 clinical trials is to develop inferences that are

15 causal, to be able to claim that the reason we see

16 drug differences are because the different

17 treatments that were in the trial were causal.

18 [Slide.

19 As a consequence, any of the decisions

20 made in terms of what must be demonstrated to get a

21 claim has to be done within that context. We have

22 not spent a lot of time this morning, some of the

23 speakers before me have, on the details of clinical

24 trial design and methodology, and I think that both

25 the beauty and the devil are in those details.



1 How to do clinical trials in the chronic

2 and acute framework are clearly needing additional

3 input, improvements in design, styles, and methods,

4 and methods for inference. I will be very brief now

5 because I have some time to talk about the acute

6 setting, so now I just want to say one brief word

7 about doing research in the chronic framework.

8 [Slide.

9 Right now there are precious few, if any,

10 I am not aware of any clinical trials that have

11 really answered the question about what to do about

12 the fact that placebo patients in a chronic

13 framework drop out very rapidly, and statisticians

14 have developed both crude and very sophisticated

15 methods for imputing data, the crudest being the

16 last observation carried forward and variance

17 thereof, and the more sophisticated using methods

18 of multiple imputation developed by some quite

19 credible and rather brilliant statisticians.

20 In my view, none of those satisfies the

21 criteria needed to draw valid causal inference

22 because there is some form of informative censoring

23 going on in these trials, in particular, placebo

24 patients are dropping out because they are not

25 getting adequate relief, and adverse effects are



1 coming into play, so the censoring mechanism may

2 very well be informative.

3 A design has been used in other areas of

4 medicine, appears to me to be potentially very

5 relevant in this arena, and that is the so-called

6 withdrawal trial. The withdrawal trial is an

7 enrichment trial in which patients stay on the

8 trial for the 12 weeks, as Lee proposed, for

9 example, and dropouts are taken note of and there

10 is some kind of inference on the dropout rates

11 done, but the only patients who are relevant are

12 those who have stayed on and had satisfactory

13 response from the test treatment by the 12th week.

14 Those people, I believe should have a

15 criteria, for example, the one I described, at

16 least some X percent of the patients who started

17 the trial have to be around for the 12th week for

18 the drug to be considered a chronic medication.

19 At the end of that week, patients are

20 randomized into one of two groups. Half remain on

21 the trial that they started with, on the treatment

22 that they started with, they remain on the drug,

23 the other half go off the treatment they started

24 with, and go on to a placebo, and proof that the

25 drug works is contained in demonstration of placebo



1 treatment superiority during the subsequent period

2 of time. Depending on the drug, it might be a week

3 or two weeks thereafter.

4 This particular approach does away with

5 the need for imputing the values of dropout

6 patients to the end of the trial, and when patients

7 are dropping out in the first and second and third

8 week, the imputation really looks quite silly.

9 This is a proposal that I think needs some

10 time and attention, and hopefully will allow us to

11 draw better inference about the treatments we wish

12 to investigate.

13 Thank you.

14 DR. FIRESTEIN: Thank you.

15 The next speaker is Mason Diamond,

16 pharmaceutical consultant.

17 DR. DIAMOND: Thank you. My name is Dr.

18 Mason Diamond. I am independent consultant,

19 pharmaceutical consultant from the Boston area. I

20 am also Vice President at Engenium [ph] Research,

21 which is a contract research organization based on

22 North Carolina.

23 I am speaking today on my own behalf and I

24 paid my own expenses to attend this meeting. At

25 this moment, I have no financial arrangement nor



1 financial interest in any company or CRO currently

2 involved in the development of analgesics.

3 Before I begin, I wish to thank the FDA

4 and the Arthritis Advisory Committee for giving me

5 the opportunity to address this group.

6 Furthermore, I would like to commend CDER, Division

7 550, and specifically Dr. Simon and Dr. Witter for

8 taking this much needed initiative. To my

9 knowledge, no other regulatory authority has done

10 this.

11 My purpose in speaking today is to

12 highlight some concerns regarding the needs of the

13 elderly population. I strongly believe that these

14 concerns should be addressed in analgesic drug

15 development.

16 There are over 34 million Americans over

17 the age of 65 that are affected by pain. Research

18 has shown that at least 62 percent have taken

19 prescription medication for more than six months to

20 treat their pain.

21 More disturbing are the estimates that as

22 much as 80 percent of nursing home residents suffer

23 from painful conditions that go untreated.

24 Arthritis has been identified as the

25 single most common cause for chronic pain in the



1 elderly, however, it is not uncommon to see more

2 than one indication requiring analgesic therapy.

3 In addition, most elderly persons have multiple

4 medical problems that require multiple medications.

5 Many drugs used to treat these concomitant

6 conditions have not been sufficiently evaluated for

7 co-administration with each other, let alone with

8 many analgesics. As a result, the comprehensive

9 guidelines necessary to deal with the complex

10 safety issues in this population are not available.

11 It is the fear of possible serious and

12 life-threatening side effects that is often the

13 barrier to adequate pain treatment in older adults.

14 The situation is further complicated by progressive

15 cognitive and emotional difficulties encountered in

16 this population.

17 This makes medical evaluation and

18 management even more challenging. The net result

19 is that while in many cases the pain management

20 with drugs and other treatments are possible, each

21 year millions of older people are forced to endure

22 unbelieved suffering.

23 The elderly represent the largest number

24 of pain sufferers and purchasers of analgesic

25 products, yet, they remain in the greatest need of



1 innovative therapies.

2 In an effort to address this need, I would

3 like to offer some points to consider as we move

4 forward in our discussions of analgesic pain models

5 and clinical study designs.

6 First, inclusion/exclusion criteria. In

7 order to minimize response variability in our

8 clinical studies, it is common for us to enroll as

9 homogeneous a population as possible. While

10 scientifically sound, this approach tends to

11 exclude those individuals who may be most

12 representative of the target population.

13 For example, in arthritis trials, the

14 actual effectiveness and safety profile common to a

15 more frail elderly population may not be reflected

16 in the Phase III study results. My recommendation

17 would be to ensure a more representative patient

18 cohort in our pivotal clinical trials or conduct

19 separate studies specifically in this population.

20 Second, the pharmacokinetics and

21 pharmacodynamics of drug interactions significantly

22 complicates pain management in older adults. The

23 resulting side effects from polypharmacy, coupled

24 with the underlying medical conditions, can be

25 daunting to deal with.



1 It is not uncommon for the elderly to be

2 on five or six medications at a time and often

3 more. Although these issues have been discussed in

4 the FDA and ICH guideline documents, and drug

5 companies do go to great lengths to evaluate drug

6 interactions, these studies need to include more

7 older adults who are being treated for multiple

8 medical conditions since they represent the

9 ultimate beneficiaries of these new therapies.

10 Third, the duration of evaluation. The

11 most common pain problem in the elderly are chronic

12 and patients often take analgesic medications for

13 long periods of time, if not for the rest of their

14 lives.

15 Many adverse events become evident only

16 after long term use. Evaluations of 12 weeks or

17 even 12 months may not be sufficient to capture the

18 long-term risks and benefits of a particular drug.

19 I am sure that everyone here agrees that we are all

20 committed to bringing safe and effective

21 medications to the public as rapidly as possible,

22 however, we must also ensure that our research

23 provides the necessary information to enable

24 practitioners to better manage their patients

25 especially those on complex treatment regimens.



1 This could be accomplished by blinded

2 studies of longer duration or by employing longer

3 open-label follow-up extension studies, which would

4 provide this much needed information while not

5 impeding the drug development process.

6 Finally, outcomes evaluation, I think on

7 everybody's mind. In a search for better methods

8 to evaluate pain, we are focusing on objective

9 measures to incorporate into our study designs,

10 mechanism-based assessments, determination of

11 biomarkers for underlying diseases, and levels of

12 pain modulating biomolecules are some of the

13 options under discussion.

14 I feel that all these options should be

15 actively pursued, however, these approaches will

16 take some time to validate. Also, in many cases,

17 the objective evidence for underlying disease may

18 not correlate with the symptoms, and symptoms may

19 wax and wane spontaneously.

20 One solution is the utilization of

21 multidimensional pain outcomes. This includes pain

22 assessment, functional assessment, psychological

23 outcomes, and quality of life measures.

24 New assessment tools designed for both

25 cognitively impaired and unimpaired elderly adults,



1 such as the geriatric pain measure developed at

2 UCLA, are in the process of being validated. In

3 addition, there are very many well-established and

4 highly validated tools dealing with each of these

5 areas that are currently available, however, since

6 pain affects so many aspects of people's lives, no

7 one measure can adequately capture the overall

8 effect of any therapy.

9 For example, in an arthritis trial, it is

10 possible to show no change in pain level, but a

11 significant impact on the patient's ability to

12 function. This is due to an individual's ability

13 to adapt their level of activity to the level of

14 pain tolerance.

15 So, if a patient takes an analgesic that

16 enables them to climb stairs, walk a greater

17 distance, take care of themselves, or play with

18 their grandchildren, but continues to report pain,

19 I would still consider this a clinically

20 significant outcome.

21 In addition, the impact of pain on an

22 individual's psychological state and overall

23 quality of life is no less relevant than pain level

24 or functional status. Therefore, until we have one

25 system that measures all of these parameters, we



1 should evaluate efficacy based on more than one

2 outcome.

3 It is clear that the treatment of pain in

4 older adults is an enormous undertaking. No less

5 so is conducting clinical trials in the elderly

6 population. We must remember that the information

7 captured during drug development provides guidance

8 for practitioners in addition to satisfying

9 regulatory requirements.

10 Therefore, I believe that by addressing

11 the needs of the elderly during the drug

12 development process, we will enable the medical

13 community to more effectively treat the millions of

14 elderly patients through a need and bring them the

15 benefits of these new drugs.

16 Thank you.

17 DR. FIRESTEIN: Thank you very much.

18 The next speaker is Daniel Carr from Tufts

19 University.

20 [Pause.]

21 DR. FIRESTEIN: While we are waiting to

22 sort out our technical difficulties, why don't we

23 move ahead to the next person that is not using

24 slides.

25 Dr. Abraham Sunshine from Analgesic



1 Development.

2 DR. SUNSHINE: Thank you. I am Abraham

3 Sunshine, Professor Clinical Medicine at NYU School

4 of Medicine. I am President of Analgesic

5 Development. I appear here on my own, and I have

6 not received any compensation from pharmaceutical

7 companies to appear.

8 I was asking myself why did I want to

9 speak, and I think I can contribute in giving some

10 historical perspective on the analgesic guidelines.

11 The 1993 Guidelines, which we well

12 described by Dr. Fang and her associates, really

13 began in the eighties, and it took 10 years to get

14 a document that went through all the hurdles,

15 first, to get a consensus and then to get it

16 through the FDA.

17 So, that document is over 20 years old. I

18 want to acknowledge the work of Lee Simon and his

19 associates for initiating this conference, and also

20 the work of Ray Dionne who ran the consensus

21 meeting at the NIH.

22 The 1992 Guidelines really were driven by

23 investigators and industry who just didn't know

24 what to do to get an analgesic approved, and the

25 ground rules were changing with each drug that was



1 approved, so to move forward, it was thought that a

2 consensus would be helpful.

3 Now, the guidelines served us well. The

4 drugs that were being developed at that time were

5 acute analgesics. There were no drugs for chronic

6 pain, and the last thing a pharmaceutical company

7 would be interested in is developing a treatment

8 for neuropathic pain.

9 So, there was no discussion, as Dr.

10 Firestein pointed out, about how to conduct chronic

11 trials because there were very few chronic trials

12 or drugs being considered, and opioids for chronic

13 nonmalignant pain was a no-no. People didn't use

14 opioids for chronic nonmalignant pain.

15 I think advances have been made now, as we

16 saw fentanyl being used, patch being used in low

17 back pain, but we also know about the OxyContin

18 story, that anybody that had a backache was put on

19 dope and got into trouble.

20 The guidelines did permit us to develop

21 many of the NSAIDs both for Rx and also to define

22 an OTC dose. The technology was developed, so that

23 one could pick up the effects of 12.5 milligrams of

24 ketoprofen, and even 100 milligrams of ibuprofen,

25 and dose-response work was done using these



1 guidelines.

2 The guidelines also helped avoid

3 pseudospecificity, and I think this is an important

4 point because we are at a road where I think as I

5 hear rumblings, that we are going to

6 pseudospecificity. For example, dysmenorrhea was

7 understood to be a drug, recycled oxygenase was

8 involved, but in order to get a claim for treatment

9 of dysmenorrhea, one had to show that the compound

10 work as a general pain medication, and then, in

11 addition, in dysmenorrhea.

12 I was on the web site that Lee talked

13 about, and it really is a good web site and I see

14 that Google has helped you get this web site

15 working, and yesterday morning I came across CDER's

16 policy on OTC analgesics 1994, signed by Dr.

17 Woodcock, who clearly points out that to get a

18 claim for menstrual cramps, one needed two positive

19 clinical trials in appropriate pain models, and in

20 addition, positive clinical trial in an OTC

21 dysmenorrhea model.

22 I don't think these guidelines are being

23 followed at the moment, and now we are getting

24 pseudospecificity where drugs which really have a

25 broad implication in terms of pain management, are



1 brought labeled for dysmenorrhea, and not for

2 general pain.

3 The other that was important to emphasize

4 in the eighties and nineties is that small sample

5 sizes of 30 to 50 patients per treatment in a

6 single center generated important data, and data

7 where you got dose response to the NSAIDs.

8 Ketoprofen, from a dose of 12.5 milligrams up to

9 100 milligrams was clearly defined.

10 Today, and I don't know the reason, one

11 needs hundreds of patients per treatment arm and

12 then there is a lot of deliberation is the drug

13 better than placebo.

14 One of the problems, I don't know that it

15 was discussed so far, is combination therapy. Very

16 few combination drugs have been approved. I mean

17 there are combinations of ibuprofen with opioids,

18 and there is a combination of tramadol with

19 acetaminophen, so polypharmacy didn't get ahead.

20 One of the reasons, it was extremely

21 difficult to show the contribution of each of the

22 ingredients. Although we know that codeine works,

23 and we know ibuprofen works, put them both

24 together, and the results were not convincing, so

25 there is no ibuprofen-codeine product even though



1 it was attempted many times.

2 I think as you move forward with the

3 guidelines, it is clear that polypharmacy is here

4 to stay. The other thing, polypharmacy was

5 discovered by patients, not by CDER, not by the

6 industry, but if you look back, there was Empirin

7 compound, acetaminophen, and aspirin--Dr. Brandt

8 talked about that--and caffeine. Then, there was

9 Empirin with codeine, and these were drugs that

10 just over time were found to be helpful, but when

11 pure science came to play, combination therapy was

12 a no-no, and you had to prove the contribution of

13 each of the compound.

14 When Burroughs-Wellcome took caffeine out

15 of Empirin compound, the sales of Empirin compound

16 plummeted, much like the stock market is doing

17 today, and that compound is off the market. I

18 think that caffeine has a role as an analgesic

19 adjuvant.

20 DR. FIRESTEIN: Dr. Sunshine, could you

21 please wrap up? Thank you.

22 DR. SUNSHINE: Okay. I think as we go

23 ahead that we have to develop tools to explore all

24 the contributions of the neuroscientists that Dr.

25 Woolf discussed today, so that we can utilize the



1 information to develop better drugs. Time does not

2 permit me to go into that aspect, but in five

3 minutes I couldn't answer the question, so I think

4 it is going to take maybe not 10 years, but a

5 couple of years.

6 Thank you.

7 DR. FIRESTEIN: Thank you very much.

8 I believe now our information technology

9 problem has been solved, and we can now go back to

10 Dr. Carr's presentation.

11 DR. CARR: I thank the committee very much

12 for having invited me down here. In particular, I

13 think Lee and Jim Witter, and as did the prior

14 speaker, I thank Ray Dionne for having organized a

15 preconference and also Ms. Reedy for getting me

16 down here.

17 As I was listening to the erudite and

18 complex discussion earlier today, I wonder what

19 might there be that hadn't yet been said. So, I

20 titled the title of this 10-minute presentation

21 "What might still be said, that hadn't yet come

22 across," and I am speaking from a rather

23 distinctive point of view of a clinician, but I

24 would like to call attention to a great resource

25 that I think has yet not been tapped, and should be



1 tapped, which is that the evidentiary body upon

2 which clinicians seek to make recommendations for

3 therapy and to treat their patients, insofar as

4 analgesics are concerned, in large part, derives

5 from approval trials.

6 So, I would say that there is an

7 opportunity to render this very robust

8 data-generating process much more useful to

9 clinicians and therefore, their patients.

10 [Slide.

11 Now, to try to lighten the postprandial

12 stupor, I thought I would begin by posing four

13 simple questions. The first is--and these are

14 reasonable questions--who won the last presidential

15 election? Did X Corporation make money or lose

16 money? As Dr. Sunshine mentioned, we are all

17 interested in that.

18 What kind of pain does my patient have,

19 and what is the most effective treatment for my

20 patient's pain? In the interest of time, I am not

21 going to cover the first two questions, but I will

22 say that in try to cover or provide mustering of

23 evidence to answer the third and fourth questions,

24 I have had the privilege to be involved with some

25 wonderful individuals over the years, with Ada



1 Jaycox for the old AHCPR acute and cancer pain

2 guidelines, and more recently with Joseph Lowe and

3 Leo Gudis and others for work with AHRQ.

4 So we have actually made an earnest effort

5 to try to muster the evidence. This report, which

6 can be cited or traced through the AHRQ web site,

7 on cancer pain, involved screening over 18,000

8 titles. A couple of weeks ago, there was an NIH

9 State of the Science Conference held here in

10 Bethesda, as well, just down the block, and for

11 that we screened an incremental 6,000 titles

12 relating to cancer pain.

13 So, we have made an effort to try to

14 muster the evidence.

15 [Slide.

16 At the same time, and I am sorry if I

17 repeat what you have heard before, but I am just

18 putting things that I think clinicians might tend

19 to focus on, is that recent insights, much of them

20 accomplished by individuals in this very room, to

21 my mind have blurred the boundary between acute and

22 chronic pain.

23 Pain is itself a widely distributed

24 process, and I am not sure we have mentioned the

25 brain yet, but the brain and imaging of the brain



1 are both very important factors to consider in

2 understanding pain.

3 I think we have heard, although perhaps

4 not in these words, that chronic pain is itself a

5 disease, and a theme that has popped up again and

6 again amongst different speakers is that the field

7 itself has arrived at what you might term

8 combination analgesic chemotherapy, much as one

9 uses combination chemotherapy for other conditions.

10 In fact, the onset of the disease of

11 chronic pain is potentially very rapid. If one

12 looks at epidemiologic data from the 1999 IASP book

13 on Epidemiology of Pain, edited by Crombie or the

14 2000 Review in Anesthesiology by Perkins and

15 Kehlet, it is quite clear that many patients who

16 undergo operations of any kind will develop

17 persistent pain.

18 I think this is an under-recognized

19 epidemiologic factor, but it is very, very

20 important, and I am actually surprised that this

21 market opportunity hasn't been seized upon. There

22 is also much insight into the long- and short-term

23 benefits of aggressive therapy, although in the

24 preemptive analgesia area, it is clear that a

25 single drug is unlikely to make an impact.



1 We have also had evolving understanding of

2 drug pharmacokinetics and pharmacodynamics in

3 particular appreciating the diversity of

4 individuals according to gender or ethnicity or

5 even as far as interpretive aspects go, culture.

6 There has been tremendous insight into

7 understanding the mechanisms of opioid tolerance,

8 and we are just beginning to see the emergence of

9 insight into disease-specific mechanisms, such as

10 in cancer.

11 For example, I refer to work by Debar and

12 colleagues on identification of endothelin-1 as a

13 cancer-specific mediator. Nonetheless, as one has

14 tried to consolidate all these published trials,

15 and by the way, I think the efforts to

16 consolidation are themselves an advance through

17 Cochrane or evidence-based practice centers, the

18 fact remains that the vast majority of most pain

19 treatment is empiric and generic.

20 In other words, one starts with

21 acetaminophen, perhaps switches to a nonsteroidal,

22 perhaps has a so-called weak opioid, or perhaps

23 changes the weak with a strong opioid, which is the

24 same algorithm you might follow for a badly

25 sprained ankle, as cancer pain.



1 [Slide.

2 One of the big problems in trying to

3 organize the evidence is that the evidence itself

4 is quite flawed, and I think the FDA can help

5 future generations. Randomized, controlled trials

6 are a tiny fraction of the pain literature. It is

7 quite shocking, but when we did the acute pain

8 guideline in '92, we pulled 13,000 titles, of which

9 675 were randomized, controlled trials.

10 Last year, when we did the cancer pain,

11 roughly 20,000 titles screened, as you saw, about

12 180 were randomized, controlled trials, and for the

13 interim State of the Science NIH Consensus

14 Conference, we got another 6,000 titles. We

15 boosted that figure from 180 to 216.

16 What are all these other trials? The vast

17 majority are observational or describe a technique.

18 Because of the nature of the literature, so many

19 different types of diagnoses, patients, and outcome

20 measures, it is impossible to do a quantitative

21 meta-analysis for most of the clinically important

22 questions.

23 In fact, for the State of the Science

24 Conference two weeks ago, of the 218 retrieved pain

25 trials in cancer pain, there were 125 different



1 pain-related instruments that were employed.

2 Now, granted, some of the differences were

3 in a 3-point scale versus a 4-point, versus a 10-

4 or 11-point scale, but the fact of the matter is

5 there could really be a great service done to

6 insist upon some standardization for pooling of

7 this colossal, but difficult-to-combine body of

8 knowledge.

9 The generalizability of the trials, as you

10 have heard before, is limited by inclusion and

11 exclusion criteria. The clinician is treating an

12 individual who has comorbidity, who may be elderly,

13 who is taking other drugs, and these are not

14 represented in the data upon which the evidence is

15 based.

16 A very important factor is the relatively

17 small amount of focus placed upon side effects.

18 Side effects, including adverse events, but even

19 predictable side effects are what keep many

20 patients from achieving good pain relief, such as

21 with opioids, and it would be wonderful if there

22 were a non-punitive shift in the process, so that

23 side effects could be monitored prospectively and

24 with greater precision than in the past without

25 penalizing the sponsor of the trial.



1 One has a sense from the literature that

2 previously, there was a process set up which

3 encouraged actually underpowered trials, that is,

4 few patients per trial. If one looks at the actual

5 retrieved trials for cancer pain treatment, for

6 example, these are on the orders of dozens of

7 patients per trial, but if you look at cancer

8 treatment, such as primary chemotherapy, through

9 collaborative groups, these number hundreds or

10 thousands.

11 In fact, if one were to calculate the

12 number of patients, let's say, with cancer pain

13 versus the number of patients enrolled in trials,

14 these are a tiny, tiny fraction of those with the

15 condition.

16 [Slide.

17 Well, what about that question, is this

18 treatment helping, well, to translate efficacy data

19 into effectiveness is the mission of a clinician,

20 and thus far I have called attention to some gaps

21 in the literature and what FDA can do to help.

22 I would say that to patients and their

23 families, the primordial outcome is low pain

24 intensity. On the other hand, particularly with

25 the treatment of chronic non-cancer pain, quality



1 of life often trumps the pain intensity on a visual

2 analog scale. Very often the approach to treatment

3 of chronic non-cancer pain is to encourage patients

4 to do more even if their visual analog scale does

5 not go down, and as you have heard, very commonly

6 in the clinical setting, patients self-titrate to a

7 visual analog scale, which may be moderate pain,

8 but they are able to do more.

9 We need standardized consensus

10 instruments. Right now there is an effort underway

11 that I am privileged to be involved with. It's a

12 tripartite collaboration of the Joint Commission

13 AMA and NCQA to try to develop performance measures

14 to evaluate the implementation on site of JCAHO

15 guidelines, but this is a bit of a struggle.

16 We will get the job done, but is not

17 helped by the proliferation of instruments.

18 Obviously, you have heard a lot of erudite comment

19 about the need for generic versus

20 condition-specific instruments.

21 One caveat is that coarse instruments, and

22 the SF-36 is a coarse instrument, may overlook

23 benefit, which is actually done to patients. I

24 guess it's a disclaimer, I have been involved in

25 the development of the Treatment Outcomes of Pain



1 Survey from Tufts or TOPS scale, that is

2 essentially an augmented condition-specific SF-36

3 validated for patients with chronic pain.

4 Of course, we are aware that we can't just

5 administer endless questionnaires because of the

6 burdens on patients and clinicians. I have already

7 mentioned that side effects seem to be approached

8 very differently in the literature, in a much more

9 cavalier haphazard way than are the desired

10 outcomes, but they are often the thing that stops

11 the patient from getting better. They just can't

12 increase the dose.

13 So, are there things one do towards an

14 answer?

15 [Slide.

16 Well, I personally believe that to frame

17 compartments about acute pain or chronic, to say

18 when does acute become chronic, it is a little bit

19 of a misleading question because it equates a time

20 course with a mechanism, but we all know there are

21 many instances of prolonged acute pain, such as

22 labor pain or arthritis, a sunburn or if someone

23 comes in with an obstructed viscus, which are

24 cured, and they never become chronic pain, or even

25 repetitive pain like muscle bruises or soreness in



1 athletes, for instance.

2 Therefore, one must infer that nociception

3 itself rarely induces chronic pain except perhaps

4 when there are psychosocial factors. These are the

5 small accidents that evolve into disabilities.

6 On the other hand, the progression of

7 acute to chronic pain is well documented

8 clinically, and as I have mentioned, is a big

9 problem in epidemiologic terms.

10 DR. FIRESTEIN: Dr. Carr, would you wrap

11 up. Thanks.

12 DR. CARR: The last slide, I think, but I

13 will wrap this up in a minute.

14 [Slide.

15 I would submit to you that we have to look

16 at the evidence and apply logic and distinguish

17 between intense nociception, which most of us imply

18 by the phase acute pain, versus the rapid onset of

19 peripheral and central nervous system

20 reorganization, that Professor Woolf spoke to you

21 about.

22 There seems to be a clue that if you have

23 concurrent nerve injury and intense nociception or

24 inflammation, that increases the risk, so in an

25 ideal world, if we all did our jobs, there would be



1 prospective identification, planning for patients

2 at risk, individualized anti-nociceptive and

3 behavioral interventions, effective treatments

4 chosen according to evidence, and combined, these

5 would be titrated, we would monitor standardized

6 outcomes to validate and calibrate our practice.

7 In so doing, we would accomplish our

8 mandated continuous quality improvement, we would

9 meet JCAHO standards and identify best practices.

10 Then, we would follow up people and we would assess

11 long-term cost and benefits.

12 Thank you very much for your attention.

13 DR. FIRESTEIN: Thank you.

14 The next speaker is Dr. Ann Berger, Chief,

15 Pain and Palliative Care at the NIH.

16 DR. BERGER: Thank you. I want to also

17 thank Radion and James Witter. In looking at what

18 I could offer here, it is similar to Dan in that I

19 can offer the clinical perspective of pain and

20 palliative care.

21 Prior to coming here, I had run both the

22 Pain and Palliative Care Service at Yale and at

23 Cooper Hospital, which is part of the University of

24 Medicine and Dentistry of New Jersey, so I have had

25 a lot of experience with palliative care patients,



1 as well as chronic benign pain patients.

2 In looking at the total pain picture, I

3 brought a handout and I am sorry I didn't make a

4 slide, I didn't know we could show slides, the

5 total pain picture is really made up of the

6 physical pain, which at least clinically, from my

7 experience, is usually not just neuropathic pain,

8 it's not just visceral pain, it's not must somatic

9 pain, it is usually a combination pain.

10 So, it is going to be pretty difficult to

11 say you are going to do a study just on neuropathic

12 pain because unless you are talking about something

13 like brachial plexopathy or diabetic neuropathy,

14 because many of the pains are mixed pains.

15 We see this all the time with patients,

16 but then besides the total pain picture of being

17 all those physical different mechanisms, we have a

18 whole element of suffering, and I think that is

19 where we really miss the boat in medicine.

20 The suffering components is not only

21 depression, it is not only the psychological

22 states, but it is social issues, it's loss issues.

23 When somebody came up and spoke about pain in the

24 elderly, that's a huge problem and partly it's a

25 huge problem because the loss issues are so huge.



1 These are people who have lost their pets,

2 their furniture, their families, their friends, and

3 that is something we never take into account.

4 Suffering also involves spiritual concerns, and for

5 anybody in pain, whether they are religious or not,

6 it is always a spiritual issue because anyone who

7 is sick or anyone is in pain, it's why is this

8 happening to me, purpose-meaning type issues, as

9 well as social family functioning, physical

10 disability, and for palliative care syndromes, it

11 is fear of death.

12 Now, the only difference in my mind

13 clinically, when I look at a patient, is, is this a

14 palliative care patient or is this a chronic benign

15 pain patient, and the way I define that is

16 palliative care are patients that can ultimately

17 die from their disease, so they have a

18 life-threatening disease, something like cancer,

19 something like HIV disease. Clearly, there are

20 lists of those, you know, because many diseases we

21 don't cure, so COPD, CHF, you know, many diseases.

22 Chronic benign pain are patients like with

23 low back pain, fibromyalgia, endometriosis, chronic

24 pancreatitis, and these people are not going to die

25 from their disease, but the treatments really need



1 to be very similar to the cancer pain population.

2 My background and how I got into this, I

3 was initially an oncologist and I consider myself a

4 reformed oncologist, and actually started the

5 Palliative Care Service at Yale, and at the time

6 started ending up seeing a lot of chronic benign

7 patients.

8 How did that happen? It happened that an

9 oncologist was doing that because the principles

10 were the same principles. So, you know, it is not

11 unusual to get lower back pain, reflex sympathetic

12 dystrophy, fibromyalgia, and I was a little

13 concerned with looking at the guidelines to say,

14 well, you are going to just divide it up into

15 little departments of all these different pains,

16 when it is really a much broader issue, and these

17 chronic pain patients are very similar in many,

18 many ways.

19 What has struck me so many times, you

20 know, initially, when I got into more of the

21 chronic benign pain part, but just all the time, is

22 that the suffering issues of these patients are at

23 least as much, if not more, than the palliative

24 care, cancer pain, HIV population, overwhelming.

25 So, I say that this is a component that we



1 have missed in medicine, we have missed the boat

2 because we always think that there is a medication

3 for that, and there is no medication for suffering.

4 I would like to share an example of a

5 patient that I took care of for a while in New

6 Jersey, a man who had back pain after being

7 disabled on his job as truckdriver, and he ended up

8 going for all kinds of epidural injections, facet

9 blocks, and continued to have pain, then had

10 surgery, and continued to have pain.

11 I mean we all know the story, we have all

12 seen it many times, and he actually became more

13 depressed, was seeing psychiatry, was put on four

14 or five different antidepressant type medication

15 anti-anxiety medicines, was in a stupor, but was

16 still having pain, and ultimately ended up going to

17 a neurosurgeon to have a dorsal com stimulator

18 placed, which failed. Not a big surprise that this

19 failed.

20 At this point, they said all right, send

21 him to Ann, she seems to know how to fix these

22 people. He came to my office crying, crying,

23 crying with his wife, and so we started--the

24 assessment I do is the same like I would on a

25 palliative care patient. I am like what is going



1 on here, what is going on.

2 He was a truckdriver, had lost his job,

3 again, all these losses, had lost his job, lost his

4 finances. This was his whole self-esteem to be a

5 truckdriver. Six months later his daughter

6 actually died of a brain aneurysm and left him with

7 a six-month old baby. Two years after that, his

8 father died of Alzheimer's, and a year after that,

9 his sister died of bone cancer.

10 This is not an unusual story. This is a

11 story that comes into my office every day, whether

12 the patient has low back pain or RSD or

13 fibromyalgia, the stories are usually very similar.

14 The losses are very similar.

15 In terms of the suffering component, the

16 only thing that helps that is all the

17 nonpharmacologic things, counseling. There is no

18 Prozac, there is no Zoloft, there is no medicine.

19 It is counseling, it's art therapy, it's music

20 therapy, it's pet therapy, it's acupuncture, it's

21 Reiki, it's spiritual, it's all these other

22 components.

23 In terms of, in my mind, when I look

24 clinically at a palliative care patient versus

25 chronic benign pain, really, the most important



1 difference in terms of how I treat them medically,

2 with the medications, is clearly, if they are

3 palliative care, quality of life has to come first,

4 and you are absolutely correct, function may not

5 increase.

6 You know, sometimes just being awake and

7 breathing is increased function. Whereas, in

8 chronic benign pain, yes, we expect function to

9 increase, and that is the big difference. I don't

10 care what numbers the patients are using. This

11 guy I was talking about before was on heavy doses

12 of oxycontin, up to actually 2,400 milligrams, and

13 still remains at that dose.

14 It didn't matter because he started

15 working, he was functioning after this, and that is

16 the important thing, are you functual again if you

17 have chronic benign pain.

18 The things that I think we don't have

19 enough data on, we clearly don't have enough data

20 on cancer drugs, on neuropathic pain, and also on

21 things like post-treatment pain syndromes. It is

22 very interesting that we don't look at

23 post-treatment pain syndromes.

24 Again, in the elderly, people who have

25 multiple, multiple operations, it is not unusual



1 that they are going to have pain after their

2 operations, and this is not something that we think

3 about. It is not only postmastectomy pain,

4 postnephrectomy pain, but it is anytime a surgeon

5 lifts the knife, you could ultimately end up with

6 chronic pain, so a lot of people with abdominal

7 surgery, it is from endometriosis, from

8 pancreatitis, from whatever.

9 DR. FIRESTEIN: Thank you very much.

10 The next speaker is Dr. Thomas Schnitzer

11 from Northwestern.

12 DR. SCHNITZER: I appreciate the

13 opportunity to be here to speak today. I am here,

14 although I do interact with the pharmaceutical

15 industry significantly, I am really here

16 representing myself as a rheumatologist, a

17 Professor of Medicine, and Assistant Dean for

18 Clinical Research at Northwestern University,

19 Feinberg School of Medicine.

20 [Slide.

21 I actually wanted to talk about three

22 specific things. I had three topics that I thought

23 I would want to discuss, but, first, I would really

24 like to commend the FDA, both of the divisions that

25 are here, and Dr. Witter and Dr. Simon for their



1 ability to bring together this discussion, which I

2 think is clearly, after the discussions we have

3 heard today, much need.

4 There were three topics I really wanted to

5 talk about, but given the fact that I had limited

6 time, which manages to focus you intensely, decided

7 to really cut down to really just speaking about

8 two of these, the nosology of chronic pain, which I

9 think we have heard a lot about, I will not speak

10 to further.

11 But I would like to talk about the

12 methodology of the efficacy trials, particularly in

13 musculoskeletal pain, really in an attempt to

14 demonstrate I think some of the limitations and

15 some of the opportunities and that exist in terms

16 of methodology.

17 As I am talking to my clinical

18 pharmacology colleagues, I think what is clear, as

19 they say, is that a really good investigator can

20 design a trial that will give the results that he

21 or she wants. So, study design is actually

22 critical, and what I would like to do is focus on

23 the traditional study design we have used to

24 demonstrate some of the limitations of this design,

25 and then to talk about opportunities.



1 [Slide.

2 In the area that certainly I have had 15

3 or 20 years experience, a flare design, whether it

4 is osteoarthritis, rheumatoid arthritis, or other

5 types of musculoskeletal disease, is typically what

6 is done.

7 This is what we use for these conditions

8 to be able to demonstrate efficacy. What we

9 haven't really I think given enough thought about

10 is the issue of defining an analgesia-dependent

11 population that we are studying, that we are

12 dealing with high levels of pain, so at the time of

13 randomization, when we actually start to treat

14 patients, their mean pain score is often greater

15 than 70 mm on a 100-mm visual analog scale, so this

16 is not minor league, minor pain, this is I think

17 high intensity pain.

18 I would submit that we are really not

19 looking at a chronic pain model, but we are looking

20 at a subacute pain model, and I was glad to see Dr.

21 Simon in his definition of acute pain actually

22 include subacute pain, which I actually think the

23 models we use would fit very well.

24 Finally, I think we are selecting for

25 drugs that work in acute pain rather than looking



1 for drugs that work in a chronic pain mode.

2 [Slide.

3 To be able to perhaps explain that better,

4 I will just take a slide here, which really

5 represents no specific trial, but is similar to

6 what we see in many of these OA trials, looking at

7 pain on walking.

8 The first point represents the patient

9 population that we are screening, so when they come

10 in on their medication. What I would want to

11 indicate is the fact that these patients, in many

12 of these trials, are required to be on full doses,

13 prescription doses of analgesic medication, so they

14 need to be on this medication.

15 To qualify to be in the trial, they need

16 to have an increase in their pain. So, they are

17 analgesia-dependent patients.

18 Now, this population is hardly

19 representative. As an active investigator and as

20 an investigator who believes in collecting metrics

21 at our research center, I can tell you that when we

22 advertise for patients with knee pain, that for

23 every 20 telephone calls we get, we may have one

24 patient enter a trial.

25 So, that is 5 percent of those people who



1 were willing to pick up the telephone, call us, and

2 say they have a problem and they would like to be

3 in a trial. Of the patients who actually come in

4 and we can talk to, and we put in the trials, about

5 20 percent qualify in this type of trial.

6 So, the idea that this is giving us a

7 representative sample of patients with

8 osteoarthritis or rheumatoid arthritis is clearly

9 not the case. This is a subset, this is not a

10 general population.

11 The second point to be made is clearly

12 these patients have to flare, so they have now a

13 chronic pain background, but we are requiring that

14 they have the onset of acute pain over the course

15 of usually five half-lives of a drug. Their pain

16 gets up in the range of 70 to 80 mm on a 100-mm

17 visual analog scale, and I will submit this is not

18 looking at chronic pain, this is looking at a flare

19 of acute pain that has been induced by the study

20 design.

21 This is hardly what we, as clinicians,

22 typically see. We don't start patients in our

23 clinic on another drug after they have stopped

24 their previous drug for three or four days. So,

25 this is an artificial situation.



1 As I said, I would submit that we are

2 looking at a subacute pain model, not a chronic

3 pain model. When you think about it, what type of

4 drug are we going to select? We need a drug which

5 is going to work quickly. Patients are going to

6 drop out if this drug doesn't work fast. This is

7 going to sound very much like the acute pain

8 argument.

9 So, we need a drug that works quickly, and

10 we need a drug, in addition, not only working

11 quickly, but a drug that is effective for high

12 levels of pain, not mild or moderate levels of

13 pain, but high levels of pain.

14 So, we are selecting for drugs that have

15 already proven that they work in the acute pain

16 setting. We have just gone through a dental pain

17 model for acute pain, which looks at issues not

18 dissimilar to this, and actually has pain levels

19 that are very similar to what we are seeing here.

20 So, I would submit that we are probably

21 not using the right model even though it has been

22 clearly validated and does develop, we will approve

23 drugs, but probably for acute for subacute uses.

24 [Slide.

25 Now, is there another way? Well, it is



1 hard to believe, but I actually did not speak to

2 Dr. Laska before this meeting, but I would like to

3 talk about withdrawal trials, as well, and

4 actually, having such an accomplished statistician

5 present this information before I am means that I

6 don't have to deal with the statistical aspect of

7 this at all, which I don't feel qualified to do.

8 But I think there are significant

9 advantages to looking at a withdrawal design. Now,

10 this is not unusual, it has been used in pediatric

11 studies repeatedly for ethical reasons. It is

12 actually included in the RA guidance document, so

13 this is not something which does not have a

14 history.

15 The advantages, in addition to the

16 statistical strengths that Dr. Laska submitted, is

17 that all subjects receive active medication, so

18 this is a real advantage. Everybody gets treatment.

19 For many patients, if you get them for trials, this

20 is important.

21 There is no necessity for disease flare

22 although you can put one in if you want, but there

23 is absolutely no necessity to have a disease flare,

24 so you can actually look at baseline pain levels on

25 treatment, and there is no artificial definition of



1 responders.

2 What I mean by that is we are going to

3 have a long discussion, I am sure, both today and

4 tomorrow, about how many millimeters if a

5 clinically meaningful response.

6 Well, in this model, the patient decides

7 that. I mean we don't have to have physicians

8 sitting back trying to make the decision about how

9 much is appropriate. What you really have is the

10 patient says I have had enough, I want out of the

11 trial. That will be different for each patient,

12 but it doesn't matter, because you will actually

13 have a response.

14 [Slide.

15 So, this is what a trial might look like,

16 and there is run-in phase here, which I shouldn't

17 leave out the importance of, because this run-in

18 phase on active medication, so patients are first

19 on active medication for a number of days, allows

20 you to learn a lot about the use of that drug in an

21 open-label fashion. I think that is also an

22 important aspect.

23 Patients are then randomized at some

24 point. The other point about this is they can be

25 randomized at anytime, so the investigator nor the



1 patient has to know when that occurs. Then, you

2 see patients dropping out for lack of efficacy or

3 whatever you want to use as your objective

4 endpoint, and a differential dropout rate between

5 patients on active therapy, which would be

6 indicated here, and on placebo or another less

7 active therapy on the bottom line.

8 The intent is really not to say the

9 withdrawal trials are the way to go. It is just to

10 say that I think we need to consider a number of

11 other approaches in terms of methodology, and this

12 may be one of them.

13 [Slide.

14 The last thing I want to talk about is

15 long-term safety. It is really something that has

16 not been talked about today, but I think is

17 absolutely critical.

18 We know from discussions here at the

19 Agency and I think eloquent discussions, that the

20 datasets at the time of NDA are really inadequate

21 to be able to detect uncommon events. We know that

22 some sort of postmarketing surveillance program is

23 required if we want to be able to determine these

24 uncommon events. So, I would say it is required or

25 let's say needed rather than making it a



1 requirement.

2 These studies need to be well defined,

3 they need to be carefully planned, and I think,

4 most importantly, they need to be done in a timely

5 manner, so these programs are going to be of any

6 value if we have them shortly after a drug is

7 approved, and long after it is history.

8 I think the way we go about this is to

9 provide appropriate incentives to pharma to do

10 these studies. What I mean by that is I think we

11 should take a page out of the book that exists, we

12 ought to look at what has been done in the

13 pediatric world, and saying that we should give

14 incentives to industry, and say if you do an

15 appropriate postmarketing surveillance study, that

16 you have the potential--and this will be something

17 clearly the Agency cannot do alone, but will take

18 Congress--the potential to have perhaps six months

19 of additional patent protection if these long-term

20 surveillance programs are put into place.

21 I think it is a shame that this country,

22 that spends so much money on health care, can't

23 spend money in determining safety of these drugs we

24 use. The point about this is that if we have a

25 drug that is used, these uncommon events, even with



1 the datasets that are as large as we see for

2 NSAIDs, 10- 12,000 patients, we can't rule out an

3 uncommon event that occurs 1 in 4,000 patients,

4 let's say, we will take rule of 3.

5 If we are treating millions of patients

6 with these drugs, which we will, very successful

7 drugs, we have the potential for having thousands

8 of people have an adverse event that may be

9 life-threatening, that could not be detected in the

10 NDA dataset.

11 So, I think we need to develop these

12 surveillance programs, and I think the only way to

13 do it is really to provide the incentives

14 appropriately.

15 [Slide.

16 So, in summary, I would like to say I

17 think we need to stimulate new approaches, and I am

18 glad to see this conference is really focusing on

19 that, different and appropriate methodologies, and

20 I think we need more in the way of safety and

21 outcomes data.

22 I really believe that the way to do that

23 is really through an effective partnership among

24 government, industry, academia, and the public, who

25 are all demanding this.



1 Thank you very much.

2 DR. FIRESTEIN: Thank you.

3 The final presentation will be by Dr.

4 Michael Hufford, Vice President, Scientific

5 Affairs, The Science of Patient Experience.

6 While he is getting set up, I would just

7 let the panel know that there is, in addition, a

8 letter from Dr. Shainhouse that will be entered

9 into the record, but will not be read today.

10 Letter from Z. Shainhouse, M.D.,

11 Dimethaid Health Care, Ltd.

12 "As Dimethaid Health Care, Inc. has an

13 interest in topical NSAIDs for symptom relief of

14 rheumatic diseases, we would appreciate the panel

15 taking into consideration the application of any

16 proposed trial models and designs to a topical


18 "In trial design for topicals in OA

19 symptom relief, one can use as a model the usual

20 designs for oral NSAIDs. The efficacy variables of

21 pain and physical function, which are used to

22 assess the study joint, are readily studied with

23 topicals. The role of the Patient Global

24 Assessment is less clear.

25 "Questions on Patient Global Assessment



1 are often used to inquire about the non-signal

2 joints which are treated simultaneously by oral

3 NSAIDs that provide full, systematic distribution

4 of a therapeutic concentration of drug.

5 "The site-specific nature of topical

6 treatment is unlikely to deliver fully-therapeutic

7 systemic drug levels to provide 'global' benefit to

8 other, non-study joints. Even if one restricts

9 enrollment through trial design, non-study joints

10 may flare during the trial. A Patient Global

11 Assessment for a topical cannot mean the same thing

12 as for an oral.

13 "There are other aspects unique to the

14 study of topicals. Approvability trials, for

15 reasons of practicality and design standards,

16 always study the hip or knee. Topicals are not

17 appropriate for treatment of hips. There is very

18 little literature for oral NSAIDs, let alone

19 topicals, in the treatment of other joints. Do we

20 have sufficient studies on the natural history and

21 spontaneous remission of symptoms in other joints

22 to determine the appropriate duration of study?

23 For that matter, is the now-standard 3-month trial

24 design for OA of the knee or hip based on any such

25 evidence on the natural history of the disease?



1 "Clinical experience suggests that where

2 disease is less than bone on bone, symptoms do,

3 indeed, tend to resolve with time - which is

4 perhaps the basis for the usual recommendations to

5 stop oral NSAIDs when symptoms resolve. Is this not

6 further proven by the failure of so many patients

7 to 'flare' during the screening, washout-out stage

8 for drug studies?

9 "The literature describes a significant

10 placebo effect for topicals, thereby complicating

11 study of the onset of pain relief.

12 "In Europe, topical NSAIDs are usually

13 approved and prescribed for the treatment of soft

14 tissue injuries. We are aware of no guidelines for

15 trial design for such studies. Duration would of

16 necessity be shorter because of the self-limited

17 nature of the disorder.

18 "We will appreciate comments from the

19 panel members on the applicability of any

20 guidelines they may propose to the field of topical

21 NSAIDs."

22 "Sincerely, Z. Shainhouse, M.D."

23 [End of letter]

24 DR. HUFFORD: You can see I have tried to

25 rise to the challenge to do a very quick swapout.



1 [Slide.

2 Let me begin by saying the company that I

3 work for, In Vivo Data, provides electronic diaries

4 to sponsors in clinical trials, and as such, a

5 number of compounds either are or will be under

6 review by the Agency.

7 [Slide.

8 What I would like to speak to you about is

9 something I have been working on myself for 10

10 years, and my colleagues, for an additional five,

11 using diaries to help patients succeed in providing

12 real-time, real-world data in clinical trials.

13 Of course, diaries are used widely in

14 arthritis trials to capture patients' experiences

15 in a variety of real world settings, and has been

16 mentioned throughout the day today, as well as at

17 the NIH-FDA Conference on Analgesic Drug

18 Development a while back, the collection of pain

19 data in particular, either using the VAS or Rick

20 Graceley's modified VAS scale, is one common

21 implementation, as well as collecting data on

22 functional attributes, stiffness, physical

23 functioning, and nighttime awakenings, and there is

24 good psychometric reasons for this.

25 A number of studies have shown that diary



1 data can be more sensitive to medication effects

2 than recall-based reports at the site. One key

3 concern, though, about paper diaries, in addition

4 to the generally poor data quality in terms of

5 legibility, is really noncompliance, because when

6 you use paper diaries, compliance with timely

7 completion if left completely up to the patient to

8 enter the time and date, and you go by that record.

9 Of course, that is very vulnerable to

10 hoarding and falsification, as I am sure many

11 people in this room, including myself when I was a

12 professor, can testify, it is not uncommon to catch

13 patients filling out a week's worth of diary cards

14 immediately before a site visit. Indeed, this

15 happens so often that John Urquhart [ph] has termed

16 it "parking lots compliance."

17 Noncompliance importantly, not only

18 violates the protocol, but it undoes the expected

19 advantage of the diary method because the reason

20 that you implement diaries is to avoid the

21 systematic inaccuracy and bias inherent in recall.

22 It is not pain patient's fault, but simply the way

23 they encode and retrieve information.

24 So, one of the best known biases is

25 patients in a great deal of pain will



1 systematically exaggerate their mean pain over the

2 course of the week. Again, it is not fault, but

3 you can't extract yourself from current pain to

4 provide an accurate estimate or recall-based pain,

5 so diaries are used as a way to avoid their recall

6 biases.

7 [Slide.

8 I would like briefly to present a study

9 that my colleagues and I recently published in the

10 March 18th issue of the British Medical Journal.

11 Dr. Arthur Stone, who is the Vice Chair of

12 Psychiatry at SUNY-Stonybrook, what we did is we

13 had two objectives. We wanted to quantify

14 subjects' compliance with paper diaries in a way

15 that was objective really for the first time, and

16 to compare that paper diary compliance to an

17 electronic diary benchmark, something that a number

18 of us, including myself, have been working on in an

19 academic context for over a decade.

20 The endpoints was reported compliance,

21 what patients said they did in terms of telling us

22 about their real-world pain, actual compliance,

23 which we will get to in just a moment, as well as

24 hoarding, that parking lot compliance that I

25 mentioned.



1 This was a randomized, parallel, two-arm

2 study with 80 heterogeneous chronic pain patients

3 being assigned to one of two groups, either a paper

4 diary or an electronic diary. What patients didn't

5 realize--and this is actually a sample one--is the

6 paper diary was covertly instrumented, such that

7 photo cells, that we built into the binder, would

8 detect the change in light and write the time and

9 date stamp to an onboard wafer-thin computer chip

10 that we had built into the binder.

11 This was unique insofar as for the first

12 time, you could have an objective documentation.

13 So, the patient said it's Monday at 10:00 a.m. and

14 I am telling you about my pain, well, you could

15 look at the objective electronic record and say,

16 well, is it possible, was the diary even open on

17 Monday for them to complete that report.

18 Again, half of the patients were then

19 assigned to a compliance-enhanced electronic diary

20 with a variety of features that helped them be more

21 compliant with the protocol.

22 It was a three-week pain study with

23 patients completing three reports of their pain,

24 both in the morning, afternoon, and evening, and we

25 asked them to do them at specific times of the day.



1 What we found is when you simply look at

2 the paper diary cards, it looks like they were 90

3 percent compliant, that is, 90 percent of the time

4 you had paper diary cards at the date and time that

5 you asked the patient to give the report, so you

6 would be thrilled.

7 Of course, we, for the first time, had an

8 objective records team and could look at actual

9 compliance.

10 [Slide.

11 To our surprise, we thought it would be

12 bad, we didn't think it would be this bad, we had

13 11 percent compliance. So, 79 percent of the time,

14 the patients were not completing the diary card as

15 they told us that they were.

16 [Slide.

17 When we compared that to the patients

18 randomly assigned to use the electronic diary,

19 because one could argue that it was an artifact,

20 chronic pain patients can't possibly be expected to

21 fill out diaries, although we asked them to all the

22 time, what we found is with the variety of

23 compliance enhancing features, we were able to get

24 very high rates of compliance documented over the

25 course of the study, time and date stamp verified



1 as required by the protocol.

2 [Slide.

3 So, we looked at the completion of those

4 paper diary cards in batches, trying to understand

5 what happened to those other 79 percent of diary

6 cards. It turns out 1 out of every 3 days, the

7 diary was never even opened. On those days,

8 reported compliance was 96 percent. So, it on the

9 very days that patients forget to do anything with

10 the diary that they are most likely to go back and

11 back-fill a day's or at times even a week's worth

12 of diary cards, so we found a great deal of

13 back-filling really more disturbing to all of us,

14 including myself. Having written the statistical

15 analytic plan, I can tell you that we did not even

16 originally take this into account.

17 We also found forward-filling, that is,

18 there were instances where the patient, say, on a

19 Wednesday evening, would open the diary for about

20 30 minutes. This was a very short pain assessment,

21 only took about 2 minutes to complete. If you open

22 it for 30 minutes and then closed, closed all day

23 Thursday, closed all day Friday, they come in for a

24 site visit on Saturday, and lo and behold, they had

25 Thursday's and Friday's diary cards, so there was



1 clear evidence of forward-filling, as well.

2 [Slide.

3 To give you a sense of whether or not the

4 high rates of compliance achieved in the electronic

5 diary group were a fluke, this is a sample of my

6 colleagues and I's peer-reviewed publications, not

7 all of them, but stretching back nearly a decade

8 now.

9 This was the paper compliance at 11

10 percent, the electronic diary compliance at a

11 verified 94 percent compliance, and this is just a

12 sample of some of the work we have done across

13 therapeutic categories showing that patients can

14 succeed in providing real-time, real-world data,

15 but they do need help to do it.

16 [Slide.

17 So, in sum, diary data are critically

18 important to a variety of trials including

19 arthritis trials to avoid retrospective bias that

20 Ike and Rademeyer and Com, and Bradburn, in his

21 famous 1987 Science paper, have outlined so

22 cogently.

23 Paper diaries, though, are vulnerable. In

24 fact, we were able to show objectively both poor

25 and faked compliance using paper diaries. On the



1 other hand, electronic diaries with science-based

2 compliance principles can be used to provide

3 documented high, real-time compliance rates. They

4 can also enable more sophisticated diary designs.

5 I don't have time to get into this, but there is an

6 entire field of study called ecological momentary

7 assessment who aim is to densely sample patients'

8 waking experience including dynamic sampling to

9 capture things like time of onset, time to relief

10 in trials.

11 Then, lastly, of course, the validity and

12 integrity in diary data is essential obviously to

13 the evaluation of medication. So, reprints of the

14 British Medical Journal study, I believe have been

15 distributed.

16 Thank you very much for your time.

17 DR. KATZ: May I ask a question, Dr.

18 Firestein?


20 DR. KATZ: Let me just first congratulate

21 you on a wonderful little study.

22 DR. HUFFORD: Thank you very much.

23 DR. KATZ: I think it is a good example of

24 how methodological issues can be subjected to

25 rational analysis and empirical investigation. We



1 so often talk about these important methodological

2 issues, and it is so unusual that we see somebody

3 that actually tries to test a hypothesis in

4 practice.

5 It also matches perfectly with our

6 experience including our published experience in

7 comparing paper and electronic diaries.

8 My question is, were the pain ratings

9 different?

10 DR. HUFFORD: That is one thing we are

11 actually currently pursuing. That has actually

12 taken a tremendous amount of time ironically, to

13 clean and lock the paper diary data. So, that is

14 something that we are working on currently, to look

15 at the psychometric differences.

16 One of the challenges is with the

17 forward-filling in particular, and how to deal with

18 that, but that is something that we are following

19 up on right now.

20 DR. KATZ: Right. We are still cleaning a

21 database that was locked in 1996 from an electronic

22 diary study, it's no small task.

23 DR. FIRESTEIN: Thank you very much for a

24 very provocative discussion.

25 At this point, we are going to take



1 another break. At five minutes to 3:00, we are

2 going to start.

3 [Break.]

4 DR. FIRESTEIN: We are going to begin this

5 session with an introduction from Jim Witter.

6 Introduction

7 James Witter, M.D., Ph.D.

8 DR. WITTER: Good afternoon.

9 [Slide.

10 What we thought this afternoon, what we

11 will try and do, and it's going to be an imperfect

12 division, was to make sure that we don't lose the

13 focus on safety, but there is going to be a little

14 bit of a schizophrenia in the sense that we will be

15 talking about some efficacy also this afternoon,

16 and then we will open it up for more general

17 discussion.

18 [Slide.

19 If we were to, for example, take, as I

20 have done here, a line, and on one side of it,

21 write "pain," and the other side "pleasure, we

22 could probably spend these two days just talking

23 about the meanings behind that.

24 What we are interested in really are these

25 concepts of safety, tolerance, and tolerability,



1 and as you look, for example, at NSAIDs and opioids

2 as general medicines, they would fall somewhere on

3 this particular line.

4 [Slide.

5 The real question then would be what is

6 the perfect drug and it should be totally safe, but

7 how safe is safe and who should be deciding that,

8 and it should be totally effective, and as we all

9 know, there is no such drug, be it analgesic or

10 otherwise.

11 [Slide.

12 What we thought we should do is take some

13 time to discuss safety and really what we do as an

14 assessment of drug safety, during the development,

15 during the IND phases, before NDA approval--and

16 realize we don't want to confuse on some of these

17 acronyms, but I think we want to use these, so that

18 everybody gets familiar with them if you are

19 not--and then what happens at approval and then

20 after that. We don't want to lose focus on any of

21 these.

22 So, before the NDA is approved, we have

23 preclinical, or I guess we should be referring to

24 this now as non-clinical studies to help guide us,

25 to get some idea of what the profile of the



1 compound looks like.

2 Then, we have, as well, various phases,

3 Phases I through III, which enroll larger and

4 larger numbers of patients, and by the time these

5 are completed, if everything has gone well, this

6 information is submitted to us, we look it over, we

7 review it and make an assessment as to whether it's

8 efficacious, really trying to judge effectiveness,

9 and then whether it is also safe enough.

10 If that is approved, then, we have a

11 compound that has a label, and yet that is not the

12 end of the drug's life cycle. There are things

13 that happen post-approval and as Dr. Schnitzer

14 noted before--and maybe we had talked about this

15 beforehand, but we didn't--there really is an

16 incomplete safety assessment when a compound is

17 released, no matter how hard we try, it is just not

18 possible.

19 [Slide.

20 So, we need to be looking at adverse

21 events. As I described, we look at adverse events

22 both before and after approval, and these are from

23 the patients and they are also from the

24 investigators.

25 Now, there has been a discussion, and



1 maybe we should have that continue today, that the

2 patient global is also something that should really

3 be intended to catch that something is not quite

4 right experience with an analgesic. Maybe that is

5 what this is best geared for in these particular

6 trials.

7 [Slide.

8 But I think it is safe to say that drug

9 safety is really synonymous with drug information.

10 The more information we have, the better.

11 [Slide.

12 Now, once something is approved, there are

13 various tools--and this important because again we

14 don't catch everything pre-approval--we have this

15 AERS database, adverse events reporting system,

16 which is a passive surveillance system, which has

17 various problems in and of itself, Weber effects,

18 when something is on people's minds, they report

19 it, when it is not, they forget it, but we have

20 other mechanisms, as well.

21 We have abilities to look for drug

22 utilization in certain databases. We can look at

23 external databases for other issues, whatever may

24 be of interest to us. We can look at background

25 incident rates of various adverse events, for



1 example, and then we can actually also undergo

2 active surveillance real-time and prospective types

3 of programs, and they have all been employed to

4 some extent.

5 [Slide.

6 So, what these are termed really is risk

7 management tools, and some these then,

8 postmarketing, there are some routine things that

9 we do. For example, we can change the product

10 labeling, we can add adverse events, we can add

11 contraindications, precautions and warnings, and,

12 in fact, the dreaded black box warning.

13 We can make recommendations on monitoring,

14 in fact, we can make this directive - you shouldn't

15 give this until that, for example, follow a lab

16 result, and we can also change indications to make

17 them second line.

18 [Slide.

19 Other things that we can do, which are

20 less commonly done, are to provide patients with

21 information, medication guides as an example here.

22 We can provide clinicians with Dear Doctor letters.

23 We can make public announcements through other

24 forums, such as today.

25 [Slide.



1 We can also have patient registries either

2 on a voluntary or a mandatory basis, and there was

3 some discussion about that earlier, too. Then, we

4 can also, and I think this is the thing that

5 everybody tries to avoid, is the product can be

6 withdrawn.

7 [Slide.

8 What are some of the lessons we have

9 learned postmarketing? With regards to labeling

10 changes, there is a feeling that in many ways,

11 these are largely ineffective for widely used drugs

12 because they send out just too complex messages,

13 and that there have, in fact, been failures due to

14 persistent adverse events or studies--some of those

15 active surveillance that I had mentioned

16 before--studies showing that contraindications have

17 been ignored, have led to market withdrawal.

18 Tomorrow, we will be hearing discussion about Durak

19 as an example.

20 [Slide.

21 Patient registries are useful for

22 estimating the denominator, so to speak, in

23 long-term safety. They don't manage risk per se,

24 but certainly overseas I think it is safe to say

25 that they are heavily utilized for gathering safety



1 information.

2 So, without further delay, I would like to

3 introduce then Dr. Katz, who will be discussing

4 some of the issues of safety and tolerance with

5 opioids, and then Dr. Lu later will follow with

6 some discussion on some efficacy issues.

7 Tolerance and Toxicity

8 Nathaniel P. Katz, M.D.

9 DR. KATZ: Good afternoon. Let me begin

10 by thanking the Division, Dr. Simon, Dr. Firestein,

11 Dr. Witter, and everybody else for giving me the

12 chance to come and share some thoughts with you

13 about side effects of opioids, also to Drs.

14 McCormack and Rappaport from the other division who

15 have given me an opportunity to gain some

16 experience in the regulatory world on that side.

17 I will be talking about side effects of

18 opioids and what I think are the potential down

19 sides of opioid therapy that are of concern to

20 patients and to physicians, and that need to be

21 understood in order to inform our risk-benefit

22 assessment.

23 I will also be trying to address what we

24 know to date about those potential side effects

25 from the clinical trials that are available.



1 [Slide.

2 Let me just begin by saying that when you

3 give a talk just on the down sides of a medication

4 or a class of medications, it may come across as

5 being very unbalanced and that you don't get a

6 chance to emphasize the up side, so let me just get

7 my balance statement out of the way upfront.

8 It has been universally acknowledged now I

9 think, at least in Western medical professional

10 societies, that opioids have an essential, an

11 unreplaceable role at this point in time in the

12 treatment of both acute and chronic pain, and that,

13 in general, they are safe medications.

14 Now, having said that, let me try to

15 expand a bit on the potential down sides of that

16 class of medications.

17 [Slide.

18 Here is what people want to know about -

19 do people get addicted, tolerance, well, I guess

20 that is not really a toxicity, is it, but it is a

21 phenomenon that may result in loss of efficacy over

22 time, potentially side effects, and so it is

23 important to talk about.

24 People are concerned about

25 neuropsychological effects of these medications,



1 can people drive, do they lose their ability to

2 function, has their psychomotor reaction time

3 changed, all those sorts of things, can they write

4 their will, can they engage in business, et cetera.

5 Then, there is the plain old garden

6 variety symptoms - nausea, vomiting, constipation,

7 dizziness, sweating, itching, et cetera, et cetera.

8 There are a bunch more. You can pick up any

9 package insert and see what they are.

10 These are the things that are of concern

11 to people, maybe others, and let's see what we know

12 about them in terms of opioid therapy, and I will

13 be focusing mainly on chronic pain.

14 [Slide.

15 Just first to get a couple of definitions

16 out of the way. I am sure that folks in this room

17 know these things, but just to make sure that we

18 are using the same language because language has

19 been a terrible problem in the study of these

20 phenomena.

21 Addiction, which is also known as

22 dependence, psychological dependence, abuse, all

23 related terms, it implies that patients on opioids

24 lose their control over their use of the drug.

25 This is the loss of control model, sort of the



1 modern model of what addiction is, compulsive drug

2 use, continued used despite harm.

3 These are things that it is sort of like

4 art or pornography. Everyone knows what it is when

5 they see it, but when you actually try to define

6 it, it is very difficult to come to any consensus.

7 But what we are talking about here is loss of

8 control over the medication.

9 Physical dependence just means that when

10 you stop the drug, you have a withdrawal syndrome,

11 or you suddenly reduce your dose, or you get an

12 antagonist or something like that, and this is

13 something that is expected of people on opioid

14 therapy.

15 It is not an adverse effect per se, it is

16 not connected with addiction in any particular way,

17 and it is just when the terminology was changed

18 from addiction to dependence, it created this

19 confusion between addiction and physical

20 dependence.

21 So, get that out of your mind right now, I

22 will not talk any further today about physical

23 dependence because it is not, as far as I can see,

24 a toxicity we need to worry about if we counsel our

25 patients appropriately.



1 Tolerance means less bang for your buck

2 over time in a word, less effective medication

3 after prolonged use, or if you want to look at it

4 the other way, you need to increase your dose in

5 order to maintain the same effect. So, these are

6 the phenomenon that I am going to be talking about.

7 What I would like to add just

8 parenthetically in a moment is that there may be

9 other negative behavioral syndromes of opioid

10 therapy that we don't have good words for, that the

11 syndromologists have not really defined yet.

12 For example, there is something that we

13 all have seen that Steve Passaic is calling "the

14 chemical coper syndrome," where we have all I think

15 seen these patients, where you have a patient on

16 high-dose opioid therapy, they are telling you that

17 they need it and that it is helping them. Their

18 pain score is still a 9 out of 10.

19 If you ask them, well, you know, how is it

20 helping you if it is a 9 out of 10, and they will

21 say it would be a 20 out of 10 without my pain

22 medication. They can't get off of it, they may

23 have subtle side effects.

24 They would give you a positive global

25 satisfaction rating, by the way, to you fans of



1 global satisfaction ratings, although their pain

2 relief is not there. These are the patients who

3 may do well after opioid detoxification. Their

4 pain scores may be no different, if not better, and

5 they may feel more alert, et cetera. There is a

6 literature on this.

7 Again, this is not a syndrome that has

8 been well defined, but it is something that we all

9 see, and we can keep it in the back of our minds.

10 I won't talk about it any further.

11 [Slide.

12 So, what do we know about these things?

13 First of all, there is nothing new under the sun.

14 In my worst moments sometimes I think I am the

15 first person to think about these things.

16 Diagoras of Melos, Third Century B.C., a

17 Greek physician, "It is better to suffer pain than

18 to become dependent upon opium." Again, they are

19 talking about the use of opiates for chronic

20 nonmalignant pain. This is what was being

21 discussed in the medical literature of the third

22 century B.C. 2,400 years ago.

23 Again, Erasistratus, if you ever want to

24 look him up, his name is spelled a number of

25 different ways, a Greek physician who actually was



1 one of the heads of the Alexandrian School of

2 Medicine in ancient Egypt. Mainly, he got his name

3 through anatomical studies, but he also said opium

4 should be completely avoided, period, and he was

5 referring there to the risk of dependence.

6 At the same time, there were other

7 physicians who were promoting the use of opioids as

8 a cure-all for all sorts of illnesses, again, just

9 showing you this does not give a balanced

10 historical approach, but it does suggest that

11 people have been concerned about these things for a

12 long time.

13 Of course, in the modern era, with the

14 advent of the randomized, controlled trial that has

15 been available to us for more than 50 years now,

16 doubtless we have high quality evidence concerning

17 the incidence of these side effects, and you will

18 soon see the quality of the evidence that we have.

19 [Slide.

20 Now, we do know that opioids are abused,

21 that is no secret to anybody. This is DAWN data

22 and shows the prescription analgesics. This is ER

23 Mentions [ph], for what that is worth, it is gives

24 you some sort of a signal, and it is really of the

25 same order of magnitude as cocaine, a bit less than



1 alcohol, far greater than marijuana, et cetera.

2 So, are these patients abusing them, are

3 they addicts who are non-patients? Again, we don't

4 know. We suspect that they are mostly

5 non-patients, but again you will see the quality of

6 the information that we have, clearly, it is an

7 issue.

8 [Slide.

9 In the 70's and 80's, during the era, as

10 was pointed out earlier by Dr. Sunshine, where

11 treating pain with opioids was basically a no-no, a

12 few radical and provocative studies were published.

13 There was one by Medina and Diamond that

14 looked at drug dependency and people treated

15 primarily with intermittent opioids for chronic

16 headaches, pointing out that of their 2,000

17 some-odd patients, few, if any, became addicted.

18 Porter and Jick, this is probably the most

19 famous study which has been quoted millions of

20 times, addiction rare in patients treated with

21 narcotics. This study, published in 1980, again,

22 11,000 some-odd patients treated for acute pain in

23 Boston area hospitals over a period of time, and

24 only something like 4 out of this 11,000 were later

25 on felt to have become addicted to their opioids.



1 Then, Perry and Heidrich, another one,

2 similar study, management of pain during burn

3 debridement, use of opioids in many thousands of

4 patients, only rarely was addiction noted.

5 These studies created a new vocabulary for

6 the discussion of addiction with opioid therapy.

7 Now, for the first time in a long time, or at least

8 we thought, we could actually discuss the

9 possibility that maybe opioids are okay for the

10 treatment of pain.

11 Then, at the same time, you had the cancer

12 pain literature that was coming out demonstrating

13 the safety and efficacy of opioids in treating

14 cancer pain. There were a number of retrospective

15 survey studies in non-cancer pain, suggesting that

16 addiction was rare.

17 From this, there created a climate, at

18 least among pain specialists, that you wouldn't get

19 your patients addicted if you gave them opioids for

20 pain, although none of these studies actually

21 addressed the issue at hand.

22 These three studies, the most famous one,

23 the Porter and Jick one, is actually a

24 one-paragraph Letter to the Editor in the New

25 England Journal of Medicine. None of these studies



1 actually defined addiction in any way. None of

2 them actually implemented any particular plan for

3 how they were going to detect addiction.

4 They were all retrospective based on the

5 judgment of the physician, and none of them were

6 related to the use of opioids for the treatment of

7 chronic pain. So, again, whether or not opioids

8 are addictive in the management of chronic pain,

9 maybe they aren't, maybe they are, maybe there is a

10 number, but we certainly don't know anything about

11 it from these particular studies.

12 [Slide.

13 It is fair to summarize this at this point

14 and say that no published study of opioids for

15 chronic pain has prospectively evaluated the

16 incidence of addiction by any definition. That is

17 the state of the literature at this point in time.

18 [Slide.

19 There are some methodological issues

20 buried in how one would assess this if one wanted

21 to anyway. There are lot of very thorny

22 methodological issues. The first issue is which

23 population.

24 The studies that I showed you earlier, in

25 general, dealt with a patient population with no



1 history of addiction, no psychiatric comorbidity as

2 are most of the randomized, controlled trials that

3 are done today.

4 So, we became interested in what happened

5 if you gave opioid therapy long term for patients

6 with a history of substance abuse, which is

7 probably not an insignificant proportion of the

8 patients that we see in pain management centers.

9 If fact, those prevalence numbers vary between

10 around 3 and 20 percent.

11 This is a retrospective study of all of

12 our patients that we could find who had a history

13 of substance abuse documented in their chart.

14 There were only 20 patients. The bottom line is

15 about half of them did fine and half of them

16 self-destructed. We tried to outline some risk

17 factors for who would be in the good outcome group

18 and who would be in the bad outcome group.

19 The only point I am trying to make here is

20 not that there is a great study either, but that

21 the choice of population determines the results

22 that you see.

23 [Slide.

24 Another very thorny issue is what

25 instrument would you use to measure the rate of



1 addiction in patients on opioids for chronic pain.

2 I think the most widely subscribed-to assessment

3 tool for opioid addiction, in the first place, is

4 the DSM-IV or various measurements, the DIS, et

5 cetera, that are based on the DSM-IV, and these are

6 the criteria. You need to have 3 of the following

7 9 symptoms. This is all based on self-report and a

8 doctor-patient interaction, and the self-report is

9 an issue that we will talk about momentarily.

10 But the bottom line is that this doesn't

11 really make sense in people on opioids for chronic

12 pain, and without spending a lot of time going

13 through the details, diminished effect with same

14 dose, does that mean you are addicted? I don't

15 think so.

16 Dose escalation or prolonged use is a sign

17 of addiction. Does that mean you are addicted? In

18 our population, I don't think so. Desire to cut

19 down, excessive time spend obtaining, using, or

20 recovering from use of the substance, well, you can

21 ask most of your patients on chronic pain whether

22 they ever had to spend excessive time obtaining

23 their medication, they have, et cetera, et cetera.

24 So, this it the most well-established

25 criteria, and they are really not relevant to the



1 patients that we are looking at, and there actually

2 is no instrument right now that has been validated

3 for detecting addiction in this population although

4 I am happy to say that there is some work being

5 done on that.

6 [Slide.

7 The measures that have been used in the

8 addiction world are based primarily on self-report.

9 Certainly, all the prevalence information that I

10 gave you based on these few quasi-studies are all

11 based on either self-report or impressions of the

12 physician, again based on patients behaviors and

13 patient reporting.

14 What do we know about self-report measures

15 in patients on opioids for chronic pain? There

16 have been four studies, to my knowledge, that look

17 at that. One is the study by Brian Ready, which

18 showed that patients with chronic pain don't report

19 accurately their use of the medications that have

20 been prescribed to them. This was based on

21 inpatient charting by nurses of what the patients

22 were actually given.

23 Another study by David Fishbain comparing

24 self-reported drug use to urine toxicology screens

25 and other measures showing that validity is not



1 reliable.

2 We did a study comparing behavioral

3 monitoring of patients to urine toxicology again.

4 I will show you that in a second. There was

5 another study that basically did what we did in a

6 way and confirmed our findings.

7 Again, in our study, I won't spend a lot

8 of time on this, but just very, very briefly. In

9 122 patients from two centers, we instituted urine

10 toxicology monitoring on all patients over a

11 three-year period of time that were on opioids.

12 The bottom line is that 29 percent of our

13 patients had a positive urine toxicology screen.

14 These are patients who had an opioid contract in

15 effect. It said we are not supposed to be doing

16 other things. Twenty-nine percent had a positive

17 urine toxicology screen meaning either illicit

18 substances, cocaine, marihuana, et cetera, or

19 things in their urine that they were not supposed

20 to have.

21 We have them on methadone, they have got

22 hydromorphone. We have them on codeine, they have

23 fentenyl, et cetera. About one-third positive, and

24 if you looked at the monitoring behavioral issues

25 suggestive of inappropriate medication use, about



1 22 percent of our patients had inappropriate

2 behaviors of one kind or another, 43 percent either

3 had a positive urine toxicology screen or a

4 suggested behavior.

5 The interesting thing to me is that there

6 is this dogma prevalent in the pain management

7 community that an astute physician, if you monitor

8 your patients carefully and you are attuned to

9 their behaviors, you know what is going on with

10 your patients, you don't need anything fancy, and

11 you can unmask the diverters and drug sellers and

12 criminals and drug addicts simply by your own

13 astute presence and by monitoring self-report.

14 This data suggests that if you only

15 monitored patient behaviors, you miss about half

16 the patients who have a positive urine toxicology

17 screen. I think it is this sort of data, which is

18 also confirmed by this other study I won't tell you

19 about in detail, that confirms, I think in my mind

20 anyway, that self-report measures alone, if you are

21 trying to monitor for noncompliance anyway, are

22 inadequate.

23 I should issue a very quick caveat just so

24 that I don't give the wrong impression. We were

25 not measuring addiction in this study. I don't



1 have any idea of the extent to which these signs

2 correlate with addiction. As far as I know, none

3 of these patients were addicted, but certainly if

4 somebody on opioids has cocaine in their urine or

5 they have opioids that they are getting from

6 another source, that is something that I think I

7 want to know about.

8 [Slide.

9 Another potential source of external

10 information outside of patient self-report that has

11 not really been talked about as a patient

12 monitoring tool on a formal basis, is the whole

13 idea of using prescription monitoring program data.

14 Many of you know that right now I think it

15 is 19 states in the United States have prescription

16 monitoring programs that track some or all of the

17 scheduled medications that these patients are on.

18 In Massachusetts, we have a prescription monitoring

19 program that tracks only Schedule II data, and not

20 any other scheduled medications.

21 So, the idea of using this as a way of

22 getting verification of patient self-report of

23 compliance has really not been pursued, and there

24 is a lot of interesting data buried in these

25 prescription monitoring programs that could be



1 used.

2 For example, we found--we are just

3 starting to validate this database--in

4 Massachusetts, in the year 2000, there were over a

5 million Schedule II opioid prescriptions that were

6 given. There is only 6 million people in the State

7 of Massachusetts, which is interesting, and it

8 looks like there were about half a million unique

9 individuals in Massachusetts that got a

10 prescription for opioids.

11 Now, this database happens to exclude the

12 VA, which is probably not a small issue, and there

13 are a few other exclusions, as well. So, about 9

14 or 10 percent of the Massachusetts population got

15 Schedule II opioids. If you include the other

16 schedules, that probably would double, triple, or

17 quadruple this number.

18 Before I started looking at this, there is

19 really no notion of the epidemiology of opioid

20 therapy, and we do have information on this

21 database on what proportion of people have five or

22 more prescribers, what proportion of people use

23 five or more pharmacies, what proportion of people

24 run out of their day's supply early every month.

25 We can get this data, and we are hoping to



1 actually report these numbers as our work goes on.

2 I think one could consider even using this in a

3 clinical trial or postmarketing or risk management

4 program to look at noncompliance.

5 I am going to leave the issue of addiction

6 there with the unfortunate conclusion that we don't

7 know a lot about the incidence of addiction in

8 patients given opioids for chronic pain.

9 [Slide.

10 Tolerance is another issue and also it

11 seems so easy when you first look at it, and then

12 it gets very complicated when you try to figure out

13 exactly what you mean by tolerance and how you are

14 going to measure it.

15 This is just a concept slide to give you a

16 sense for how one might think about tolerance and

17 begin to approach the idea of how to measure it.

18 Look at these green lines here for a minute. These

19 are little graphs looking at--and this is all

20 invented out of my mind, this is not clinical trial

21 data, this is all conceptual--this is the dose

22 required to produce analgesia over time.

23 In an ideal world, a medication that did

24 not produce tolerance would have a flat line. Here

25 is a different way it might go. You might have a



1 bit of a dose escalation at the beginning and then

2 you might be stable over time, in fact, there is a

3 school of thought that suggests that this is what

4 happens to most people on chronic opioid therapy,

5 or it might escalate over time, or it might

6 escalate faster over time.

7 So, this is fine. Looking at dose

8 escalation is a perfectly good place to start I

9 think if you allowed patients to free titrate to

10 the dose that gives them adequate analgesia.

11 The complexities start to emerge, though,

12 and one of the complexities is side effects.

13 Because the usefulness of the drug, or if you want

14 to call it the therapeutic index of the drug,

15 really depends upon having a dosage range for an

16 individual patient where they can get adequate

17 analgesia without intolerable side effects, that is

18 what we are talking about.

19 If that difference between the dose they

20 need for analgesia and side effects remains in a

21 useful range, that is more useful sign of a

22 medication that is not associated with problematic

23 tolerance. Of course, if both of them escalate

24 equally, then, that is fine, too.

25 Tolerance might even be a good thing. For



1 example, we know from clinical experience that

2 people often become tolerant to nausea and

3 dizziness and neuropsychological side effects, and

4 other bad things, so you may find that, in fact,

5 tolerance can work in your favor. Your therapeutic

6 index may broaden over time.

7 On the other hand, it is conceivable that

8 your does that you need for analgesia increases,

9 but you don't become as tolerant to the side

10 effects, in which case you crash and burn on your

11 drug. They maybe is someone who drops out of your

12 clinical trial.

13 Unless these things are assessed, unless

14 you are assessing adequacy of pain relief, unless

15 you are assessing overall tolerability of your

16 drug, which is never done to my knowledge, and you

17 are modeling how those go over time, then, you

18 can't really say anything about tolerance or you

19 can't make a sophisticated statement about

20 tolerance, to my view.

21 [Slide.

22 So, what do we know from clinical trials?

23 This, sorry to say, I know nobody can read this,

24 but it is just there to give you a visual

25 impression, anyway, these are all the randomized,



1 controlled trials that have been published using

2 non-opioid comparators, placebo or a non-opioid,

3 for chronic, non-cancer pain where we are watching

4 the patients for at least one month. I think that

5 is a reasonable benchmark if you are having a

6 discussion about tolerance.

7 These are all the ones in the published

8 literature. For those of you with good eyes, if I

9 have forgotten one or two, then, you can come up

10 and yell at me after we talk, but this will give

11 you a good visual.

12 I put the asterisks next to the trials

13 where you can learn something about tolerance from

14 the trial, usually because there is a prolonged,

15 so-called open label extension period where

16 patients are watched open label on their drug for

17 some period of time.

18 I will just briefly highlight what it is

19 that we know. Again, here is one trial where pain

20 relief was stable at 19 weeks, don't have dose

21 information, and again, in all these trials, a

22 blurb doesn't really do justice, and you can learn

23 a lot more from getting to the trials themselves.

24 There are people in the room who have been involved

25 with these trials who could probably educate us



1 further about them, but just to give a visual.

2 Here, this is the trial that we did. We

3 found that actually in our patients, only 36 dose

4 and pain relief were stable after an initial period

5 of escalation. This is the Watson and Babul, Najib

6 Babul addressed this earlier today, their very nice

7 study of oxycontin for postherpetic neuralgia.

8 Again, in their open label extension,

9 there was a small subgroup of patients--Najib, you

10 will have to remind me--I think it was about 11 or

11 so out of the 50 patients were still there at the

12 end of follow-up, still enjoying analgesia, and you

13 can go on down the line.

14 The bottom line is that as you follow

15 patients out, here is an example, about 18 months,

16 only 15 of 106 patients still in the trial, still

17 getting good analgesia, still at a stable dose.

18 I think what these sorts of studies tell

19 us is that although none of these studies have

20 actually, to my knowledge, said we define tolerance

21 in this way, this is how we are going to measure

22 it, this is our result. That has never been done,

23 to my knowledge. Somebody can challenge me if they

24 think I am wrong about that, but all we can get is

25 an indistinct window about what happens long term.



1 It looks like only a minority of patients

2 are still on drug over time. Now, should we expect

3 that everyone should be on drug a year later?

4 Obviously not. If you look at trials of NSAIDs for

5 osteoarthritis, you are also not going to have

6 everybody on trial at the end of a year because

7 that's not how it works.

8 People get better people get worse and

9 drop out, people move to Florida, people die of a

10 heart attack, all sorts of things happen to people,

11 but it still suggested to me that--it doesn't

12 really reassure me that tolerance is not a problem

13 in clinical practice--and it suggests to me that we

14 need a methodology for evaluating this

15 prospectively with some rigor.

16 Interestingly, this study, which I put in

17 italics, is a study of tramadol. I excluded

18 tramadol except for this one study for patients

19 with painful diabetic neuropathy, 117 patients.

20 Tramadol is a drug that is an opioid and a

21 non-opioid in the same drug, and clinically

22 speaking, we don't think tramadol is associated

23 with tolerance or at least not much.

24 Interestingly, only 4 out of 117 patients

25 at six months dropped out due to lack of efficacy,



1 which is interesting because that is dramatically

2 different than what we see in the trials of the

3 pure new agonist, and it makes me wonder whether

4 the fact that only a small number of patients are

5 in these new agonist trials is indeed indicative of

6 tolerance developing because we didn't see that to

7 the same extent in the tramadol study.

8 [Slide.

9 Now, this is all speculation, nuance. I

10 think really the only robust conclusion is that we

11 need to start measuring tolerance. Again, just to

12 give you a quick visual of that, what we often see

13 in the way these studies are reported--and again

14 this is whitewash data of not any particular drug,

15 is that as the months wear on, the patients' dose

16 or their pain score, if you want to look at pain

17 scores, remains stable, but the trick is that only

18 a small fraction of the patients are present here

19 that started here, and we no doubt have informative

20 censoring, and can't say too much about long-term

21 efficacy from this type of report.

22 [Slide.

23 In my view, it is fair to say that the

24 phenomenon of tolerance to opioids in the treatment

25 of chronic pain has not been systematically



1 investigated in the published medical literature.

2 [Slide.

3 Neuropsychological function, I outlined

4 the concerns earlier. I am not going to really

5 speak about that because again, there is actually

6 no published prospective controlled trial on

7 opioids for non-cancer pain that has evaluated

8 neuropsychological function.

9 There is a published uncontrolled trial

10 where patients on a hodgepodge of opioids were put

11 on controlled release opioids. That is Jennifer

12 Hathorne Waites [ph] trial that actually suggested

13 in that setting, neuropsychological function

14 improved.

15 There is a study that, Mitchell, you

16 alluded to earlier that you did with Raja and those

17 folks that is still unpublished, that I have heard

18 rumors about, that I have heard rumors is going to

19 reassure us all about neuropsychological function

20 measured in a prospective way.

21 I, myself, have been involved in yet

22 another unpublished trial that I hope will come to

23 light soon, that also will find reassuring, so I

24 think that this is going to probably work out okay,

25 but at this point in time, this remains the fact of



1 the matter.

2 [Slide.

3 One final note on another sort of occult

4 toxicity that has been getting a little more press

5 lately, but hasn't really been addressed formally,

6 is the whole issue of opioids in endocrine

7 function. I think this is actually a very big

8 deal.

9 It is known that in animals, every animal

10 endocrinologist knows this. When I go up an animal

11 endocrinologist and I say, you know, I am a little

12 concerned about opioids and testosterone, they say,

13 da, what are you talking about, we have known about

14 that for 100 years already, about opioids and

15 testosterone.

16 It is known that opioids lower

17 testosterone and actually have other endocrine

18 effects, as well, in animals. There is one study on

19 heroin addicts showing low testosterone levels, one

20 study on methadone maintenance patients showing low

21 testosterone levels, and two studies now of

22 patients on intrathecal opioids showing profoundly

23 lower testosterone levels in men who develop a

24 central or hypogonadotrophic hypogonadism on

25 intrathecal opioids.



1 In the intrathecal studies, those were the

2 only ones that tried to address symptoms, and it

3 does turn out that loss of libido and impotence are

4 associated with low testosterone seen in those

5 trials.

6 In one of the two trials, it was actually

7 a pre-post study where they measured endocrine

8 function before going on intrathecal opioids and

9 then after, showing the declines, so very

10 interesting information. We have known about that

11 anecdotally for a while. In women, we see

12 amenorrhea and infertility, and other things.

13 What are the symptoms of low testosterone?

14 Fatigue, loss of muscle mass, you don't want to get

15 up and go, mood disturbances, osteoporosis and

16 compression fractures, so a potential public health

17 hooked to this.

18 So, has anyone seeing patients with

19 chronic pain ever seen any of these symptoms in

20 anybody? I think that these symptoms are basically

21 universal. So, you would think that somebody would

22 have asked the question of what proportion of

23 patients on opioid therapy for chronic pain have

24 low testosterone levels. You would think that that

25 question would have been asked.



1 [Slide.

2 This is preliminary data from our group,

3 our data, trying to address this question. Again,

4 I am always a little bit nervous about presenting

5 unpublished and non-peer-reviewed data, but I think

6 this is big enough to at least flag your interest

7 in this area.

8 All of my patients on opioid therapy for

9 nonmalignant pain had to undergo an endocrine

10 battery of blood tests at least once a year, and

11 this has been going on for about four years now.

12 There were complete enough data available on 25

13 males. I haven't tried to understand the female

14 data because it is just too confusing.

15 We found that free testosterone, which I

16 think is the more sensitive of the two, was below

17 the reference range in 63 percent of our patients

18 age 25 to 49. This is how the normal testosterone

19 levels come packaged at least at our institution,

20 25 to 49, and 50 to 75.

21 Free testosterone levels were below the

22 reference range in 88 percent of patients age 50 to

23 75, the older group, and our mean LH and FSH

24 levels, compared to normal controls, were below

25 normal, suggesting that the majority of our



1 patients had central hypogonadism, were on opioids

2 for chronic pain.

3 We looked at mean levels compared to

4 healthy controls, et cetera, and also found that

5 they were low.

6 Again, I think this is very provocative

7 and needs to be followed up further by a properly

8 controlled trial, and suggests to me anyway that

9 endocrine dysfunction may actually be the major

10 organ toxicity of opioid therapy.

11 [Slide.

12 Let's not forget about the little

13 symptoms, the garden variety symptoms I spoke about

14 earlier - nausea, vomiting, blah-blah-blah. In

15 clinical trials, we all know how these side effects

16 are captured. They are captured by the passive

17 capture methods. The patient has to raise their

18 hand and speak up and say I am dizzy or I am

19 nauseous.

20 Then, the study coordinator has to write

21 it down. Then, it has to be coded by somebody and

22 put in the database. We know from a variety of

23 sources of information that passive side effects

24 captured like that are inadequate in the sense they

25 don't nearly tell you what you would find if you



1 asked patients how they are feeling.

2 We know that dropouts due to symptomatic

3 side effects are substantial in both acute and

4 chronic pain trials of opioids, and the chronic

5 pain trials that I see, that range from 10 to even

6 50 percent, so it has got to be that these inform

7 the risk-benefit analysis of opioids for chronic

8 pain.

9 We also know that if you look at--I am not

10 going to take the time to present data--but if you

11 do symptom distress assessments prospectively by

12 giving patients a checklist on how they are

13 according to a variety of symptoms, and how severe

14 they are, you can find out a lot more, and you can

15 actually get data that predicts dropouts more

16 accurately than just passive side effects captured,

17 and there are some very nice studies by Richard

18 Anderson and Marsha Testa and other people showing

19 that these are very sensitive measures of how

20 patients are doing.

21 You would think that somebody would have

22 asked the question about how patients with opioids

23 do if you give them a prospective symptom checklist

24 to inventory. We did that in at least a

25 preliminary way in our study that came out in 1998



1 of patients and back pain.

2 We gave them a checklist like this, it had

3 20 items. It had them rate none, mild, moderate to

4 severe, and got a lot of interesting information,

5 which I won't take the time to give you, but one of

6 the interesting things was that we were able to

7 discriminate side effects intensity scores between

8 a high dose and a low dose opioid regimen and also

9 from a nonsteroidal anti-inflammatory drug regimen.

10 So, this checklist analysis did

11 discriminate between regimens. We also found

12 interestingly--I don't really know how to

13 understand this--people on low-dose opioids had

14 fewer side effects, but were more bothered by them,

15 people on high-dose opioids were less bothered by

16 their side effects, strangely.

17 So, it seemed like maybe opioids

18 influences how much you are bothered by whatever it

19 is that ails you. Maybe you understand that better

20 than I do. Anyway, do this, that is what I am

21 trying to say.

22 [Slide.

23 I will end with just a quick comment on

24 the use of opioid sparing as an outcome measure

25 since that was mentioned as a question in the



1 background materials, so everybody knows what this

2 means. You have a drug X compared to placebo or

3 some comparator, and you look at how much opioid

4 the patients in both groups use in outcome measure,what does

5 that mean, is that good, is that bad.

6 First of all, just conceptually, if a

7 patient in one treatment group has decreased opioid

8 requirements, there is a few things that could be

9 due to. The first, which is the one that we are

10 all interested in, is that your study drug is an

11 analgesic. That is good, and the obvious examples

12 there are NSAIDs compared to placebo in

13 postoperative pain, where patient controlled

14 analgesia or other things are very nice

15 discriminative analgesic effect.

16 The other possibility is that your drug is

17 not an analgesic by itself, but together with

18 opioids, enhances opioid analgesia, and some people

19 think that are some NMDA receptor antagonists that

20 might do that. It is hard to discriminate between

21 an analgesic and an opioid enhancer in that sort of

22 model.

23 The other possibility I will just mention,

24 although you maybe you won't like hearing it, is

25 that the study drug, all it does is enhance opioid



1 side effects, so that patients can't use as much,

2 and that certainly is a conceptual possibility

3 although one should be able to tease that out by

4 looking at pain scores and by looking at side

5 effects, if you look at side effects in an

6 appropriate way, which is often not done.

7 So, you have to be able to provide

8 supportive data to classify what is going on in

9 terms of these possibilities, should you have

10 opioid sparing.

11 [Slide.

12 Lastly, is opioid sparing meaningful in

13 your clinical trial. I am remind of the

14 expression, "A difference is only a difference if

15 it makes a difference," and so if you do reduce

16 your opioid dose, does that mean anything.

17 Well, I think it does mean something if

18 the scientific question is whether the drug has

19 analgesic activity in the model that you chose, so

20 for a proof of concept trial, for example, if you

21 are just trying to show does your drug have

22 analgesic effects or not, given the caveats I

23 mentioned earlier, you know, I think that answers

24 your question, but if you are trying to show does

25 the treatment help the patient, which I think



1 ultimately is what we need to have an evidentiary

2 body of information about, the answer is no, by

3 itself, if you are on 10 milligrams of morphine or

4 20 milligrams of morphine, that doesn't mean you

5 are better or not better.

6 You need to show I think, in my opinion,

7 if you are interested in whether the patient is

8 benefiting, some benefit, which could be decreased

9 pain, it could be decreased side effects, which

10 again you are not going to get unless you address

11 in an aggressive way.

12 By decreased pain, we have to be a little

13 bit careful there. The example that comes to mind

14 for me is that we know that in the postoperative

15 setting, opioids work pretty well for rest pain,

16 but not as well for movement-associated pain,

17 whereas, NSAIDs tend to work well for

18 movement-associated pain, maybe even better than

19 opioids in some circumstances.

20 In the postoperative world,

21 movement-associated pain is where the rubber meets

22 the road, because patients get up and rehab

23 themselves and ship themselves out of the hospital

24 these days.

25 So, one could conceive of showing benefit



1 of NSAIDs by focusing specifically on

2 movement-associated pain compared to an opioid-only

3 regimen as opposed to just global pain. As people

4 were saying earlier, just looking at global pain,

5 you may miss the boat on something important.

6 So, I think that opioid sparing, by

7 itself, needs to be looked at very carefully, and

8 you have to really address the scientific question

9 of the study by looking at clinical benefit.

10 [Slide.

11 In conclusion, opioid toxicity, just to

12 recapitulate, opioids are generally safe

13 medications. We don't have 17,000 patients a year

14 dying of GI bleeding in the United States from

15 opioids.

16 So, looking at the big picture, opioids

17 are generally safe medications. I think it is fair

18 to say that the treatment response does appear to

19 be durable in a subgroup. How large is that

20 subgroup, I don't know, and again, tolerance has

21 really not been systematically looked at in any

22 published studies.

23 In my view, symptom distress scales or

24 toxicity scales, especially trying to look at why

25 people drop out, so that you don't have informative



1 censoring going on, must be used to assess the

2 overall treatment effect.

3 Addiction, the major concern in chronic

4 treatment I think has not been investigated, in my

5 view, using any legitimate methods, and

6 endocrinopathies may, in fact, wind up if this

7 preliminary data pans out to be actually the major

8 organ toxicity of opioids as we go forward.

9 Thank you for your attention.

10 DR. FIRESTEIN: Thank you very much, and

11 we will have an opportunity to discuss some of this

12 in a few minutes during our open discussion after

13 the next talk, which is Statistical Issues for

14 Measurements by Dr. Lu.

15 Statistical Issues for Measurements

16 Laura Lu, Ph.D.

17 DR. LU: Good afternoon. I am going to

18 discuss issues in time-specific measurements and

19 time-weighted average for pain in chronic and acute

20 analgesia trials.

21 This discussion is to set a stage for

22 tomorrow's further discussion of endpoints.

23 [Slide.

24 First, I am going to introduce

25 time-specific measurements and time-weighted



1 average. Then, I will discuss issues in chronic

2 analgesia trials for those measurements in terms of

3 interpretation of drug benefit and data imputation

4 methods, and the parallel issues in acute analgesia

5 trials. At the end, I will provide summary.

6 [Slide.

7 I will use an individual patient's pain

8 curve to illustrate those measurements I will talk

9 about. Suppose a patient's pain was evaluated at

10 time 2, 4, 8, and 12, and these vertical segments

11 represent change from baseline in pain scores at

12 each specific time 2, 4, 8, and 12. So, these are

13 what I call time-specific measurements.

14 I will refer to the area under this pain

15 curve as AUC later.

16 [Slide.

17 I denote those time-specific measurements

18 for change from baseline in pain as d1, d2, d3, and

19 d4, and the time intervals between each

20 neighborhood measurements as t1, t2, t3, and t4.

21 [Slide.

22 The time-weighted average can be defined

23 as AUC divided by the patient's treatment period.

24 In another form, it can be also described as a

25 weighted average of time-specific measurements, and



1 the weights are decided by the neighborhood

2 intervals of disorder and the treatment period.

3 That is why we call this normalized AUC

4 measurements as time-weighted average, and one-time

5 weighted average is used as an endpoint we quite

6 often refer to it as AUC approach.

7 [Slide.

8 Now, the issues in chronic analgesia

9 trials. First, the interpretation of drug benefit

10 by those measurements.

11 [Slide.

12 End-of-the-trial measurement is a

13 time-specific measurement. It is commonly used in

14 chronic analgesia trials. It measures drug effect

15 at the end of the trial. Time-weighted average is

16 another endpoint being used. It measures average

17 effect through the trial.

18 The two measurements actually describe

19 different aspects of drug effect, and no matter

20 which measurement is used at the endpoint, the

21 consistency of drug benefit over time is always an

22 important review issue.

23 [Slide.

24 As shown in this graph, when two

25 treatments switch advantage over time, then, there



1 is inconsistent drug effect. In this situation,

2 none of the single measurements can really describe

3 drug benefit for one over the other.

4 [Slide.

5 When there are missing values, for the end

6 of the trial measurements, the last observation

7 carried forward is a commonly used imputation

8 method. It imputes measurement at withdrawal time

9 to later period.

10 For time-weighted average, one would say

11 that there is there is no imputation as long as

12 there is at least one post-baseline measurement,

13 but actually, it is not true.

14 When the patient dropped out earlier, the

15 average treatment effect before withdrawal time

16 will be used to represent the average effect in

17 overall treatment period. So, this is a form of

18 imputation.

19 [Slide.

20 Both of the imputation methods imply

21 assumptions that later evaluations of drug efficacy

22 is similar to that of earlier evaluation. This is

23 a very artificial assumption, and cannot be

24 verified by data we have seen.

25 Also, the results generally favor drug



1 with imputation than without imputation due to

2 different dropout mechanisms in treatment groups,

3 for example, different dropout rates and dropout

4 reasons.

5 [Slide.

6 We have seen those problems with

7 imputation methods. Can we make any improvements

8 in terms of trial design and data analysis? First,

9 I think we should continue efficacy evaluation even

10 after a patient drops out even the patient is on

11 rescue medication, and these measurements can

12 provide additional treatment information, so a true

13 ITT analysis can be performed.

14 Also, if a clinically sensible responder

15 analysis can be performed like a definition can be

16 found, now, we can perform responder analysis in

17 terms of time to respond, percentage of responder,

18 and duration of response.

19 A responder analysis may better

20 characterize drug effect and avoid artificial

21 imputation methods by taking into account of

22 dropout status.

23 [Slide.

24 Parallel issues in acute analgesia trials.

25 [Slide.



1 In single-dose acute analgesia trial, we

2 focus on onset, duration, and pain curves. For

3 multiple-dose acute trial, we focus more on

4 duration of effect.

5 [Slide.

6 In single-dose trials, time-specific pain

7 measurements provide more information about onset

8 and duration, but time-weighted average

9 measurements, such as some of pain intensity

10 difference or some of pain relief and intensity

11 difference do not.

12 So, in single-dose trials, we prefer more

13 of the time-specific pain measurements over

14 time-weighted average. In multiple-dose trials,

15 time-specific measurements and time-weighted

16 average face similar issues as those in chronic

17 analgesia trials, so I will only focus on the

18 imputation methods for time-specific pain

19 measurements in single trials.

20 [Slide.

21 The three commonly used methods we have

22 seen for data imputation are these three -

23 last-observation-carried- forward approach,

24 baseline-observation-carried-forward, and

25 worst-observation-carried-forward methods.



1 The last two methods are generally more

2 conservative than the

3 last-observation-carried-forward approach, but all

4 these three approaches are very unrealistic by

5 carrying forward earlier pain intensity scores into

6 later period. This is against the self-limiting

7 nature of acute pain.

8 [Slide.

9 I will use this example to show the

10 artificial effect of those imputation methods.

11 This is not a real example, but it represents the

12 common scenario we have seen in trials.

13 Suppose patients' pain was evaluated for

14 24 hours after dental surgery, and these two curves

15 represent the mean pain intensity a long time for

16 placebo and the treatment group. These are

17 observed curves without any data imputation.

18 Because of the short duration of dental pain, at

19 the end of 24 hours, no matter how many patients

20 left in the trial, the patients' pain will be very

21 mild, so the mean scores approach zero.

22 [Slide.

23 Now, if we use early pain intensity scores

24 to impute later period, these two red curves

25 represent the imputed curves for pain intensity,



1 and then we got the impression that at the end of

2 the day, the patients are still in pain and also

3 the drug is still effective over placebo, this

4 artificial effect is caused by different dropout

5 mechanism. Mainly it is because more placebo

6 patients drop out in the early stage, and also most

7 of those patients drop out due to lack of efficacy.

8 [Slide.

9 In summary, for chronic analgesia trials,

10 end-of-the-trial measurement and time-weighted

11 average represent different aspects of drug effect,

12 and consistency of drug benefit through the trial

13 is always an important issue for review.

14 In acute analgesia trials, time-specific

15 measurements are more informative than

16 time-weighted average in single-dose trials.

17 [Slide.

18 We should continue to measure efficacy

19 even after patients withdraw, even after patient is

20 on rescue medication, and these measurements can

21 provide additional treatment information for drug

22 effect.

23 Also, if we can come up with clinically

24 sensible responder definition, we can carry out a

25 responder analysis, which may better characterize



1 drug effect and avoid artificial imputation by

2 taking into account the dropout status.

3 Thank you.

4 DR. FIRESTEIN: Thank you very much.

5 Open Discussion of Points #1, 2, 3, 4 and 5

6 DR. FIRESTEIN: Now, we come to the time

7 at the end of the say where there is a spirited

8 discussion, and we can resolve all of the issues

9 that have been raised, so that the FDA can go ahead

10 and make its formal recommendations.

11 Before we move ahead, I just wanted to try

12 to briefly summarize some of the points that have

13 been brought up and then open them up for

14 discussion.

15 One of the issues was the notion of

16 whether or not separate acute versus chronic pain

17 indications has utility not only for drug

18 development, but also for our patients compared

19 with simply a single indication for pain, and also

20 whether or not this should be more mechanism versus

21 clinical indication oriented.

22 With regard to the chronic pain

23 indication, a proposal was put on the table that

24 this could potentially be achieved with a very high

25 bar where three separate indications would be



1 looked at, each with two studies and each involving

2 three separate domains.

3 Notably, there were a couple of

4 alternatives that were proposed during the open

5 discussion or the public forum, one involving two

6 separate indications and then another involving

7 four separate indications, but with only one study

8 for each one.

9 Then, we talked about low back pain,

10 whether or not that would be one of these potential

11 clinical indications for chronic pain, and, in

12 particular, whether or not all low back pain could

13 be lumped together or whether or not there is some

14 rationale for taking the vast majority, which is

15 mechanical low back pain, and then using that as a

16 separate location.

17 Finally, we have talked a bit about safety

18 and the issues regarding dose and indication creep,

19 as well as off-label use. That was raised a number

20 of times.

21 So, those are I think the major issues

22 that are before us right now.

23 DR. MAX: I would like to return to the

24 issue of mechanism-based diagnosis and ask my FDA

25 colleagues about some possible incentives for this.



1 If we go back to Dr. Woolf's talk, he

2 mentioned several dozen molecules involved in pain

3 processing, and actually, we could probably get

4 very close to some mechanisms in patients right

5 now, because imagine, let's say we have the results

6 of a large chronic pain trial, say, in back pain

7 with some novel drug that works on one of those new

8 mechanisms, and overall, there is just

9 nonsignificant trends towards efficacy.

10 However, it is already known that probably

11 half a dozen of the molecules Clifford was talking

12 about this morning have common human polymorphisms

13 with two forms of the molecule, either one made in

14 higher volume expressed with a molecule expressed

15 more or with higher functioning levels of the

16 molecule and with some very common people with less

17 expression or less functional forms of the

18 molecule.

19 So, what if the company could for a few

20 cents an assay take all the pain molecules and

21 characterize the patients as high functional or low

22 functional for that, so what if they do that for a

23 number of different molecules and found that if

24 they just take the subset, say, with a hyperactive

25 NMDA NR2B molecule function polymorphism, in those,



1 the drug really was effective.

2 So, now they have found by dredging a

3 prospective mechanistic-based subset, so they come

4 to you and say, okay, could we now go and do one

5 more study and get approval for this, what might

6 you say to a company like this?

7 DR. GOLDKIND: We might say a number of

8 things. I think that the assay that would

9 differentiate a responder or potential responder

10 from a non-responder has to be something clinically

11 available, so that a doctor can use that in

12 guidance, so it has to be referable to the

13 population. It wouldn't really help a doctor or

14 patient if they didn't have that.

15 In terms of the evidentiary base, is an

16 exploratory analysis adequately supportive of a

17 prespecified primary outcome for a second trial,

18 that has been used before. There is not a global

19 answer to that question, but that is what you are

20 describing is an analysis where a subpopulation is

21 looked at and where you are exploring for an effect

22 on subpopulation, and you identify one, and then

23 you confirm that in a second study.

24 That, I would say is really dealt with on

25 a case-by-case.



1 DR. MAX: With regard to that, I think,

2 you know, the tests themselves now cost like about

3 25 cents a genotype, so the company might even

4 provide that. To say just that you need one new

5 trial for it, that sounds pretty encouraging,

6 because if I just came up and dredged a database

7 with a new hypothesis, I think your earlier

8 guideline, Lee, would suggest you are starting from

9 scratch and you should have two trials for

10 replicate evidence for a new indication. So, if

11 you said that, that would be very encouraging.

12 DR. SIMON: Well, let's be clear. I

13 always like being clear. What we did propose was

14 that mechanistic models that had clinical relevance

15 would be acceptable without further definition of

16 the number of trials that would be necessary. We

17 don't know yet how to go about this. One could even

18 envision that the argument could be that such a

19 design would lead to a definition in only

20 subpopulations, and it would not be extrapolatable

21 to the general population.

22 The down side would be that. The up side

23 would be, well, so what. You have identified a

24 patient population that would respond, you have a

25 clinically measurable test that is clinically



1 applicable and accessible to the treating

2 clinician, so therefore, you can identify the

3 patient that could potentially respond, and that

4 should be something that should be rewarded.

5 We would believe that that should be

6 rewarded. There is nothing in our presentation that

7 precluded a unique way of going about this. All we

8 suggested was in a traditional trial design, that

9 the three-model, two-replicate, three co-primaries

10 would be important.

11 But if a mechanism could be defined, could

12 be reproducible, and could be clinically applicable

13 and available, then, I think all bets are off.

14 DR. FIRESTEIN: I think the key point is

15 that it must be clinically applicable.

16 DR. DAVIDOFF: I was going to say that I

17 have a feeling that the statisticians in the room

18 are having acute epigastric pain hearing that by

19 dredging a single database, you can, in fact, have

20 the basis for approval.

21 I would think that that should be handled

22 with extreme caution and that there should be

23 required at least one replication of a planned

24 trial.

25 DR. WOOD: I would like to return to the



1 opiate sparing issue. I was very concerned that

2 there has been absolutely no discussion of the

3 underlying assumption in these studies, and the

4 underlying assumption in these studies is that

5 there is no alteration in the pharmacokinetics of

6 the opiate induced by the co-administered drug.

7 That may seem somewhat obscure, but when

8 you recognize that erythromycin would be an

9 extraordinary effective opiate sparing drug if

10 administered with fentenyl or that inducing

11 codeine's metabolism to morphine would be extremely

12 effective by some drug with no primary analgesic

13 effect, or more subtle changes, like we can turn

14 Imodium, the anti-diarrheal drug, into a very

15 potent analgesic and a very potent opiate by simply

16 inhibiting the transporter responsible for normally

17 keeping it out of the brain.

18 The ability to have unrecognized effects

19 that have nothing to do with analgesia, I think are

20 substantial. In addition, some of the metabolites

21 that are produced from these drugs produce

22 toxicity, and if they accumulate or are induced,

23 they are likely to produce side effects that may or

24 may not be recognized as being due to the

25 metabolites.



1 So, it seems to me that there is an

2 absolute necessity in an opiate sparing trial that

3 we have a standard that dictates that the drug does

4 not produce some pharmacokinetic interaction. That

5 is tough actually. It is relatively easy to define

6 the obvious ones like the drug concentration in

7 plasma doesn't increase.

8 It is much harder to do that in, for

9 example, supposing Imodium was on the market--well,

10 it is on the market over the counter--we can turn

11 Imodium into an extraordinarily potent sensory

12 acting opiate by simply administering drugs that

13 inhibit the transporters.

14 That is not something you would spot from

15 an obvious plasma concentration time profile. So,

16 I think there is a great danger in an overly

17 simplistic analysis of opiate sparing as an

18 endpoint, and there needs to be independent data

19 that demonstrates that the drug has analgesic

20 effect on its own.

21 DR. FIRESTEIN: Maybe Dr. Katz can address

22 that concern with regard to the pharmacokinetics

23 and opiate tolerability, and then Dr. Farrar, if

24 you had anything to add, that is.

25 DR. KATZ: I agree.



1 DR. FIRESTEIN: Thank you.

2 DR. FARRAR: I think the point about the

3 use of opioid sparing as a potential measure is an

4 important jumping-off point to consider what was

5 brought up in the last two discussions, the last

6 one in particular, which is that what is it we are

7 trying to do here.

8 I would argue, as I think Dr. Katz did

9 very nicely, that opioid sparing might be a nice

10 way to at least think that maybe the drug has some

11 effect, but ultimately, what we are interested in

12 is making the patient better.

13 At the end of the day, whether you are

14 using a specific protein that you assay to identify

15 a group in which people get better, which I think

16 is a great idea and hopefully will pan out, but at

17 the end of the day, we really need to decide what

18 it is when a patient gets better.

19 I would ask Mitchell, in terms of the

20 situation that he is talking about, would you want

21 a particular group to respond a lot or a little,

22 does it matter whether you have got a BRAC gene, so

23 that you have got a 90 percent chance of developing

24 breast cancer or a 90 percent of responding to a

25 drug, or does it matter whether you have got a 51



1 percent chance of responding to the drug, because I

2 think no matter how we slice this and no matter how

3 we look at it, at the end of the day, we are left

4 with the issue of does it make the patient better

5 or not.

6 You can use any statistical technique you

7 like or you can use any analytic technique you

8 like, you can use any assay technique you like, but

9 we can't escape that issue.

10 In terms of the discussion today, we have

11 talked about a lot of different mechanisms, and I

12 wonder what these people's thoughts are on that.

13 DR. FIRESTEIN: Janet and then Dr. Katz.

14 DR. ELASHOFF: In terms of the data

15 dredging to find a subgroup that you then test in

16 that subgroup, and that that might be a very good

17 way to find subgroups in which it does, in fact,

18 work, from a statistical point of view, the

19 likelihood of the second trial coming out should be

20 pretty small because you are mainly picking up

21 false positives with that kind of multiplicity of

22 testing, so that it might be that the first 5, 10,

23 15 times somebody tries that, it doesn't pan out in

24 the second trial.

25 DR. KATZ: I just wanted to add one more



1 point about the opiate sparing trials, because I

2 don't want us to leave the discussion with having

3 trivialized the opioid sparing. I mean there are a

4 number of clinical scenarios in which you have to

5 give the patients concomitant opioid therapy with

6 whatever your analgesic of interest is.

7 For example, in the postoperative

8 thoracotomy or postoperative pain setting, it would

9 be unimaginable to not allow the patients to have

10 access to opioids, and the setting of cancer pain

11 would be another example.

12 So, you often have to co-administer your

13 study drug with an opioid analgesic, and then

14 opioid sparing is a natural thing to look at. So,

15 having said that, there are reasons to look at

16 opioid sparing, but the bottom line is that you

17 still need to decide whether or not your patients

18 are better on your study drug.

19 DR. WOOD: A patient would not be better

20 on a study drug just because you inhibited fentenyl

21 or fentenyl's metabolism. I mean that is exposing

22 them to the same dosage exposure as they would have

23 got from a higher opiate dose, and we need to make

24 that distinction.

25 DR. FIRESTEIN: And the patient wouldn't



1 necessarily be better, they would just use less

2 opiates.

3 DR. KATZ: That is exactly my point and

4 that if it was just a pharmacokinetic interaction,

5 presumably, the patients would be the same. Your

6 outcome measures would fail to show in that case

7 that your patient was better off despite the opioid

8 reduction, and it should be considered a failed

9 trial. That is what I am trying to say.


11 DR. SIMON: In fact, that is the

12 conundrum. We are confronted in proposals to look

13 at the question of opioid sparing as a primary

14 outcome, and the reason we ask the question for

15 this debate was we don't know what to do with that,

16 (a) we don't know what is minimally clinically

17 important decrease - is a 3 mg decrease, a 30 mg

18 decrease clinically important unless you tell us

19 what the measures are that tell us that it is

20 important, meaning is the patient more aware, are

21 they able to walk faster, is the recovery

22 postoperatively improved, is there less pneumonia,

23 if, in fact, pneumonia is an issue.

24 These are the issues that have to be

25 clinically relevant to make a measure, such as a



1 change in opioid use, important, and that

2 discussion is no different than the one that was

3 raised by Mitchell just before.

4 The measurement of a receptor change or

5 whatever is really not different than the

6 measurement in the change in how much morphine that

7 one might use unless there is a change in the

8 clinical relevance and an improvement to the

9 patient care.

10 I just want to make it clear to Dr.

11 Davidoff that we would not be looking at only one

12 unique database for such an event. One would have

13 to define clinical relevance by multiple databases.

14 Thank you.

15 DR. FIRESTEIN: Dr. Davidoff and then Dr.

16 Brandt.

17 DR. DAVIDOFF: I was really just going to

18 say essentially the same point about opiate

19 sparing, that it might not be necessary to find

20 better overall pain relief, but fewer side effects

21 associated with it.

22 After all, some of the major distinction

23 between antidepressants is not that there is

24 overall better therapeutic efficacy between SSRIs

25 and tricyclics, but that there are fewer side



1 effects.

2 DR. BRANDT: I think this whole discussion

3 on opioid sparing is very interesting, but I would

4 suggest that in the context of the meeting, it is

5 perhaps a little too narrow, we could raise the

6 same issues with regard to NSAID sparing or chronic

7 NSAID use.

8 DR. SIMON: So, in that case, Dr. Brandt,

9 would you propose that a primary outcome for a new,

10 perhaps analgesic that would not have opioid

11 effects and would not have the traditional effects

12 one associates with the traditional nonsteroidal

13 anti-inflammatory drugs, could use as an outcome

14 measure for primary approval, the decrease in

15 requirement for the rather ineffective nonsteroidal

16 anti-inflammatory drugs?

17 DR. BRANDT: When you consider the side

18 effects associated with NSAIDs, the answer is yes.

19 DR. WOOD: But only provided you have

20 demonstrated it is not just due to a simple

21 interaction.

22 DR. BRANDT: Surely.

23 DR. FARRAR: At the end of the day, it

24 makes no difference if you reduce the opioid or the

25 NSAID. What makes the difference is whether the



1 patient is better, and if they are better, as Dr.

2 Davidoff was suggesting, because the side effects

3 are better, that is better. It is not that they

4 are using less of one drug or another drug.

5 It really doesn't matter. I mean I agree

6 with you, and I am not arguing the issue about

7 opioid sparing, I think opioid sparing is

8 suggestive at best, and you clearly need to

9 differentiate between the amount of opioid that

10 they are actually taking orally and the amount

11 absorbed and the amount that is reaching the active

12 sites and the amount that is causing the effect,

13 and there are lots of drugs in which you get the

14 buildup of toxic byproducts, as well.

15 But at the end of the day, what you really

16 need to know is whether that patient postsurgically

17 had a better experience with the combination of

18 drugs that you gave than if you didn't.

19 How you define better depends on the

20 circumstances that you are looking at, but I think

21 there are clearly lots of indicators that we can

22 use to look to see what we should be measuring and

23 how we should be measuring. But at the end of the

24 day, the question is, is the patient better, would

25 I want to give that patient that drug the next time



1 around because they said, you know, I had three

2 surgeries so far, this was the best experience I

3 had so far.

4 That was very true with epidural

5 anesthesias. I mean there is absolutely no

6 question that people post-op with thoracotomies did

7 better because they were able to breathe better, et

8 cetera, et cetera. How much opioid you gave them

9 didn't make a difference.

10 DR. FIRESTEIN: Dr. Sherrer and then Dr.

11 Anderson, Dr. Strand.

12 DR. SHERRER: I think that at the end of

13 the day, it is, is the patient better. I think

14 that is very important, but I also think we need to

15 consider some of the social issues with the chronic

16 use of opiates, that impact on whether the patients

17 are actually better.

18 We have many patients who are afraid to

19 take opiates because of the issue of addiction, and

20 there are many physician who are afraid to

21 prescribe opiates because of the issue of

22 addiction, and the bottom line of that is it

23 impacts on whether the patients are better, because

24 if they are not going to take the drugs or if the

25 drugs are there and the physicians are afraid to



1 use them, then, it is not going to make the patient

2 better even if theoretically they could.

3 So, I think we do need to look at this

4 issue of addiction and tolerance, and what is the

5 relationship more, and what I am hearing is that we

6 can't really define that well enough to do that, or

7 at least we don't have measures of predicting or

8 defining addiction.

9 I think that is very important. One of

10 the major issues with the use of opiates and

11 chronic pain is whether, despite those six studies

12 that you showed us that suggest there is not

13 addiction, there is still fear on behalf of

14 physicians and patients that there is addiction and

15 that tolerance itself may lead to addiction.

16 DR. ANDERSON: My concern is about what

17 you were saying just now, about the patient, at the

18 end of the day, the patient being better, and that

19 if this was solely in terms of having fewer side

20 effects, that was okay.

21 I didn't like that, I guess because, you

22 know, side effects don't happen, you know, happen

23 sporadically or should happen sporadically, but

24 efficacy is something that one would hope would

25 happen in a large proportion of patients.



1 Historically, the FDA has kept efficacy

2 and safety, I mean they are linked, but they are

3 not considered the same thing, and it bothers me

4 that a drug combination could be considered could,

5 not because it was efficacious, but just because it

6 had fewer side effects. I may be misunderstanding

7 what you are were saying.

8 DR. FIRESTEIN: In some cases, the side

9 effects are mechanism based, and that is a

10 situation where it would be optimal to lower the

11 dose. So, for instance, with opiates, constipation

12 or nausea or vomiting, those are clearly based on

13 the pharmacology of the molecule, and so if one can

14 get past those by using a lower dose, and using

15 another adjunctive therapy, then, there would be

16 some benefit to the patient.

17 Dr. Strand.

18 DR. STRAND: I would just like to say this

19 reminds me of some steroid sparing discussions that

20 some of us have had in the past, and it seems to me

21 that it is all find and good if we can decrease the

22 dose of opioids or the dose of steroids, but if, in

23 fact, there isn't some benefit that is measurable

24 in addition, in terms of patient-reported outcomes

25 of efficacy and/or tolerability, then, I don't know



1 that we have demonstrated very much of anything.

2 The other point that I would like to make

3 is that I think data dredging is not the way we are

4 going to get approvals or try to look at different

5 ways of approving products, say, in chronic pain,

6 or possibly even subacute pain or whatever we are

7 calling it, but there is room to develop these

8 analyses from the Phase II data, particularly since

9 there is much more emphasis on doing better Phase

10 II trials, dose finding and dose interval finding

11 or schedule.

12 From that point of view, one could, in

13 fact, develop evidence-based, responder type of

14 outcomes, or one could combine certain outcomes for

15 a certain type of response in the Phase III trials.

16 That has been done before.

17 DR. FIRESTEIN: Dr. Cush and then Dr.

18 Farrar.

19 DR. CUSH: My summary of what I heard

20 today that I would hope that the Agency would take

21 away is I think that we are probably still wedded

22 to some of the methods of the past, and that would

23 be acute and chronic indications and some of the

24 primary outcome variables that have been used for

25 those indications, but that we hear that the



1 science has come along and we would like to see

2 mechanistic issues being raised, may be secondary

3 outcomes measures where applicable, and that would

4 be ideal as we move forward and designing better

5 trials that mean something.

6 Secondly, I think that making low back

7 pain a priority and either incentivizing that or

8 requiring that in some way would be nice, and

9 lastly, the words of Dr. Carr reminded me of

10 something that Ted Pinkus said at a meeting that I

11 think Lee and I were at, which is that as

12 clinicians and biometricians we have done a good

13 job in defining outcomes and coming up with

14 acceptable measures, but we have missed the boat

15 because we are still not at a point where clinical

16 trials are approximating what goes on in the

17 office, so clinicians and patients won't understand

18 an ACR-20 or a WOMAC, and whatnot, and at the

19 Agency, I think it could go more towards that

20 direction, I think it would also further not only

21 clinical trials, but patient care, as well.

22 DR. FARRAR: To take off from what was

23 just said by Dr. Cush and perhaps try and persuade

24 Dr. Anderson that there may be some aspects of this

25 that don't apply to everyone.



1 I agree with you. I think, Dr. Cush, that

2 making the trials understandable to the clinical

3 circumstance is of paramount importance, so that

4 when I, as a clinician, sit down with my patient, I

5 know what to do, and I don't just know that

6 patients got better on the WOMAC by an average of

7 4. I don't know what that means now, and I know

8 what the WOMAC is, even use it.

9 I think, though, the issue that I wanted

10 to bring up more specifically is that what Dr. Max

11 was suggesting was not, I think, that data dredging

12 should be used as the sole purpose or the sole way

13 in which a drug should be approved, but that it be

14 used as a hypothesis-generating event, and I think

15 that makes sense.

16 Then, he was trying to see whether one

17 trial after that would be enough in terms of

18 stimulating that kind of research, and I agree that

19 there is issues there on whether it is one or two

20 can be debated.

21 What he was getting at, though, was that

22 with a 50 by 50 slab of gel, you might be able to

23 tell what the makeup of that patient is with

24 regards to their response. This gets at what Dr.

25 Anderson I think was saying was that, in fact, the



1 drug that we use has to be good for lots of people,

2 and we are getting to the stage now where we are

3 developing drugs, especially in neuropathic pain,

4 perhaps not so much in arthritis, where individuals

5 who respond to a single drug are a minority of the

6 patients that we are treating.

7 You can look at that two ways. One is we

8 just don't know how to predict who is going to

9 respond, and that is very true. If we could

10 predict who was going to respond, then, 100 percent

11 of those patients would respond, but the clinical

12 fact is that people see arthritis, they don't see

13 the variance of the arthritis that we might able to

14 see here.

15 People see pain. They don't see the

16 variance and the subtleties of it that an expert

17 might see, and they treat them with the medications

18 that we have.

19 There are some very good examples in

20 postherpetic neuralgia and diabetic neuropathy

21 where drugs that are clearly effective worked in

22 about a third of the patients treated. About a

23 third of the patients got a moderate or better

24 improvement. That is 1 out of 3 and if I am

25 treating in the office, and only 1 out of 3 people



1 get better, I am might decide that is not the right

2 drug.

3 On the other hand, I might look at it and

4 say 1 out of 3 in something where nothing else has

5 worked, that is really good. The same applies in

6 arthritis in that there are clearly differences

7 between the NSAIDs, and they are not as dramatic

8 perhaps as the differences in the anticonvulsants,

9 but there are differences, and it may be that one

10 group responds better to one kind of NSAID and a

11 different one to a different.

12 So, the idea that we have to somehow have

13 a drug that works in 50 percent or 70 percent of

14 our patients in clinical trials is not I think the

15 issue. I think the issue is being able to identify

16 the people in whom it does work, and it really

17 works, not just a little, but it makes them really

18 better.

19 DR. FIRESTEIN: Dr. Dionne and then Dr.

20 Abramson.

21 DR. DIONNE: I have heard the phrase

22 "end-of-the-day" mentioned a few times. I am

23 struck by the fact that this is the end of the

24 first day that was supposed to be devoted to

25 chronic pain, and I have heard a minimum consensus



1 of opinion on some of the issues that were raised

2 for the Agency, and I would be afraid that they

3 might go back up Rockville Pike and disappear into

4 the back room, so to speak, and come back in four

5 years or 10 years, as Al Sunshine said it took last

6 time, with a document that reads like the Ten

7 Commandments.

8 I am wondering, is there room for

9 discussion of the processes that might allow us to

10 resolve some of these issues based on some sort of

11 a scientific process rather than an opinion-based

12 process.

13 For example, the 125 pain measurement

14 scales that Dan Carr mentioned are ones that it

15 would be hard to imagine we could sort through and

16 just by opinion say these are the two or three that

17 should work, yet, we are still using Category and

18 VAS, which are as old as the drug classes we use to

19 test them on, ignoring all the new technology,

20 which might include the electronic diary we heard.

21 Other outcome measures, how would we go

22 about getting at which ones are desirable, let

23 alone grappling with the issues like analgesic

24 combinations, what would be the criteria for those.

25 That was an issue that raged all through the 80s.



1 I am not sure whether it got resolved or people

2 just stopped trying to get combos of NSAIDs and

3 opiates put together.

4 Is there room for some discussion of the

5 process that the Agency might use to arrive at from

6 where they are now to where they would be when a

7 document appears?

8 DR. FIRESTEIN: Is there room, Dr. Simon?

9 DR. SIMON: There is always room at the

10 table. I think that this meeting and two meetings

11 that have been held by the Advisory Committee of

12 170, talking once about neuropathic pain and issues

13 about opioids reflects the fact that we are very

14 interested in dialoging with the community, the

15 patient community, about these particular areas.

16 We are talking on a regular basis, and

17 will be talking on a much more regular basis, with

18 the individuals in the FDA who are interested in

19 pain and issues regarding pain, particularly the

20 other Division 170, and coming up with a consensus

21 as much as we can as it relates to the various

22 different products that we are assigned

23 responsibility for, and those products that we can

24 possibly imagine will be developed in the future,

25 to then lead us towards a document.



1 Furthermore, there are discussions that

2 are ongoing with the NIH about establishing a

3 meeting to discuss outcome measures, both acute and

4 chronic, addressing issues regarding function

5 versus health-related quality of life that need to

6 be addressed before we can put pen to paper to try

7 to design and craft a document that will fulfill

8 all the needs that we have been talking about just

9 so long today, not the less tomorrow.

10 So, that is the process. The process has

11 got a was to go. We have got more internal debate

12 to do, more external debate to do, more to learn,

13 and to address Ray's issue of going to the evidence

14 and the science using the science as we interact

15 with the group at the NIH, in understanding more

16 about outcome measures as we did at the last March

17 meeting. So, that is the process.

18 DR. FIRESTEIN: Steve.

19 DR. ABRAMSON: I guess part of the process

20 I would like to express is that we have this

21 dilemma of wanting, at the end of the day, to do

22 the best globally for the patients, and yet we are

23 confronted by very specific syndromes that differ,

24 and we have an iterative process to get a global

25 overarching kind of indication, but, in fact, that



1 iterative process is going to take a lot of very

2 focused specific kinds of analyses of different

3 pain syndromes, developing clinical criteria of

4 those syndromes, the way we have done in other

5 diseases, in OA, and outcome measures, as Mitchell

6 was getting at, even prospectively looking at

7 certain biomarkers in those areas.

8 So, I think it is a time of great

9 opportunity to look at different pain syndromes, to

10 use this new development of analgesics as a way to

11 use the clinical trial tool to answer questions

12 that are mechanistic.

13 Part of the dilemma, the conflict is that

14 one does not want to get a global approach too

15 early without this iterative process having been

16 gone through to really understand these different

17 diseases, which, in fact, are quite distinct one

18 from another, even in the musculoskeletal, so that

19 is just the process comment.

20 Going to back to Dr. Anderson's, and Dr.

21 Katz mentioned this, and it is a very focused

22 question, back to the opioid use as a surrogate

23 endpoint. There is a difference I think between

24 what is good for the patient at the end of the day

25 versus the regulatory agencies need to determine



1 whether a drug is efficacious.

2 Absent the metabolic effects of opioid,

3 metabolism, for example, and drug-drug interaction,

4 the question still is, is opiate use a legitimate

5 endpoint, primary, secondary, by which you can

6 judge the efficacy of a new drug.

7 That doesn't mean whether the patient is

8 better to be on one or two, and I think you alluded

9 to this, but I am not sure sillet [ph] isn't a

10 valid measure. I don't know about the area, but it

11 is worth discussing, which is not the patient's

12 contentedness with their combination of drugs, but

13 whether it's a tool, an instrument to judge the

14 validity of a new drug being presented to the FDA.

15 I am just curious what people think. I

16 don't know if I want to open that up to

17 discussion, it is just kind of a comment.

18 DR. FIRESTEIN: That is another major area

19 of discussion in and of itself. One of the reasons

20 that the Division gathered this meeting was to

21 address certain specific questions, and as we are

22 getting towards the end of the day, although it is

23 only 1:30 in San Diego right now, so I am just

24 waking up, I think.

25 From what I heard said, I don't know



1 whether or not it can at least try to offer some

2 more concrete guidance or at least advice to the

3 Division with regard to some of the key questions,

4 and one is whether or not there is, in fact,

5 utility to having acute and chronic pain as opposed

6 to just pain as a potential indication.

7 It seems to me that that is not an

8 unreasonable approach, and I was wondering if there

9 is any additional discussion that would help sort

10 that out or if people are relatively comfortable

11 with that.

12 DR. ASHBURN: I would say yes with the

13 caveat that the definition goes away from time

14 lines with regard to duration of the pain, and kind

15 of goes towards the acute versus chronic pain

16 definitions that Dr. Woolf presented to us earlier

17 this morning with regard to pain that is expected

18 to be of short duration with some expectation that

19 it goes away over time.

20 Again, that goes towards a concern that

21 chronic pain states sometimes can be rapid onset

22 and can deserve study and therapy early rather than

23 late in their time line, and should not wait three

24 or six months prior to being allowed to include

25 patients for investigation, and the example, that



1 is, patients with postherpetic neuralgia or with

2 cancer pain.

3 DR. FIRESTEIN: I think that is an

4 excellent point, and again raises the question of

5 an acute persistence pain and acute chronic--I

6 don't know.

7 DR. ASHBURN: One terminology that comes

8 to my mind when we talk to medical students about

9 this concept is short-term pain versus long-term

10 pain, and the perception of getting away from the

11 terms acute and chronic, which mean different

12 things to different people, but rather, the

13 expectation of whether this pain is of short

14 duration, of limited area, whether or not the

15 expectation is, unless one intervenes on the

16 patient's behalf, that the pain will persist over

17 long periods of time.

18 DR. FIRESTEIN: Dr. Borenstein.

19 DR. BORENSTEIN: Well, one of the points I

20 wanted to make is what happens in the clinical

21 trial situation and what comes into the clinic. I

22 think all the basic scientists would agree if you

23 can attack pain early, you would like to keep it

24 from becoming chronic, so intervening as early as

25 possible in the process to keep that from happening



1 may have a mechanistic way of trying to keep

2 chronic pain from appearing, but if the patient

3 appears to you already with a process which seems

4 to be chronic pain, then, I think what you may find

5 to be effective there may be somewhat similar to

6 what you would use in the very acute circumstance,

7 but you may need more interventions at that point

8 to really make a difference in that individual.

9 So, what you would do if you had someone

10 who was your patient over time, you would treat

11 them differently than you might if you find them

12 later on in the process when you have them as your

13 patient.

14 DR. FIRESTEIN: Brief comment from Dr.

15 Farrar and then Dr. Katz.

16 DR. FARRAR: There are I think two

17 important components of this, and very briefly, one

18 is just to remind us that acute and chronic are

19 time frames and that the acute pain and chronic

20 pain does not necessarily imply acute treatment and

21 chronic treatment, and I think that those two

22 things are very different in terms of thinking

23 about the safety of a drug and the overall use.

24 The second issue I think has been brought

25 out before, but would suggest that what we are



1 really talking about is reversible pain versus

2 non-reversible, and there are certainly syndromes

3 which occur and can, as I was learning at lunch

4 today, snake bites last an awfully long time. If

5 you don't know what I am talking about, you will

6 find out at dinner, I guess.

7 But the point is that there are pains that

8 occur for a very long time, but are reversible and

9 are treated aggressively, and there are acute types

10 of pains best brought up I think by Clifford

11 earlier, which is that, you know, trigeminal

12 neuralgia is an acute pain that is very, very

13 different than postsurgical pain.

14 I think that it is very important to

15 differentiate, but we have to be careful about the

16 way in which we do that.

17 DR. KATZ: I was going to make a similar

18 point, I think, which is that when we think about

19 treatment of acute pain, the way it actually works

20 out very frequently in real life is that patients

21 are actually treated for months often for their

22 so-called acute pain, which we normally might think

23 of as just a few days. Thoracotomy, you know, 50

24 percent of patients six months after a thoracotomy

25 have moderate to severe pain, spinal fusion



1 surgery, the patients are often on analgesics for

2 six months or a year, knee replacement, et cetera,

3 et cetera.

4 So, I think it is also worthwhile keeping

5 in mind that how is the medication likely going to

6 be used in practice, and the trials that are done

7 to support that use ought to have some relationship

8 to the actual way that they are used.

9 DR. FIRESTEIN: A couple of more brief

10 comments over here and then we will go to the next

11 point.

12 DR. WOOLF: It seems to me, coming back to

13 the issue of what encouragement we can give to the

14 Agency in terms of development plans, we have heard

15 from Dr. Farrar that 30 percent of these patients

16 may respond to a certain treatment, and he has no

17 way of predicting at the moment who those patients

18 may be.

19 My plea would be that in any discussion

20 with the industry in terms of any development plan,

21 as we are in this transition mode from a rather

22 empirical approach to the management of pain to one

23 where mechanisms can be identified, is to try and

24 get as much information as possible.

25 While, on the one hand, of course, we all



1 agree we want the patient to feel better and we

2 need some global measure of that, but the point I

3 was trying to make this morning was that there are

4 many aspects of a pain that are simply ignored in

5 trials and that may be very useful in terms of

6 seeing whether patients do respond in different

7 ways to different forms of therapy.

8 So, I think part of the process has to be

9 not to prejudge and to try and gather as much

10 information as possible from the patient as to what

11 their pain is composed of and how different aspects

12 of the pain respond to different therapies.

13 DR. DIONNE: I think Clifford just said

14 what I was going to say, but let me just try to

15 restate it. If the Agency is interested in

16 mechanisms, and if we think the way to the future

17 is having a better understanding of the mechanistic

18 process by which a new drug works rather than just

19 extrapolating from animal models which may or may

20 not be relevant, would there be a possibility of

21 developing some sort of incentive into the claim

22 structure or the approval process that would give

23 greater favorability to coming up with a rational

24 study of the mechanism underlying an acute drug

25 versus a chronic drug, so you might discover, in



1 fact, as has been stated all day, that some drugs

2 may be actually acting on a chronic pain mechanism

3 that may be starting at the first day or two, and

4 this may have long-term benefit for preventing the

5 pain a preemptive fashion rather than having to

6 wait two or three months and then try a treatment

7 that is ineffective because that mechanism is no

8 longer active.

9 So, have some mechanistic approach built

10 into the acute versus chronic studies that allows a

11 little bit of information to be gathered, and the

12 best way to harness the resources that the industry

13 could bring to that, of course, would be to have

14 some sort of incentive in the approval process for

15 that.

16 DR. CALLAHAN: I was just going to say I

17 think you made a compelling argument this morning

18 about the mechanisms, but if we don't have the

19 instruments to measure the components, is it fair

20 to ask the industry to look at those components

21 until those measurements are available, or should

22 we go with the global and ask them to look at that

23 sort of in a secondary fashion as they evaluate the

24 new drugs that are coming on.

25 DR. FIRESTEIN: This really brings us to



1 the second question, and that is, whether one

2 focuses on mechanism-based indications of clinical

3 indications, and by and large, over the course of

4 the day, most of the emphasis is that while

5 mechanism-based indications are of tremendous

6 interest, the science isn't there yet in order to

7 use that as the touchstone for specific drug

8 approvals, and that we still are relying primarily

9 on clinical situations and clinical indications

10 even at this point.

11 I was wondering if again there was any

12 comment or disagreement for that. Did you want to

13 comment on that?

14 DR. KATZ: I agree that right now it is

15 premature to begin a drug development program for

16 pain due to excitable nociceptors or central

17 sensitization or something like that, but one has

18 to be careful not to just by default allow any

19 clinical classification system.

20 Some of them make a lot more sense than

21 others. For example, the idea of having a

22 medication for cancer pain makes no sense to me

23 whatsoever, because some people with cancer pain

24 have a brachial plexopathy from tumor invasion,

25 some people have bone metastasis, some people have



1 visceral obstruction with almost no connection

2 whatsoever.

3 So, to me, that would not make a lot of

4 sense specifically because the mechanisms are so

5 different among those different types of pain, so

6 again, you can't forget the mechanism either,

7 whereas, musculoskeletal pain, it seems to me that

8 medications that work for one kind of

9 musculoskeletal pain tend to work for another -

10 osteoarthritis, rheumatoid arthritis,

11 non-neuropathic low back pain, et cetera, I would

12 suspect because the mechanisms are similar in those

13 disorders.

14 I don't think that you can just allow any

15 clinical classification system, but you can pick

16 and choose from ones that make more sense.

17 DR. MAX: I just want to mention what I

18 heard Lee Simon and Larry Goldkind saying a few

19 minutes ago seemed very new, that they said that if

20 they get some novel evidence about how can you

21 reliably predict response with a new mechanistic

22 test, they have the authority to approve it after

23 the post-hoc searching with one new prospective

24 trial, and since it so new and they don't have to

25 maintain a level playing field when there aren't



1 many other things, every situation is unique, it

2 sounds like it is a real green light for industry

3 to try to be imaginative and scientifically

4 creative. That is the first time I have heard

5 that.

6 DR. FIRESTEIN: I would not overinterpret

7 those comments.

8 [Laughter.]

9 DR. FIRESTEIN: It is clear that exciting

10 new discoveries, novel targets that have clear

11 proven efficacy in clinical situations can move

12 very quickly into the clinic, into approval.

13 An example of that would be some of the

14 TNF inhibitors for rheumatoid arthritis. Under

15 those circumstances, I suspect that what you

16 envision would be possible although I wouldn't dare

17 speak on behalf of the Agency--well, I think I just

18 did.

19 This actually brings us to the other sort

20 of difficult problem, and that is the notion of if

21 there is going to be a chronic type of indication,

22 what is the benchmark for that. I don't know what

23 the right answer is. We have a couple of different

24 possibilities. I didn't know if anybody on the

25 committee had specific recommendations.



1 From my own perspective, I was intrigued

2 by the proposal of the four different indications

3 with single studies, because if you are using

4 chronic pain as the actual indication, then, you

5 are not going for the separate indication of OA

6 versus something else. You are using chronic pain

7 as the indication, and the second confirmatory

8 study would be in a different indication.

9 So, there is actually a rationale and

10 maybe a middle road whereby you actually require

11 fewer studies, but more indications.

12 I would want to know if anybody had a

13 comment there.

14 DR. WOOD: As written here, it seems to me

15 to be counterintuitive. It seems to me that to put

16 a bar up that says you have to demonstrate, for

17 example, response in low back pain and diabetic

18 neuropathy and cancer pain, seemed to me to be

19 counter to everything we have discussed in terms of

20 mechanisms.

21 It would seem to me that demonstrating

22 that a drug is effective in multiple indications

23 demonstrates just that, that the drug is effective

24 for multiple indications, and at that point,

25 physicians can and do make decisions every day



1 about extending the drug's use into other

2 indications for which it has not been tested.

3 But making the leap in terms of a labeling

4 for indications for which it has not been tested

5 seems to me something that has never been done in

6 any other setting. I don't see even why you need

7 to do it. If you have studied the drug in four

8 indications, that is normally what you label it

9 for.

10 Just to follow that up, the ACE inhibitors

11 were all approved for the treatment of heart

12 failure with subtle differences in the indications

13 for which they were approved, reflecting the

14 studies that were actually done.

15 That hasn't obviously affected their use

16 in these indications.

17 DR. FIRESTEIN: Dr. Woolf and then Dr.

18 Goldkind.

19 DR. WOOD: I find myself feeling a bit

20 uncomfortable with this notion that there is going

21 to be a global chronic pain analgesic. I think it

22 goes against everything we know and everything that

23 we are beginning to understand, and I think that is

24 exactly what your comment relates to.

25 So, which four different indications would



1 you need in order to make sure that it was global?

2 How many neuropathic pain and how many

3 musculoskeletal pain, what is the balance that one

4 would feel comfortable with, that would encompass

5 all forms of chronic pain that crossed all

6 mechanisms?

7 I don't think we have a consensus on that.

8 I think that if one were careful in selecting four

9 indications that were predominantly

10 musculoskeletal, that would leave you with a

11 situation where you may have a drug with an

12 indication for chronic pain that would still not

13 work in many patients who have postherpetic

14 neuralgia or diabetic neuropathy or radicular pain.

15 DR. FIRESTEIN: Well, the FDA would have

16 to think very carefully about how one would choose

17 those particular indications, it seems to me.

18 You were going to make a comment.

19 DR. GOLDKIND: In response to Dr. Wood's

20 comment, our current reality is that we are

21 approving drugs as analgesics, and there is an

22 assumed generalizability, and that is part of why

23 we wanted to discuss this, but we do see drugs that

24 have dental pain and maybe one particular post-op

25 setting that form the pivotal basis for approval.



1 They are marketed as analgesics and even

2 if we describe the particular pain settings or

3 model, depending on semantic difference, in the

4 Clinical Trial Sections, so people know where the

5 evidentiary base came from, it still is an

6 analgesic indication.

7 This lumping and splitting, we play out

8 all the time, and we do want to optimize that.

9 DR. FIRESTEIN: But that is precisely why

10 the bar is so high potentially for a true global

11 chronic pain indication.

12 DR. MAX: I am very sympathetic towards

13 setting such a high bar for general chronic pain

14 claim. That is the part of Lee's proposal that I

15 love, and I think it is because of this syllogism.

16 When I talk to company marketing people,

17 they say we would really like a chronic pain claim,

18 or even if it is neuropathic pain, a generalized

19 neuropathic pain claim, because we can send our

20 marketing people and our detail men and sell more

21 drug, and have higher profits, and I think the

22 logic is that incentive would lead to many more

23 trials and from multiple trials, multiple trials in

24 many different disease conditions are the best way

25 to advance the science, and I think that is a great



1 way to go about things, so we will be able to

2 generalize even better later on.

3 The missing piece of data, however, is I

4 have asked whenever I have had those conversations,

5 I have asked the marketing person, industry, is

6 there any evidence how much a general claim is

7 worth, why it makes a difference, do you need it

8 for the managed care organization or the pharmacy

9 to pay for it, et cetera, and I haven't encountered

10 any rigorous data or modeling, so let me ask

11 anybody from the committee or agency, would we be

12 better served if there were some economic model or

13 data, if that is partly underneath the reason for

14 going for this high bar.

15 DR. McLESKEY: I won't respond in any

16 detail, but I would say there is a general

17 understanding that the bar to the claim largely,

18 the likelihood is the larger the market will be.

19 DR. ABRAMSON: I just want to pick up on

20 Dr. Woolf's comment that a general global approval,

21 if we lower the bar for individual approvals is

22 going counterintuitive to the notion that we are

23 funding their differences among the different pain

24 syndromes, and I think the concept of general

25 chronic pain, I think we have to be very careful



1 about given this morning's discussion.

2 I would argue that even if a broad

3 indication was met because you had three

4 indications in these separate areas, that we

5 shouldn't lower the bar in any of those individual

6 indications by the numbers of studies that you

7 would need to show that your drug worked in

8 neuropathic pain, fibromyalgia, low back pain,

9 whatever it is.

10 So, my concern about having one study in

11 four different areas is that you are diluting the

12 individual iterative process and that everything

13 should be able to stand alone as an indication in

14 that area, and if you hit three or four, you have a

15 global marketing advantage, but you haven't diluted

16 the process for any area.

17 I think the word "counterintuitive"

18 becomes very critical that we separate all these

19 different pains as much as we can as we better

20 understand them.

21 DR. FIRESTEIN: Dr. Katz.

22 DR. KATZ: I wonder if it might be useful

23 to use the opioids as a model to do a thought

24 experiment with the idea of a chronic pain

25 indication. Barring the issues that I mentioned



1 earlier about addiction and tolerance, and all

2 that, we know that there are clinical trials

3 supporting efficacy of opioids in neuropathic pain,

4 musculoskeletal pain, there are a bunch of

5 different studies, headache, short-term studies

6 even if we want to go that far, cancer pain

7 certainly, does anybody feel that opioids would not

8 meet anyone's threshold to be a general analgesic

9 for chronic pain?

10 Now, granted, they don't work for every

11 kind of pain. Probably they are not effective for

12 central pain, I would guess, but does a medication

13 have to be effective for every single kind of pain

14 in order to be considered generally to have broad

15 applicability, just as a medication for

16 hypertension might not work for every single

17 patient or subtype of hypertension, but still might

18 have broad applicability within hypertension?

19 It seems to me that the opioids are a

20 broad spectrum analgesic. Why, therefore, is it

21 not possible that another medication could be a

22 broad spectrum analgesic?

23 DR. WOOD: Let me just respond. I think

24 one thing that we were talking about over here is

25 there seems to be the impression that 30 percent is



1 a bad response rate. That is about the average you

2 get in every trial of almost any indication. It is

3 40 percent for anti-hypertensives, it is lower for

4 antidepressants.

5 I mean 40 percent is about the rate of

6 response you get to a single drug in the pivotal

7 trials which are submitted to the Agency, less than

8 that for some. So, 30 percent ain't so bad, and if

9 it's 33 percent, so expecting that we will see

10 substantially more than that seems to me to be

11 counter to what we have seen with almost every

12 other drug class we have approved.

13 DR. FIRESTEIN: Dr. Borenstein will get

14 the last comment from the committee today.

15 DR. BORENSTEIN: One of the points I

16 wanted to be sure about from the clinical situation

17 is when the drug is approved for a general pain

18 indication or is used in one area, it does get used

19 in another to see if it works.

20 That ends up being what happens in the

21 clinical situation. I think what it is for the

22 Agency is to decide whether three out of four at a

23 certain level, and pretty good on another is close

24 enough, or is it really great on two and okay on

25 two others, is that good enough.



1 What you see in patients is whether they

2 respond or not. In individuals, it is really yes

3 or no, do they get an effect and can they tolerate

4 it. So, I think the question for the group is what

5 is adequate to allow a drug to have this indication

6 to allow it to be used in the general public for a

7 variety of pain syndromes that will allow patients

8 to get better and at the same time, use it

9 reasonably safe.

10 That is what I think the group has to

11 decide, whether that is three or four, certainly

12 the Agency has a better idea of what that truly

13 means. In the clinical situation, I see a patient

14 where if I have a drug where I think it might be

15 helpful, I am going to try it. At some time, I am

16 going to be smart enough to figure out the

17 mechanism by why it works, but sometimes you just

18 have to try.

19 DR. FIRESTEIN: Before I adjourn, I did

20 want to see if there is any of the officers from

21 170 that had any additional comments. No? Okay.

22 Thank you very much, everybody. It has

23 been an exciting day and we have more in store for

24 tomorrow. Thank you.

25 [Whereupon the proceedings were recessed



1 at 4:45 p.m., to reconvene on Tuesday, July 30,

2 2002, at 8:00 a.m.]

3 - - -