1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

ANESTHETIC AND LIFE SUPPORT DRUGS

ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

Thursday, May 16, 2002

8:00 a.m.

 

 

 

 

Holiday Inn Gaithersburg

Two Montgomery Village Avenue

Gaithersburg, Maryland

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PARTICIPANTS

Chair: Nathaniel P. Katz, M.D.

Executive Secretary: Kimberly Topper, M.S.

MEMBER

Janice Bitetti, M.D.

INDUSTRY GUEST

Charles H. McLesky, M.D.

CONSUMER GUEST

Thomas Foster, Pharm D.

PATIENT REPRESENTATIVE

Yvette Delph

CONSULTANTS

Solomon Aronson, M.D.

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

Vera Bril, M.D.

Robert H. Dworkin, Ph.D.

GUEST SPEAKERS

David Cornblath, M.D.

Eva Feldman, M.D., Ph.D.

Michael Polydefkis, M.D.

Michael Rowbothom, M.D.

GUESTS

Peter Dyck, M.D.

John Farrar, M.D.

Mark Rendell, M.D.

Steven Shafer, M.D.

David J. Wlody, M.D.

Clifford Woolf, M.D., Ph.D.

FDA STAFF

Cynthia McCormick, M.D.

Gerald Dal Pan, M.D., M.H.S.

Sharon Hertz, M.D.

Bob Rappaport, M.D.

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C O N T E N T S

Opening Remarks: Nathaniel P. Katz, M.D. 4

Conflict of interest Statement:

Kimberly L. Topper, M.S. 7

Introductions 11

Welcome: Cynthia McCormick, M.D. 14

Open Public Hearing:

Najib Babul, Pharm.D. 20

FDA Presentations

General Clinical/Regulatory Issues in Development

of Drugs Intended for Treatment of a Chronic

Illness:

Sharon Hertz, M.D. 39

Specific Clinical/Regulatory Issues:

Gerald Dal Pan, M.D., M.H.S. 49

Electrophysiologic Tests Used in the Evaluation

of Peripheral Neuropathy and Neuropathic Pain:

David Cornblath, M.D. 70

Scales Used in the Evaluation of Peripheral

Neuropathy:

Eva Feldman, M.D. 97

Skin Biopsy in the Evaluation of Peripheral

Neuropathy and Neuropathic Pain:

Michael Polydefkis, M.D. 151

Charge to the Committee:

Cynthia McCormick, M.D. 182

Committee Discussion

Entry Criteria 190

Outcome Measures 235

Point-Counterpoint: Extrapolation of Findings

from One Type of Neuropathy Pain to Another

Neuropathic Condition:

Robert Dworkin, M.D.

and Michael Rowbothom 258

Committee Discussion

Patient Populations 321

Primary Endpoints 331

Wrapup 367

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

2 Opening Remarks

3 DR. KATZ: Good morning. This is the

4 meeting of the Anesthetic and Life Support Drugs

5 Advisory Committee. We will be speaking today

6 about neuropathy, clinical trials and neuropathic

7 pain. So, if that is the meeting you are

8 interested in, you are in the right place.

9 Otherwise, they can help you find the right meeting

10 outside.

11 My name is Nathaniel Katz. I will be

12 chairing the meeting this morning.

13 What we will do now is I will just make a

14 few brief introductory comments and set out some

15 ground rules for everybody. We will do

16 introductions and then we will have a welcome and

17 introductions from Dr. McCormick.

18 First of all, the topic, again, that we

19 will be speaking about today is clinical-trial

20 issues in patients with peripheral neuropathy or

21 neuropathic pain. I would like first to extend my

22 welcome to our invited guests. We have managed to

23 assemble a great group of individuals here who

24 really are the true thought leaders in this area so

25 I am sure we will have a very productive discussion

5

1 today.

2 In terms of some concrete ground rules for

3 the people around the table, there are a few things

4 that you have to know that will make the meeting

5 work. First of all, when you speak, you have to

6 speak into the microphone because everything is

7 being recorded, so don't forget that. I will be

8 sort of obnoxious. When you forget the first few

9 times, I will cut in and remind you and then would

10 should cruise after that.

11 You do have to press your "speak" button

12 on the microphone which sets up this little red

13 light. So don't forget to do that and, unless you

14 want people to hear all the little whispered

15 comments that you make during the rest of the

16 meeting, don't forget to hit the button and turn it

17 off.

18 Secondly, the way that I will know who

19 wants to talk is if you could just raise your hand.

20 Then Kimberly Topper, our Executive Secretary, will

21 take your names down and we will try to get to you

22 in order. It is not a pure first-come-first-served

23 basis in that we may call on people first who maybe

24 have to leave or may not have expressed their

25 viewpoint prior to that. So don't be upset if it

6

1 seems like we are not calling on you in the exact

2 order that you raised your hand.

3 That being said, there are sometimes

4 visibility problems. If you find that I am

5 persistently not recognizing you, then say

6 something at some point because, last meeting, for

7 example, we had somebody over there who kept

8 raising his hand. I couldn't see him and that was

9 a problem that I had to correct about halfway

10 through the meeting. So let me know if that seems

11 to be the case.

12 In terms of the nature of our discussion

13 today, for the people, again, around the table, I

14 want to emphasize a few aspects of our goals for

15 today. What we are trying to do today is to try to

16 define some of these problems, shed light on some

17 of the issues that have been raised and bring to

18 bear some of the scientific and clinical knowledge

19 and experience that will help illuminate these

20 issues.

21 What we are not trying to necessarily do

22 today is come to any consensus about anything.

23 That would seem to be premature before we have

24 fully defined the problem and I wouldn't want to

25 stifle discussion by any efforts to reach a

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1 premature consensus.

2 So disagreements are fine. I will

3 encourage minority points of view. We want to,

4 again, bring out all the relevant points for

5 discussion here before we seek towards achieving

6 consensus. Of course, if we achieve consensus,

7 that is fine but that is not the primary goal so

8 don't be afraid to bring out countervailing points

9 of view.

10 So, with that, I will introduce Kimberly

11 Topper, our Executive Secretary, who will read the

12 conflict of interest statement.

13 Conflict of Interest Statement

14 MS. TOPPER: The Food and Drug

15 Administration has prepared general matters waivers

16 for the following special government employees who

17 are participating in today's meeting of the

18 Anesthetic and Life Support Drugs Advisory

19 Committee Meeting being held by the Center for Drug

20 Evaluation and Research for Dr. Nathaniel Katz, Dr.

21 Vera Bril, Dr. Michael Ashburn, Dr. Solomon Aronson

22 and Dr. Robert Dworkin.

23 The waivers permit them to participate in

24 the committee's discussion of specific issues in

25 the development of pharmaceuticals for the

8

1 treatment of neuropathy and neuropathic pain.

2 Areas for discussion will include the duration of

3 clinical trials, evaluation of nerve function,

4 evaluation of electrophysiological endpoints,

5 appropriate clinical endpoints and appropriateness

6 of general and specific claims.

7 A copy of these waiver statements may be

8 obtained by submitting a written request to the

9 FDA's Freedom of Information Office located in Room

10 12A30 of the Parklawn Building.

11 Unlike issues before a committee in which

12 a particular product is being discussed, issues of

13 broader applicability such as today's meeting

14 involve many industrial sponsors and academic

15 institutions. The committee members have been

16 screened for their financial interests as they

17 apply to the general topic at hand. However,

18 because general topics impact so many institutions,

19 it is not prudent to recite all potential conflicts

20 as they apply to each member.

21 FDA acknowledges that there may be

22 potential conflicts of interest but, because of the

23 general nature of the discussion before the

24 committee, these potential conflicts are mitigated.

25 With respect to FDA's invited guests, we

9

1 would like to disclose that Drs. Peter Dyck, David

2 Cornblath, John Farrar, Thomas Foster, Michael

3 Polydefkis, Mark Rendell, Michael Rowbothom,

4 Stephen Shafer and Clifford Woolf have reported

5 financial interest in firms which may be affected

6 by the committee's discussion.

7 Dr. Dyke reported that he has received

8 honoraria and grant support from Asta Medica and

9 Eli Lilly over the past three years. Dr. Cornblath

10 reports that he has been involved in clinical

11 trials supported by Pfizer and Wyeth-Ayerst. He

12 has been a consultant to Asta Medica, Vertex

13 Pharmaceuticals, R. W. Johnson and Pfizer. He has

14 also been a member of the Schwarz Biosciences Data

15 Safety Monitor Board.

16 Dr. Farrar reports that he has been a

17 consultant to Endo Pharmaceuticals and has been

18 involved in Pfizer-supported research. Dr. Foster

19 reports that he owns stock in Johnson & Johnson and

20 Pfizer. Dr. Polydefkis reports that he has

21 received research support from Pfizer

22 Pharmaceuticals and Johnson & Johnson. He has also

23 received consulting fees from Johnson & Johnson.

24 Dr. Rendell reports that he is a principal

25 investigator on many studies and does studies on

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1 many neuropathic drugs. Dr. Rowbothom reports that

2 he is a researcher on Pfizer and Johnson &

3 Johnson-supported studies and has an Endo

4 Pharmaceuticals study pending. He also receives

5 consulting fees from End Pharmaceuticals.

6 Dr. Safer reports that he does consulting

7 for Ethicon-Endo Surgical Division of Johnson &

8 Johnson. Dr. Woolf reports that he is the

9 principal investigator on Pfizer and

10 Pharmacia-sponsored studies and he receives

11 consulting fees from Pfizer, Pharmacia, Endo

12 Pharmaceuticals and Wyeth. In addition, Dr. Woolf

13 receives speaker fees from Pfizer and Pharmacia.

14 In addition, we would like to note for the

15 record that Dr. Charlie McLesky is participating in

16 this meeting as an industry representative acting

17 on behalf of regulated industry. As such, he has

18 not been screened for any conflicts of interest.

19 In the event the discussions involve any

20 other products or firms not already on the agenda

21 for which FDA participants have a financial

22 interest, the participants are aware of the need to

23 exclude themselves from such involvement and their

24 exclusion will be noted for the record.

25 With respect to all other participants,

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1 we ask, in the interest of fairness, that they

2 address any current and previous involvement with

3 any firm whose products could be affected by the

4 committee's decision.

5 Thank you.

6 DR. KATZ: Thank you.

7 Introductions

8 What I would like to do now is to go

9 around the table and do introductions just so we

10 can get to know each other and to help facilitate

11 our efforts together today. So if we could just go

12 around the table and if everybody could take 30

13 seconds and let us know who you are, where you are

14 from, what you do and what your role is with

15 respect to neuropathy and neuropathic pain.

16 Why don't we start at that end of the

17 table, please.

18 DR. McCORMICK: Hi. I'm Cynthia

19 McCormick, FDA. I am the Director of the Division

20 of Anesthetic, Critical Care and Addiction Drug

21 Products.

22 DR. RAPPAPORT: Good morning. I am Bob

23 Rappaport. I am the Deputy Director of the

24 Division of Anesthetic, Critical Care and Addiction

25 Drug Products at the FDA.

12

1 DR. HERTZ: Hi. I'm Sharon Hertz. I am

2 also with the FDA, the same division. I am a

3 medical reviewer.

4 DR. DAL PAN: I am Gerald Dal Pan. I am a

5 medical reviewer in the same division at FDA.

6 DR. McLESKY: I am Charlie McLesky. I

7 work for Abbott Labs today representing industry.

8 DR. FOSTER: Thomas Foster, Professor of

9 Pharmacy and Anesthesiology at the Colleges of

10 Pharmacy and Medicine, the University of Kentucky

11 Medical Center, Lexington, Kentucky. I am the

12 consumer representative.

13 MS. DELPH: Yvette Delph. I am patient

14 representative from the HIV community, Silver

15 Spring, Maryland.

16 DR. ASHBURN: I am Michael Ashburn. I am

17 Professor of Anesthesiology at the University of

18 Utah. I am Medical Director of Pain Programs at

19 Primary Children's Medical Center and at the

20 University of Utah.

21 DR. BITETTI: I am Janice Bitetti. I am

22 with the Department of Anesthesia and Critical Care

23 at George Washington University and I am one of the

24 committee members.

25 DR. SHAFER: Steve Shafer. Despite what

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1 it says here, my primary appointment is Professor

2 of Anesthesia at Stanford University, Adjunct

3 Professor of Biopharmaceutical Science at UCSF and

4 I am here for both anesthesia and clinical

5 pharmacology.

6 DR. BRIL: I am Vera Bril. I am a

7 neurologist from Toronto. I am a consultant to the

8 FDA. I am interested in clinical trials of

9 diabetic neuropathy and various other neuropathies

10 and neuromuscular disorders.

11 DR. DWORKIN: I am Bob Dworkin, Professor

12 of Anesthesiology and Neurology at the University

13 of Rochester School of Medicine.

14 DR. ROWBOTHOM: Michael Rowbothom,

15 Professor of Clinical Neurology and Anesthesia,

16 University of California, San Francisco.

17 DR. POLYDEFKIS: Michael Polydefkis. I am

18 a neurologist at Johns Hopkins and I am interested

19 in the use of skin biopsy in diabetic neuropathy

20 and in clinical trials.

21 DR. RENDELL: Dr. Rendell. Mark Rendell.

22 I am Director of the Diabetes Center at Creighton

23 University. I am interested in diabetic

24 neuropathy.

25 DR. WLODY: I am David Wlody. I am an

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1 Associate Professor of Anesthesiology at the State

2 University of New York, Downstate Medical Center.

3 DR. FARRAR: I am John Farrar. I am a

4 neurologist with appointments in the Department of

5 Neurology, Anesthesia and Epidemiology at the

6 University of Pennsylvania. My interest is in the

7 design and methodology of analysis for clinical

8 trials of pain, in particular neuropathic but also

9 somatic pain.

10 DR. CORNBLATH: Hi. I'm David Cornblath.

11 I am a neurologist at Johns Hopkins. I have been

12 interested in electrophysiology and nerve

13 conduction in clinical trials.

14 DR. WOOLF: I am Clifford Woolf, Professor

15 of Anesthesia Research at Harvard Medical School

16 and Massachusetts General Hospital. I am

17 interested in pain mechanisms and its application

18 to new clinical outcome measures.

19 DR. KATZ: Thank you.

20 With that, let's have introductory

21 comments from Dr. McCormick.

22 Welcome

23 DR. McCORMICK: Thank you. Dr. Chairman,

24 committee members, invited guests, members of the

25 FDA and members of the public, welcome to today's

15

1 meeting of the Anesthetic and Life Support Drugs

2 Advisory Committee to discuss issues surrounding

3 the development of drugs for peripheral neuropathy

4 and to treat neuropathic pain.

5 This meeting has been convened to provide

6 an opportunity for the FDA to gain advice from its

7 distinguished advisors and experts in the area of

8 neuropathy and neuropathic pain on issues that will

9 enable the FDA to provide guidance for industry to

10 develop solid programs that will ultimately support

11 the approval of new pharmacotherapies for these

12 conditions.

13 There are currently over forty agents in

14 various stages of development for the treatment of

15 neuropathy and neuropathic pain. Along with the

16 pharmaceutical industry, we face many challenges in

17 the development of drugs for these conditions. For

18 example, there is little history or precedent of

19 drugs demonstrated to be successful to treat

20 peripheral neuropathy.

21 The course of many neuropathies such as

22 diabetic polyneuropathy is slow and others variable

23 and this must be factored into the duration of

24 trials, particularly if the agent under evaluation

25 is anticipated to slow the course of the

16

1 neuropathy.

2 To perform clinical trials of several

3 years duration may be a huge undertaking for

4 industry and should be embarked upon with the best

5 information on the most relevant outcomes and best

6 analysis methods in hand to deal with the

7 inevitable problems that we will see; for example,

8 high dropout rates.

9 The definition of an outcome that is

10 clinically meaningful to patients may be disputed.

11 The tools used to measure outcomes are abundant and

12 choosing the most appropriate is a challenge. The

13 role of objective measures of nerve structure and

14 function such as biopsies, electrophysiologic

15 testing and quantitative sensory testing may have a

16 role but should be placed in an appropriate context

17 relative to clinical outcome, either as a

18 supportive role or potentially as a surrogate

19 marker if appropriate validation exists. We will

20 be discussing some of these today.

21 As in any rational drug-development

22 program, attention should be given to the projected

23 target population or populations and should neither

24 be too broad nor too narrow as this will ultimately

25 be reflected back in the labeling for the product

17

1 once it is approved.

2 Ideally, the characteristics of that

3 population should be described in the label.

4 Attempts to acquire broad marketing claims from

5 large open-label safety studies gained in

6 populations not relevant to the identified target

7 population will likely not gain inclusion in the

8 label.

9 The populations studied in Phase III

10 efficacy trials is too narrow. Labeling that is

11 overly narrow may result. While that may not

12 affect how the drug is used in real practice, it

13 will affect how it can be advertised, something of

14 importance to industry. In that context, there is

15 also the potential that the important safety

16 information is not collected in the most relevant

17 populations.

18 Turning to neuropathic pain, today's focus

19 will solely be on pharmacologic therapy for

20 neuropathic pain recognizing that there is a also a

21 role for non-pure-pharmacologic approaches such as

22 nerve block, dorsal-horn stimulation and so on.

23 There are only two drugs that are

24 currently approved for pain associated with

25 neuropathy, carbamazepine, initially approved in

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1 1968 for epilepsy and later gained an indication

2 for trigeminal neuralgia and Lidoderm patch

3 approved in 1999 for postherpetic neuralgia.

4 Quite a large number of medications are

5 currently under development for the treatment of

6 the symptoms associated with postherpetic neuralgia

7 as well as for the treatment of pain of neuropathic

8 origin associated with many diverse etiologies.

9 For these agents, we need to understand whether

10 there is consensus on what outcomes are clinically

11 meaningful, what measures are best to describe

12 them.

13 To what extent should specific

14 characteristics of neuropathic pain such as static

15 and dynamic allodynia, pain descriptors,

16 spontaneous pain and so forth be assessed.

17 One of the most challenging questions from

18 a regulatory standpoint is the whole issue of the

19 extent to which the success of a new agent in one

20 neuropathy or disorder manifested by neuropathic

21 pain can be extrapolated to a second or a third or,

22 even more generally, is the state of knowledge

23 advanced sufficiently to be able to consider a

24 general claim for neuropathic pain. If so, what

25 should be the criteria; common mechanisms of drug,

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1 common underlying mechanisms of disease, PK-PD

2 modeling considerations, some other thoughtful or

3 reproducible criterion or some have proposed simply

4 an arbitrary number of replicated trials.

5 These are the things that we are

6 struggling with on a daily basis. It is our hope

7 today that we may hear the thoughts from the

8 committee on some of these areas. The questions

9 that have been formally submitted to us from

10 industry have been incorporated into the questions

11 that we have brought forth for the committee or, in

12 other cases, you will hear from the FDA speakers.

13 It is important to have adequate consideration for

14 these.

15 Today, you will be hearing from the FDA

16 staff of the Division of Anesthetic, Critical Care

17 and Addiction Drug Products to give you the

18 regulatory context for today's discussion. We have

19 asked several of the guest speakers to speak on

20 selected topics that will, hopefully, stimulate

21 discussion surrounding questions about quantitative

22 measurements, of nerve function, confirmatory

23 measures in clinical trials, discussion of

24 neuropathy scales which are most appropriate for

25 clinical drug trials.

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1 This afternoon, we will hear a

2 point-counterpoint discussion on the issue of

3 general versus individual claims for pain

4 associated with neuropathy, the lumping versus

5 splitting debate.

6 We hope to gain new insights from the

7 discussions of the committee today viewing it as a

8 starting point, applying what we learn from today's

9 meeting to the first steps of developing a guidance

10 for industry.

11 Thank you and welcome.

12 DR. KATZ: Thank you, Dr. McCormick.

13 What we will go to next is the open public

14 hearing. As most of you know, members of the

15 general public are invited to share their thoughts

16 and comments with us as part of these committee

17 meetings. One member of the general public has

18 requested time and that is Dr. Najib Babul. Dr.

19 Babul, you could step to the podium, please. You

20 have got ten minutes to share your thoughts with

21 us.

22 Open Public Hearing

23 DR. BABUL: Good morning, Dr. McCormick,

24 Dr. Katz, FDA and members of the advisory

25 committee.

21

1 [Slide.]

2 My name is Najib Babul. I am the Chief

3 Scientific Officer of TheraQuest Biosciences based

4 in Blue Bell, Pennsylvania. I am here because of a

5 keen interest in analgesic drug development

6 including neuropathic pain. I would like to

7 address the committee on the issue of analgesic

8 drug development for neuropathic pain specifically

9 some of the methodologic issues that we have been

10 struggling with.

11 [Slide.]

12 At the present time, the regulatory

13 framework for development of analgesics is actually

14 fairly limited. We have the 1992 guidelines.

15 These guidelines are directed primarily at

16 single-dose evaluation of analgesics in acute pain.

17 They say virtually nothing with respect to the

18 evaluation of drugs for chronic pain or with

19 respect to the evaluation of drugs for neuropathic

20 pain.

21 More recently, the CPMP has issued a draft

22 guidance document on evaluation of analgesics for

23 pain. These guidelines, too, although more recent,

24 don't provide substantive support and direction to

25 drug developers and, in my opinion, to regulators

22

1 for chronic pain and for neuropathic pain as well.

2 [Slide.]

3 We also have a number of supportive

4 guidelines, both from the CPMP and from the FDA. I

5 would argue that if we look at the osteoarthritis

6 guidance document, while directed at a more mature

7 discipline, may represent a basis for some

8 long-term approach by the agency for guidelines

9 development in neuropathic pain.

10 [Slide.]

11 What is the regulatory framework for

12 approval of drugs for neuropathic pain? Put

13 another way, should a sponsor be able to obtain a

14 broad indication for neuropathic pain or is it

15 necessary to replicate evidence of efficacy for

16 each neuropathic-pain state. This is an issue that

17 a number of us have been struggling with and I know

18 that the division, likewise, has been considering

19 this issue.

20 [Slide.]

21 Let's look at the pros and cons on this

22 issue. I certainly will not be able to do a kind

23 of justice that speakers later on who have a bit

24 more time will be able to do, but let me just

25 review this issue by saying that proponents of a

23

1 broad indication for approval for neuropathic pain

2 would argue that the response is often

3 generalizable, that pivotal studies in several pain

4 states should be adequate for a broad claim, that

5 if we require a sponsor to replicate evidence in

6 every neuropathic-pain state that this will push

7 developers to a minimalist approach to development

8 getting a very narrow indication with the attendant

9 off-label use of the drug.

10 Consequently, some would argue that many

11 painful neuropathies may remain orphaned. People

12 who support the view that we ought to look at this

13 on a subindication, if you will by a subindication

14 basis, would argue that the etiology, presentation

15 and natural course of these neuropathies is

16 different, that the mechanisms of pain are

17 frequently different, that replication is, indeed,

18 essential in order to avoid erroneous chance

19 findings, and we have seen some in the literature,

20 to be sure, and that, quite to the contrary,

21 failure to require studies in each painful

22 neuropathy may, itself, result in orphaning of

23 specific neuropathies

24 [Slide.]

25 I think it will come as no surprise to Dr.

24

1 McCormick and Dr. Rappaport that I would make a

2 case for a broad neuropathic claims structure.

3 [Slide.]

4 But, before we do that, we need to make

5 sure that we have our operational definitions in

6 order because when we are talking about neuropathic

7 pain, it conjures up different things to different

8 individuals.

9 Are we talking about peripheral

10 neuropathies? Are we talking about phantom pain?

11 Are we talking about complex regional-pain syndrome

12 I or type II. Are we talking about nerve-root

13 disorders, central pain or spinal-cord-injury pain.

14 These are all different issues, different

15 presentations and natural histories and we need to

16 be certain that we are using the same terminology.

17 [Slide.]

18 If we drill it down further, just looking

19 at peripheral neuropathic pain and, again, to

20 buttress the point that a

21 subindication-by-subindication claim would be very

22 difficult, we have a wide variety of clinical

23 presentations. We have patients with traumatic

24 mononeuropathies which could range from entrapment

25 neuropathies to transection to causalgia to stump

25

1 pain and post-thoracotomy pain to other

2 mononeuropathies and multiple mononeuropathies

3 including diabetic and postherpetic neuralgia and

4 trigeminal neuralgia and, of course, a series of

5 polyneuropathies of varying etiology from

6 nutritional and metabolic to drug-induced, each one

7 with a somewhat different mechanism, to hereditary

8 polyneuropathies and neuropathies secondary to

9 malignancy.

10 [Slide.]

11 I hope this is not a rhetorical question,

12 but the question I would have is will we ever get

13 drugs approved for neuropathic pain or at least a

14 broad indication of neuropathic pain if there is a

15 requirement for replicate evidence in each painful

16 neuropathy.

17 [Slide.]

18 To compound the issue further, when we are

19 talking about neuropathic pain, we are not just

20 dealing with neuropathic pain of noncancer origin.

21 Indeed, in a series of randomized clinical trials

22 that we have been doing for the last fifteen years,

23 we have attempted to systematically stage the

24 patient's pain characteristics. This slide shows

25 data from four specific studies where anywhere from

26

1 2 to 12 percent of patients had solely neuropathic

2 pain or primarily neuropathic pain as their

3 reporting symptom.

4 In terms of contributory neuropathic pain,

5 anywhere from 9 to 45 percent of patients had some

6 contributory neuropathic-pain component. So it is

7 certainly a complex challenge for drug developers.

8 [Slide.]

9 One of the questions that we ask ourselves

10 is whether there is a wide divergence in efficacy

11 response to various pharmacologic agents in painful

12 neuropathies. I would suggest that if the answer

13 is yes, that there is wide divergence, then a broad

14 claim may not be possible. If the answer is no,

15 then, clearly, a broad claim may be possible.

16 What is the evidence for a comparable

17 response across painful neuropathies?

18 [Slide.]

19 We recently completed a retrospective

20 evaluation of the literature looking at randomized

21 double-blind placebo-controlled studies, looking

22 only at orally administered drugs that were given

23 for at least four weeks duration. We restricted

24 our evaluation only to studies in the public domain

25 involving postherpetic neuralgia and diabetic

27

1 neuropathy given that there is a fair bit of

2 evidence in those two neuropathies.

3 We looked at baseline and final endpoint

4 scores and attempted to calculate an overall

5 response by subtracting the placebo response which,

6 in general, was anywhere from 30 to 50 percent of

7 the overall response from the drug response.

8 [Slide.]

9 What I have here is a slide with the data

10 on diabetic neuropathy. As you can see, a series

11 of agents including amitriptyline, desipramine,

12 gabapentin, pregabalin, limotrigine, mexiletine,

13 tramadol, oxycodone and dextromethorphan show a

14 fairly robust response in diabetic neuropathy.

15 There are some missing data here because

16 we were unable to obtain baseline data in some

17 cases and there was a carryover effect in a number

18 of crossover studies. In the case of limotrigine,

19 there is also data in HIV neuropathy and in central

20 pain although there is inconsistent data in

21 spinal-cord-injury pain and mixed polyneuropathy.

22 [Slide.]

23 If we look at postherpetic neuralgia, we

24 find that, at least for a number of commonly used

25 drugs including amitriptyline, desipramine,

28

1 gabapentin, pregabalin and oxycodone, there is also

2 a similar robust pharmacologic response almost of

3 comparable effect size within the variability we

4 expect from study to study.

5 These data would suggest, at least to me,

6 that it should be possible, within a preponderance

7 of evidence, to generalize and obtain a broad

8 neuropathic-pain claim.

9 [Slide.]

10 One of the other issues that we have been

11 struggling with is what it is that we need to

12 measure in neuropathic-pain studies.

13 [Slide.]

14 In a study that Peter Watson and I did in

15 and published in Neurology in 1998, we

16 systematically looked at this issue. Mitchell Max

17 and others have done this as well.

18 Almost all patients, 97 percent of the patients,

19 had ongoing or steady pain and about 90 percent of

20 patients had brief pain and evoked pain described

21 by a variety of different descriptors.

22 [Slide.]

23 If you look at the specific pain

24 characteristics, certainly in terms of peripheral

25 neuropathies, steady pain, paroxysmal pain and

29

1 allodynia are fairly common features. These

2 patients often have some sensory impairment as

3 well. Certainly these are some of the things we

4 ought to look at in all randomized clinical trials

5 in neuropathic pain.

6 [Slide.]

7 These are data from a randomized

8 placebo-controlled clinical trial we did with

9 oxycodone, in this case, OxiContin, looking at

10 these three dimensions of pain, steady pain,

11 paroxysmal pain and allodynia. On all three

12 dimensions, we found a fairly robust pharmacologic

13 response for oxycodone.

14 These data are not unique to oxycodone or

15 to opioids. The have been shown with meprotalin,

16 amitriptyline, desipramine and a number of other

17 pharmacologic agents.

18 [Slide.]

19 The other issue is what else should we be

20 measuring. Clearly, as Dr. McCormick suggested,

21 the durability of the response needs to be

22 measured. My presentation here largely deals with

23 symptom relief. I am not here to speak to the

24 issue of disease progression and the subset of

25 agents that are being looked at in terms of

30

1 disease-modifying agents, but the durability of

2 efficacy response is an important issue given that

3 these patients are going to be on treatment for a

4 long period of time.

5 Quality of life and function are also

6 important issues. The role of quantitative sensory

7 testing certainly is something that is the subject

8 of some debate. One of the issues that I would put

9 to the division and to the advisory board is if you

10 find a significant difference or a positive finding

11 on electrophysiologic testing and find no actual

12 subjective benefit, what does that mean?

13 If, on the other hand, you find a negative

14 finding on objective electrophysiologic testing and

15 find a positive finding on the subjective findings,

16 what does that mean? In other words, I am not

17 entirely certain that, other than in an exploratory

18 or mechanistic sense, that this adds much to the

19 labeling, itself.

20 Finally, if we are looking at centrally

21 acting drugs, as we often are, we need to consider

22 neuropsychological and cognitive effects of these

23 drugs.

24 [Slide.]

25 This is my last slide. I would like to

31

1 just briefly suggest to you, at the cost of being

2 somewhat prescriptive because I think this is where

3 the rubber meets the road, as to what a core

4 development program could look like for a 505(b)(1)

5 drug for a broad neuropathic-pain indication.

6 I would suggest that one of the things

7 that is lacking uniformly with a range of

8 pharmacologic agents across therapeutic agents and

9 divisions is proper dose-finding studies. So I

10 think it is important that dose-finding and

11 dose-frequency-finding studies be conducted in at

12 least two painful neuropathies. However, these

13 studies probably can be incorporated into pivotal

14 clinical trials.

15 In addition, I would suggest that

16 replicate evidence of twelve-week efficacy, which

17 is a standard that I think most of us, including

18 the division, have accepted in chronic pain of

19 noncancer origin, replicate evidence of twelve-week

20 efficacy in postherpetic neuralgia combined with

21 replicate evidence of twelve-week efficacy in

22 diabetic neuropathy ought to be a sufficient basis

23 for a broad neuropathic claim.

24 I think, however, if the division should

25 take such an approach, sponsors should be given

32

1 some latitude in terms of drug development.

2 Perhaps robust response in twelve-week efficacy

3 studies in two separate painful peripheral

4 neuropathies plus one or two other models such as

5 central pain, spinal-cord pain, complex

6 regional-pain syndrome, nerve-root pain, et cetera,

7 might be adequate as a basis for a broad

8 indication.

9 I think cognitive impairment, both acutely

10 and chronically, need to be evaluated. Obviously,

11 there is a need for long-term safety data.

12 Finally, the clinical pharmacologic section of the

13 label should reflect the efficacy data, the precise

14 studies in which the drug has been found to be

15 effective, ineffective, the magnitude of the

16 pharmacologic response and, indeed, the specific

17 pain dimensions that have shown a positive

18 response.

19 Thank you.

20 DR. KATZ: Thank you, Dr. Babul. Stay

21 there for one second.

22 Does anybody around the table have any

23 questions for Dr. Babul based on the information he

24 has just presented?

25 DR. KATZ: Dr. Farrar?

33

1 DR. FARRAR: I was interested in knowing,

2 with the effect-size slide that you showed, you had

3 subtracted out the placebo rates. I am not quite

4 sure how you calculated an effect size. Was it the

5 remaining effect size?

6 DR. BABUL: That's correct. What we did

7 is we took the baseline value, subtracted the final

8 endpoint value from that to come up with the effect

9 of the test drug, did the same thing for the

10 reference drug and then subtracted one from the

11 other.

12 In general, what we found is the placebo

13 response was about the same as what we see in

14 osteoarthritis, for instance.

15 DR. FARRAR: If I could follow up. The

16 effect size was presented as a percent. I am

17 wondering, a percent of what?

18 DR. BABUL: That was a percent of the

19 baseline value in terms of percent reduction of

20 baseline value, probably more appropriately labeled

21 as response rather than effect size.

22 DR. KATZ: Dr. Woolf?

23 DR. WOOLF: You used that same slide to

24 argue the case that different drugs had similar

25 degrees of efficacy. But your desipramine had

34

1 about a 10 percent effect in diabetic neuropathy

2 and over 30 percent in postherpetic neuralgia.

3 That, obviously, could be by chance but it does

4 raise the issue that there may be differences in

5 efficacy between different conditions.

6 DR. BABUL: You are quite correct. Let me

7 make a couple of points in that respect. The first

8 is that I think most of us have accepted, although

9 not all, that a minimum clinically perceptible

10 difference is about 10 percent and some have argued

11 perhaps 15 percent.

12 So, in that sense, I think that most

13 clinicians agree that desipramine provides a

14 reasonable response in postherpetic neuralgia and

15 in diabetic neuropathy. I think part of the

16 challenge here is that a number of studies did not

17 lend themselves to calculating a pharmacologic

18 response because of the absence of baseline values.

19 Without a doubt, there are some

20 differences which, perhaps, would argue for

21 replication. My point is that replication may be

22 reasonable. Certainly, there is a sound foundation

23 for replication at the agency although arguments

24 have been made for large single studies as well.

25 But replication in all neuropathies may be

35

1 challenging.

2 The other point I would make is that

3 mechanistically, within a given neuropathy, there

4 are substantial differences. So, if we start

5 looking at diabetic neuropathy, there are

6 mechanistic differences in terms of presentation of

7 patients within a given neuropathy so where,

8 exactly, does this process end?

9 There are also other differences. I

10 talked about lamotrigine in terms of some

11 variability where in certain states, like HIV

12 neuropathy, the findings are positive. In central

13 pain, they are positive. There are no data on

14 postherpetic neuralgia, unfortunately, that I am

15 aware of but we know that in a recent study

16 published in Pain, in spinal-cord injury pain, the

17 results were negative and in mixed neuropathy the

18 results were negative.

19 So it always hard to know whether it is

20 the design, a function of dose, whether it is a

21 question of polypharmacy, appropriateness or

22 washout, the instruments that are being used and I

23 think there is probably a need for standardization.

24 DR. DAL PAN: Any other questions? Dr.

25 Shafer?

36

1 DR. SHAFER: Our pain group at Stanford

2 feels fairly strongly that VAS scores for chronic

3 pain can be very hard to interpret and primarily

4 push for quality-of-life indicators. But, in your

5 presentation here, talking about postherpetic

6 neuralgia, at least what I am inferring from your

7 presentation is you see VAS as being more the

8 primary endpoint and things like quality of life

9 being potentially secondary endpoints on the

10 studies.

11 Is that a correct interpretation of your

12 experience and where you are directing this?

13 DR. BABUL: In the literature, a majority

14 of investigators have used either a visual-analogue

15 scale or a categorical scale for evaluating pain as

16 a cardinal feature. Most studies have not looked

17 at various dimensions of pain. To be sure, people

18 have--Mike Rowbothom and others have employed the

19 McGill Pain Questionnaire with the various

20 descriptors that that provides, but most people

21 have not specifically targeted at each visit

22 specific dimensions of pain.

23 But a majority of people have used the

24 visual-analogue scale. There is this separate

25 issue about what constitutes a win. This is an

37

1 ongoing struggle. Drug developers concerned about

2 coprimaries--in other words, a requirement that a

3 win be based not just on pain but on quality of

4 life. Some would argue function or return to work

5 which is a rather daunting task.

6 I think many of us who are involved with

7 pain management feel that pain relief alone is a

8 reasonable endpoint. Certainly, we hope that that

9 translates into quality of life. There is not a

10 huge amount of work done in terms of

11 quality-of-life instruments in neuropathic pain

12 although there is some literature out there.

13 DR. SHAFER: Just to quickly follow up,

14 part of the distinction was acute- versus

15 chronic-pain syndromes. Do you see any bifurcation

16 between the measures for acute and the measures for

17 chronic?

18 DR. BABUL: In both acute pain and in

19 chronic pain, in chronic pain as it relates to,

20 say, osteoarthritis, myofascial pain, cancer pain,

21 any neuropathic pain, both categorical and

22 visual-analogue scales have shown validity and

23 actually fairly good reliability. Unfortunately,

24 VAS seems to be something that most investigators

25 and academics seem to prefer and I think most

38

1 patients probably prefer some sort of a numerical

2 or categorical scale and there is this challenge.

3 But both in acute and chronic pain, we have used

4 VAS successfully.

5 DR. KATZ: Thank you.

6 Dr. Farrar?

7 DR. FARRAR: Just two quick comments. One

8 is the minimal perceptible difference is clearly a

9 different measure than a clinically important

10 difference and the second is that, to try and

11 conclude something from the graphs that you have

12 here, it is very important to remember that these

13 measures are looking at the mean value and that the

14 mean value is not a unique answer to the question

15 of how many people actually got better.

16 You can come up with any of a number of

17 different interpretations and I would be interested

18 if any of these studies actually published

19 something about the number of patients who actually

20 got better to try and look at some of that data as

21 well.

22 DR. BABUL: Dr. Farrar, I would certainly

23 approach this issue with some trepidation in your

24 presence, but let me suggest that, from a

25 number-needed-to-treat basis, there are generally

39

1 consistent findings as well for most of these

2 pharmacologic agents with some discrepancy that you

3 would expect across clinical trials.

4 DR. KATZ: Thank you, Dr. Babul. We

5 appreciate your comments.

6 We do have a little bit of time left in

7 the Open Public Forum so if there is anybody in the

8 room who would care to come up and share some

9 thoughts with us about these issues, you are

10 welcome to do so at this time. Just approach the

11 center mike right up front.

12 I feel like I have a clean conscience that

13 everyone has been offered an opportunity. We will

14 go on with the rest of the program, then.

15 Next, we will have a number of

16 presentations from the FDA folks on some of the

17 regulatory issues in this area beginning with Dr.

18 Sharon Hertz.

19 FDA Presentations

20 General Clinical/Regulatory Issues in

21 Development of Drugs

22 Intended for Treatment of a Chronic Illness

23 DR. HERTZ: Good morning.

24 [Slide.]

25 I am going to discuss the general

40

1 regulatory issues that are involved in drug

2 development in general so that we can think of them

3 as we discuss neuropathies specifically. The

4 general regulatory framework in which we work here

5 at the agency compels us to keep the entire

6 drug-development process in mind when we review all

7 submissions. This extends from the time of the

8 initial application to study the drug in humans,

9 the IND submission, to the time when the product

10 will be considered for marketing at the submission

11 of the New Drug Application, or NDA.

12 Clinical drug development plans and NDAs

13 are reviewed for efficacy in the context of the

14 drug safety profile. At the same time, the choice

15 of clinical-trial design and study populations are

16 considered for the future promotional and marketing

17 implications.

18 The clinical trials used to support an NDA

19 are the basis for the drug's indication and will be

20 reflected in the language of the product label.

21 Marketing and promotional claims are based on the

22 information in that label. This last point is

23 important and I will refer to it later at the end

24 of my talk.

25 [Slide.]

41

1 Basically, a company has a hypothesis that

2 Drug A is capable of treating a symptom or a

3 disease in a safe and effective manner. The proof

4 is at least two adequate and well-controlled trials

5 demonstrating this hypothesis to be true with

6 additional safety information as needed. The

7 results, hopefully, are approval of the product and

8 a label. Then the product will be promoted based

9 on the findings of efficacy.

10 [Slide.]

11 So what is the regulatory basis for

12 studies in support of efficacy? What is the

13 regulatory basis for the requirements of the safety

14 database? And how are these findings, the product

15 label and promotion related?

16 [Slide.]

17 The legal standard requiring the

18 demonstration of effectiveness was added to the

19 Food, Drug and Cosmetic Act in 1962. It states

20 that no person shall introduce, deliver for

21 introduction, into interstate commerce any new drug

22 which basically hasn't been shown to be effective.

23 [Slide.]

24 The regulations also state that full

25 reports of these investigations which support the

42

1 demonstration of efficacy must be submitted to the

2 application and that a finding of substantial

3 evidence that the drug will have the purported

4 effect in the intended conditions of use must also

5 be provided to support approval for the

6 application.

7 [Slide.]

8 The regulations also describe the term

9 substantial evidence that is necessary in support

10 of a finding of efficacy. Substantial evidence is

11 defined as evidence consisting of adequate and

12 well-controlled studies by experts qualified to

13 perform those studies so that the studies can be

14 the basis to conclude the drug will have the effect

15 purported.

16 The term "adequate and well-controlled

17 investigations" was taken by the agency to mean at

18 least two adequate and well-controlled trials.

19 [Slide.]

20 The Code of Federal Regulations describes

21 the essential characteristics of an adequate and

22 well-controlled trial. This includes the required

23 documentation of planning, conduct, data handling

24 and record keeping. The purpose of conducting

25 these clinical investigations is to distinguish the

43

1 effect of the drug from other influences such as

2 spontaneous change within the course of the

3 disease, placebo effect or biased observation.

4 Additional, the Regulations describe the

5 types of study designs that permit what is

6 considered a valid comparison using a control to

7 provide quantitative assessment of drug effect.

8 This section also describes the use of concurrent

9 placebo control or dose-comparison controls or the

10 use of objective measures when available and a

11 placebo effect is expected to be negligible.

12 Concurrent acting controls are described

13 along with the potential pit fall for a lack of

14 assay sensitivity if not used with other types of

15 controls.

16 [Slide.]

17 There is some flexibility with respect to

18 the number of trials required for approval based on

19 the situation and the availability of other

20 supportive data according to the FDA Modernization

21 Act.

22 The legal and scientific bases for the

23 quality and quantity of evidence necessary to

24 support effectiveness are summarized in a guidance.

25 I just want to say that the requirement for more

44

1 than one adequate and well-controlled study doesn't

2 reflect so much the need to replicate findings in

3 the same type of study but more the need to provide

4 independent substantiation of experimental results.

5 The intent is to avoid unanticipated bias

6 or chance results and to demonstrate the findings

7 are generalizable to patients under different

8 conditions.

9 [Slide.]

10 The finding of safety is more accurately

11 the finding of acceptable risk in the context of

12 the efficacy of the drug. The requirements for the

13 safety database for drugs intended for chronic

14 administration are also described in a guidance.

15 [Slide.]

16 The finding of effectiveness is then

17 reflected in the product label in pertinent

18 sections, particularly indications and usage

19 material must be supported by substantial evidence

20 of effectiveness. Comparative statements about

21 other products must also be supported by

22 substantial evidence.

23 [Slide.]

24 Findings referable to safety are reflected

25 in several sections of the label according to the

45

1 regulations and postmarketing information can be

2 added as needed.

3 [Slide.]

4 Once the wording in the label is agreed

5 upon and approved, the sponsor may advertise and

6 promote the product in accordance with the

7 regulations. The advertisements must be accurate

8 and balanced and limited to the indications

9 included in the label. This is a point that has

10 been mentioned already and it is an important point

11 for the following reasons.

12 First of all, a product that is effective

13 for more than one indication may be effective under

14 different conditions of use, different dosing

15 regimens, so it is important that findings of

16 efficacy be supported by data for that indication.

17 [Slide.]

18 It is also particularly important because

19 a product that is used in different populations may

20 have different safety profiles based on the

21 characteristics of those populations so age,

22 comorbidity, concomitant medications with potential

23 for drug-drug interactions are all important

24 features that need to be explored in an adequate

25 safety database.

46

1 The one other feature why this is

2 important is because it is necessary to set a level

3 playing field where all companies are held to a

4 comparable standard. So, for a company to promote

5 their product for a specific indication, it is

6 incumbent on them to demonstrate the effectiveness

7 and safety for that indication.

8 That is not to say that a product cannot

9 be used in a manner according to clinical judgment

10 by any given physician, but the approval and

11 promotion of drugs are regulated processes and the

12 FDA is responsible for implementing those

13 regulations.

14 [Slide.]

15 So as we discuss the approach to drug

16 development for products to treat neuropathic pain

17 and underlying neuropathies, please keep in mind

18 how these different pieces, the clinical trials,

19 the safety data, the product label and product

20 promotion fit together.

21 Thank you.

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

23 Any questions from around the table for

24 Dr. Hertz? Dr. Farrar?

25 DR. FARRAR: The one area that the

47

1 guidelines don't really speak to is with regards to

2 the size of the beneficial effect. I wonder if you

3 could just comment on that.

4 DR. HERTZ: I hope we cover that somewhat

5 today in the discussions. We struggle with

6 statistically significant differences in effect

7 size between the placebo group and the active

8 treatment groups versus the concept of a clinically

9 meaningful difference. That is going to be on the

10 roster for discussion today, so we don't have an

11 answer yet specifically in this area.

12 DR. KATZ: Other questions for Dr. Hertz?

13 I have a question. It sounded like, and correct me

14 if I am wrong, you were making the point that, in

15 meeting this criterion of two adequate and

16 well-controlled trials for a specific indication

17 that the agency is more impressed by a pair of

18 trials where one actually differs from the other in

19 terms of details of study design, location where

20 the trial was conducted, et cetera, et cetera, as

21 opposed to what we sometimes see which is two

22 replicate trials that truly are replicated, where

23 the trial is exactly identical and you could

24 combine them or split them and it is the same

25 thing.

48

1 Am I hearing you correct? Is that how

2 that issue is perceived?

3 DR. HERTZ: Yes, short answer, for the

4 reason that you want to have a little bit more

5 generalizability. Otherwise, it is basically one

6 big trial separated by some other divider.

7 DR. KATZ: Thank you.

8 Dr. Woolf, please?

9 DR. WOOLF: In terms of indications, it

10 wasn't clear whether you were talking about, in the

11 context of this meeting, symptom, let's say acute

12 versus chronic pain, or neuropathic pain or

13 postherpetic neuralgia.

14 Is there a difference between indication

15 as a symptom or as a disease syndrome?

16 DR. HERTZ: The indication is basically

17 what the claim for efficacy is based on. So, if

18 you are going to say that a product is capable of

19 relieving the pain of diabetic neuropathy, then

20 that is your indication, symptom relief. It could

21 also be that your product is intended to slow the

22 progression or reverse the changes associated with

23 diabetic neuropathy and then that would be the

24 indication.

25 So it is really defined by what you see

49

1 the product, what the company sees the product,

2 capable of doing and capable of proving efficacious

3 doing.

4 DR. KATZ: Other questions for Dr. Hertz?

5 Thank you very much. Next we will have

6 Dr. Dal Pan from the FDA who will be speaking

7 further about specific clinical and regulatory

8 issues that arise.

9 Specific Clinical/Regulatory Issues

10 DR. DAL PAN: Good morning.

11 [Slide.]

12 We have just heard from Dr. Hertz about

13 the clinical requirements for the development and

14 regulatory approval of drugs to treat chronic

15 disease. The basis of this is embodied in the

16 substantial evidence requirement which states that

17 the drug will have the effect it purports or is

18 represented to have under the conditions of use

19 prescribed, recommended or suggested in the

20 proposed labeling thereof. In other words, the

21 drug has to do what the label says it does.

22 What does this mean, then, for drugs for

23 peripheral neuropathy and for chronic neuropathic

24 pain. The basic challenge for the agency, for the

25 industry and for researchers is to operationalize

50

1 the substantial-evidence requirement into

2 clinical-trial design and clinical-development

3 planning for drugs to treat peripheral neuropathy

4 and chronic neuropathic pain.

5 So I would like to take a little bit of

6 time today and just present to you some of the

7 specific examples in clinical-trial design and

8 clinical-development planning that confront the

9 industry and confront us when we meet with industry

10 to go over trial design and development planning.

11 The examples are not so much today to get

12 specific answers to specific questions or specific

13 plans but rather to present to you the scope of the

14 important issues that are facing us and to be

15 followed later today by a discussion of what the

16 scientific and clinical issues are and how we can

17 best be informed about these issues so we can carry

18 that into sound decision-making in the future.

19 [Slide.]

20 So let's start with the example of Company

21 A. The company wants to develop a drug to slow or

22 reverse the progression of diabetic polyneuropathy.

23 So several issues come up here with regard to

24 clinical-trial design.

25 One of the first issues is what is the

51

1 appropriate outcome measure or measures. Some of

2 the challenges here are there is no regulatory

3 precedent. No drugs have been approved for this

4 indication and there aren't many large-scale trials

5 to guide us or to inform us as to what the best

6 outcome measures are.

7 Because diabetic polyneuropathy is a

8 complex disease, the issue of a composite outcome

9 versus a single-measure outcome comes up. There

10 are many composite-measure outcomes in the

11 literature and we have seen a lot of proposals to

12 use such composite outcome measures.

13 An example of such a measure would be the

14 Neuropathy Impairment Score, or NIS, of the lower

15 limbs known as NIS(LL)+7. This is a composite

16 clinical measure that looks at weakness, sensory

17 loss, reflexes and electrophysiologic studies of

18 motor and sensory nerves, heart rate variability

19 and vibratory-detection threshold.

20 One of the challenges is defining the

21 degree to which this composite measure or any

22 composite measure, or any single measure, for that

23 matter, really reflects what the clinically

24 important effect of a drug to treat diabetic

25 neuropathy really is. Closely related to what the

52

1 outcome measure is is something we have heard in

2 some of the discussion already this morning; what

3 is the magnitude of the effect size.

4 We are translating clinical issues into

5 quantitative measures, be they measures of

6 percentage of patients who respond by a given

7 criteria or mean values on some numeric outcome.

8 What is the scientific and clinical basis for

9 determining how big an effect size should be? That

10 is important because that, then, becomes the

11 measure of the effectiveness of the drug and, from

12 a practical point of view, it is important in trial

13 design because it forms part of the basis for

14 sample-size determination.

15 When we also look at this class of drugs,

16 we want to distinguish between slowing progression

17 versus arresting progression of disease versus

18 actually reversing disease. This may have

19 implications for what the outcome measure is. It

20 may also have implications for the duration of the

21 trial as well as the sample size.

22 We want to also consider what is the role

23 of other testing such as electrophysiologic

24 testing. Measures of nerve-conduction studies have

25 been well documented in diabetic polyneuropathy as

53

1 measures of extent and severity of disease as well

2 as change over time. To what degree can these

3 measures serve as markers or surrogate markers of

4 the important clinical effects we want the drug to

5 be able to have.

6 If a drug is going to reverse or slow the

7 progressive neuropathy, it may also have a

8 beneficial effect on symptoms during the course of

9 the disease and how can we capture this in the

10 trial as well. So these are some of the challenges

11 involved in drugs for slowing the progression of

12 diabetic polyneuropathy.

13 [Slide.]

14 Let's turn now to a different scenario.

15 Company B wants to develop a drug to treat chronic

16 neuropathic pain due to diabetes. Several of the

17 previous issues are important here as well. Again,

18 we come back to the appropriate outcome measure or

19 measures.

20 What is the role of pain intensity

21 reduction? What is the role of pain relief. What

22 is the role of function as an outcome. What is the

23 role of quality of life as an outcome? Because

24 neuropathic pain can vary from person to person,

25 what is the role of characterizing different

54

1 symptoms such as allodynia, lancinating pain,

2 burning pain and, again, for both composite

3 measures and single effect measures, what is the

4 magnitude of an effect that is clinically important

5 and what is the basis for determining what that

6 effect size is?

7 Because chronic diabetic neuropathic pain

8 is a complication of a systemic disease, we want to

9 also consider how to account for the role of

10 potential confounders; for example, the severity of

11 nerve dysfunction and the level of diabetic control

12 during the trial, especially since those may

13 actually impact the outcome of the trial. Finally,

14 because it is chronic disease, we want to be able

15 to assess the durability of the effect.

16 [Slide.]

17 My last example is a sponsor that wants to

18 have a drug to treat both chronic painful diabetic

19 neuropathy and postherpetic neuralgia. The central

20 issue here is the degree to which data from one

21 etiology of neuropathic pain can support data from

22 another etiology of neuropathic pain and, more

23 broadly, can results from these studies be

24 generalizable to types of neuropathic pain not

25 studied.

55

1 So I have tried to give you an overview

2 here of some of the important issues that are

3 facing us today. We have more talks on the agenda

4 to address some of these issues in particular, and

5 we have put forth a variety of questions to spark

6 some discussion.

7 Thank you.

8 DR. KATZ: Thank you.

9 First, we have a new arrival at the table.

10 Everyone else had to introduce themselves, so, in

11 the interest of equal treatment, please introduce

12 yourself.

13 DR. FELDMAN: My name is Eva Feldman. I

14 am a Professor of Neurology at the University of

15 Michigan and I also direct a juvenile diabetes

16 research foundation center where we study

17 complications of diabetes.

18 DR. KATZ: Thank you. For logistical

19 reasons, what we will do now is have Dr. Cornblath

20 speak on electrophysiologic tests used in the

21 evaluation of peripheral neuropathy and neuropathy

22 pain.

23 Oh; I'm sorry. My mistake. Any questions

24 for Dr. Dal Pan before he steps down? Dr. Shafer?

25 DR. SHAFER: Just quickly one thought, or

56

1 question, rather. There are a number of issues

2 that you allude to including things like

3 sensitivity to covariate effects. These kinds of

4 trials have other complications. Commonly, the

5 data are right sensors. People drop out of the

6 trials. Trying to separate out the inter- and

7 intra-individual variability which you were

8 referring to would try to distinguish effect size

9 from the number of people who actually have any

10 effect at all.

11 To what extent do you expect to see

12 population approaches brought into the analysis of

13 data in pain trials?

14 DR. DAL PAN: Population approaches; you

15 mean by percent responders?

16 DR. SHAFER: Population approach is really

17 where you have a model of intra- and

18 inter-individual variability and are modeling those

19 effects simultaneous with an overall model of

20 effect including, actually, survival in the trial

21 which allows you to account for right censoring of

22 your data.

23 DR. DAL PAN: The issue of censoring has

24 come up in a lot of pain trials. I would actually

25 like the committee maybe just to address that later

57

1 this afternoon. I think that one of the issues

2 that concerns us is differential dropout rates.

3 People in placebo groups drop out because they are

4 not getting pain relief and people in active

5 treatment groups drop out because they are getting

6 toxicity from the drug or can't tolerate it, even

7 if they had, say, pain relief in a pain trial.

8 So I think that might be something

9 interesting for the committee to address, how to

10 handle that. It is something we have dealt with.

11 DR. SHAFER: For acute pain, there has

12 been a lot of good work with population modeling.

13 I haven't seen much in chronic pain.

14 DR. DAL PAN: I am not very familiar with

15 that, either.

16 DR. KATZ: Other questions for Dr. Dal

17 Pan? Dr. Bril?

18 DR. BRIL: Hi. One of the basic issues

19 that I find confusing is in trials in diabetic

20 neuropathy when we are trying to prevent

21 progression. They are very difficult. And we know

22 that the rate of progression really varies very

23 much with glycemic control. And we know that we

24 can improve control in a lot of people but we know

25 we don't improve it in many people.

58

1 We know a lot of people are out there with

2 poor control and those are the people who have more

3 complications. Yet, in some of our long-term

4 studies now we are designing, we are selecting for

5 people whose control is as good as we can make it

6 but we kind of exclude the population who may be at

7 highest risk for the complication.

8 I am just wondering what the agency thinks

9 about broadening the study population to include

10 people who might benefit most from the

11 interventions you may want to be using. It is a

12 real problem, I think, and has implications for the

13 generalizability of use if a drug ever was found

14 effectiveness for diabetic neuropathy.

15 You would be saying it is in those who

16 have fairly good control. This is something that

17 really exercises my mind. I wonder what the agency

18 thinks.

19 DR. DAL PAN: I think it is a good point.

20 I think that it is important that the drug be

21 studied in the patients who could benefit from it.

22 At the same time, I think your point is also right

23 that control of diabetes during the trial can

24 confound the outcome. So that is why we have

25 wanted some criterion in the beginning as to who

59

1 can enter.

2 It is not necessary to include only people

3 with the best diabetic control. I think that is

4 actually one of the questions we have for the

5 committee later is about the entrance criteria for

6 diabetics. So I think maybe we can have some

7 discussion on that later by the committee.

8 DR. KATZ: Dr. Farrar?

9 DR. FARRAR: I think, actually, the

10 question was targeted more at the issue of efficacy

11 versus effectiveness. I think the question was

12 that if you use a very selective population and are

13 able to show an effect size of some magnitude, the

14 question then becomes what about people who are

15 likely, or perhaps even more likely, to benefit

16 from them but because of other issues may have a

17 different set of problems.

18 I think you are referring to a population

19 that is not generally studied which are the people

20 who have highly variable glucose control.

21 DR. BRIL: I am referring to the

22 population where a lot of studies now have

23 upper-limit cutoffs for glycosylated hemoglobins.

24 Yet, there are still people who are out there with

25 these levels in spite of all efforts to improve

60

1 their control and then the argument is said, well,

2 these are noncompliant people anyway.

3 But, actually, they are not. They would

4 be happy to be in a study. I don't think they

5 should be dismissed. So the question is how do we

6 incorporate them into long-term trials and not

7 exclude them?

8 DR. DAL PAN: I think that is something

9 that we would like the committee to discuss this

10 afternoon, actually.

11 DR. KATZ: Dr. Foster next.

12 DR. FOSTER: A question along the same

13 vein. In the introduction this morning, we learned

14 that there are multiple agents in development now.

15 I think if you parse them into disease-modifying

16 agents versus palliative agents, the question comes

17 in Dr. Hertz' presentation at the end, in

18 advertising, as we fast forward to the end, does

19 the agency consider plans for polypharmacy in this

20 area where drugs would be, say, in a diabetic who

21 is developing neuropathy where initially palliative

22 agents would be placed, then prescribed with

23 disease-modifying agents. Is there a plan to

24 incorporate this type of multiple drug use into the

25 design of clinical trials?

61

1 DR. DAL PAN: I am not aware of any plan

2 for that right now. The disease is to slow or to

3 reverse the progression of diabetic neuropathy.

4 Studies are generally entering patients with

5 earlier-stage disease so who haven't developed a

6 lot of the severe complications such as this

7 chronic neuropathic pain.

8 So, usually patients with severe chronic

9 neuropathic pain are not entered into those

10 studies. They are entered more into studies for

11 palliation.

12 DR. KATZ: Dr. McCormick, did you care to

13 amplify on that?

14 DR. McCORMICK: Sure. I think, in so far

15 as these many drugs that are under development are

16 all being developed by different sponsors, each may

17 have its own intent. I think that there certainly

18 is a precedent for having approval for adjunction

19 therapy. That is something that would have to be

20 studied but could potentially make it into a

21 product label if it had been studied.

22 DR. KATZ: Dr. Woolf.

23 DR. WOOLF: You mentioned the complexity

24 inherent in studying the progression of a chronic

25 disease that may be changing. Some of those

62

1 changes may be associated with the mechanisms that

2 may be responsible for the pain so that, early in

3 the disease, the pain may be responsive to a

4 particular pharmacological mechanism and later it

5 may not be.

6 That needs the mechanisms to separate out

7 the response of different patients according to

8 where they are along the natural history of that

9 disease.

10 DR. DAL PAN: I think you are right. I

11 think we are going to have some discussion later

12 today about mechanism-based selection of agents.

13 DR. KATZ: Are you suggesting, Dr. Woolf,

14 that it may be important in clinical trials of

15 neuropathic pain to categorize patients up front

16 based on duration of disease among other things in

17 order to, later on, look at subgroups of patients

18 who may be more or less responsive based on their

19 position in the natural history?

20 DR. WOOLF: We all recognize that some

21 patients respond and others don't to the treatment.

22 I think, certainly, one of the explanations would

23 be that the symptoms that are being generated are

24 reflecting different mechanisms which occur at

25 different times in the disease course.

63

1 So, rather than always doing that post

2 hoc, I think one of the ways is to try and define

3 that up front.

4 DR. KATZ: Dr. Dworkin, then Dr. Rendell.

5 DR. DWORKIN: I was wondering, with

6 respect to this issue of a broad indication versus

7 specific indications, are there any precedents

8 where the FDA has approved a drug in other areas of

9 medicine for a broad indication based on controlled

10 trials in several more specific diseases?

11 DR. DAL PAN: I frankly have to admit

12 ignorance to answer that question. I can't answer

13 you yes or no because I just don't have an example.

14 Maybe one of my colleagues does.

15 DR. KATZ: Anybody else from FDA?

16 DR. McCORMICK: Actually, I think in the

17 area of pain, there has been that precedent. We

18 are currently examining that issue but that has

19 been the precedent since about 1992.

20 DR. KATZ: Anyone else from FDA have any

21 comments about the areas of medicine perhaps

22 outside of pain where there is a precedent for

23 providing broad labels after studies are done in

24 specific subcategories? I wonder if acute pain,

25 itself, might be an example of that where trials

64

1 are typically done, and correct me if I am wrong,

2 in usually dental pain and some post-surgical model

3 with a pair of controlled trials in each one and

4 then the label is given for acute pain broadly

5 despite the fact that there may be different types

6 of acute pain that were not addressed in the

7 program.

8 DR. McCORMICK: Right. That is what I was

9 referring to.

10 DR. KATZ: Dr. Rendell?

11 DR. RENDELL: One of the greatest concerns

12 that I have, having looked at most of the

13 diabetic-neuropathy agents and having seen them

14 fail on statistical grounds time and time again is

15 that we are dealing with diabetic neuropathy as if

16 it were a single disease as opposed to a condition

17 with multiple different etiologies, the

18 recognition that there may be certain subgroups of

19 patients who may respond to a given agent and that

20 subgroup of patients is not enough to sway the

21 overall statistic in the favor of significance.

22 I have no answers, but I would like to

23 throw out the consideration that we need to start

24 making an effort to identify responders, subgroup

25 responders, and try to decide what it is about them

65

1 that makes them respond to a given drug so that we

2 might be able to offer these subgroups meaningful

3 treatment although the overall response of a given

4 drug, as David and I both know, having done this

5 for years, is going to be negative when we look at

6 the overall statistic.

7 So I throw that out as a challenge and

8 certainly I have no ideas on how to do that.

9 DR. KATZ: It sounds like there are at

10 least two implications from your comments. One is

11 that the trials may be false negative in the sense

12 that, while overall negative, they may fail to

13 identify, indeed, an important effect in a subgroup

14 that otherwise there is no specific technology for

15 identifying.

16 Secondly, the splitting issue may become

17 even more complicated than that. Even a medication

18 that works for painful diabetic neuropathy in

19 general may, in fact, indeed only works for a

20 subgroup of yet those patients which makes the

21 splitting debate even more complicated.

22 Dr. Farrar is first and then Dr. Shafer.

23 DR. FARRAR: Just a couple of comments.

24 There are, actually, some design methods of getting

25 at what you are talking about, one of which is

66

1 using an enriched population and there is,

2 obviously, great concern about how one does that.

3 But, for instance, if you are interested in

4 studying if a tricyclic is effective in a

5 particular group, you could take patients who were

6 responsive already to a previous tricyclic, take

7 them off an put them back on.

8 There are a lot of design problems with

9 that and we don't need to get into it. The second

10 thing is that there are some statistical issues one

11 can look at to enhance the ability to find small

12 populations that, in fact, respond. We can talk

13 about those at some point later, too.

14 DR. DYKE: Dr. Shafer?

15 DR. SHAFER: Again, just in follow up, I

16 am wondering if there is a role in the study

17 design, potentially in the labeling, too, for

18 exactly that kind of enrichment that Dr. Farrar is

19 referring to. We often do things--like if we are

20 interested in trying a sodium channel blocker,

21 mexiletine, we will bring patients in and

22 essentially give them a total-body beer block. We

23 give them lidocaine and examine their acute

24 response to it to see if they have an analgesic

25 response and then, if they do, consider them a

67

1 reasonable candidate for sodium-channel blockade.

2 Or they could just be responsive to

3 opioids, an acute trial in the clinic of I.V.

4 opioids to see if they are going to respond before

5 trying them long-term of opioid maintenance. Is

6 there a role in the process and, potentially, in

7 the labeling as well for enriching it on a

8 mechanistic basis, to say that the patients will

9 first be shown responsive to this class of

10 compounds.

11 DR. KATZ: Dr. Dal Pan, any comments on

12 the issue of the regulatory issues for enriched

13 enrollment trials?

14 DR. DAL PAN: First I would like to say

15 that some of the things that have been brought up

16 here about identifying who the drug is affective,

17 and which subgroups may respond, a lot of that is

18 what Phase II of drug development is about. It is

19 about defining and characterizing the effect of the

20 drug.

21 Then we traditionally call, then, Phase

22 III, the confirmation of that finding. So I think

23 what some of the committee members here have really

24 done is distinguish between what should be done in

25 Phase II and what should be done in Phase III. You

68

1 don't just start with an hypothesis and jump into a

2 confirmatory trial. There is some not only

3 dose-finding but also some hypothesis-testing of

4 what the range of what the range of effects of the

5 drug could be including in specific subpopulations.

6 So I think that is a lot of what is going

7 on here. With regard to specific labeling, maybe

8 one of my colleagues could answer. If we could

9 actually put something in the label about what Dr.

10 Shafer was mentioning, the patient may be

11 responsive to Drug X if they respond to an I.V.

12 opioid, for example.

13 DR. McCORMICK: First let me just say that

14 what you have just described as the ideal in Phase

15 II development is an ideal. It is something that

16 we often don't see bear fruit in Phase III so

17 frequently we aren't able to really identify the

18 real responders and parse them out of the clinical

19 trials.

20 But, if we were, if we had a mechanism to

21 identify responders and if it was adequately

22 studied, then we certainly would consider how that

23 would find its way to the label.

24 DR. KATZ: Other comments from FDA folks

25 on the regulatory implications of enriched

69

1 enrollment designs?

2 Thank you, Dr. Dal Pan, very much. Why

3 don't we then go on to Dr. Cornblath. I'm sorry;

4 one question, Dr. Rowbothom?

5 DR. ROWBOTHOM: I was just going to make

6 one comment about study designs using some kind of

7 a potentially predictive test. I have had a number

8 of discussions with various pharmaceutical

9 companies about Phase II studies that use things

10 like I.V. lidocaine infusion or I.V. opioid

11 infusions. Generally, there has been hesitancy to

12 adopt those designs because of potential risks of

13 the I.V. infusion, what do you do with patients who

14 don't respond to the I.V. infusion, a number of

15 other methodologic questions, plus there is very

16 little published literature in that area.

17 So, although it is a very intriguing idea

18 and the evidence that is available suggests that it

19 would be a valid and successful approach, there is

20 still very, very little data actually in the public

21 domain that is available on that.

22 DR. KATZ: Thank you.

23 Without further ado, Dr. Cornblath.

24 Electrophysiologic Tests Used in the Evaluation

25 of Peripheral Neuropathy and Neuropathic Pain

70

1 DR. CORNBLATH: Thank you.

2 [Slide.]

3 I would like to make three sort of opening

4 comments. One, I would like to thank the

5 organizers for asking me to come. It is a pleasure

6 to be here. Two, I notice the chair next to me,

7 Dr. Dyke, is not here. I think a lot of us in the

8 room owe him a great gratitude of thanks for all

9 the work that he has done over at the Mayo Clinic

10 over many, many years. I will be quoting liberally

11 from that.

12 The third is that I think there are still,

13 and we will hear this from Michael and Eva, a lot

14 of unresolved issues from the scientific standpoint

15 here that are, if you will, separate from the

16 industry issues but tie in very closely. Eva, I

17 know, will be bringing up a number of these talking

18 about these composite measures and particularly

19 their use over time.

20 There is a document currently in

21 preparation coming from the NIH to the Congress, I

22 believe, on issues related to diabetic neuropathy

23 and unresolved scientific issues that, if I am

24 correct, Eva, should be available in the next

25 months, should be out, and will highlight a number

71

1 of the issues that all of us are bringing up that

2 are still ripe for funding from the NIH.

3 So, with that brief introduction, let me

4 just say I am going to talk briefly on this topic.

5 There is a lot written and what I have tried to do,

6 basically, is boil it down to sort of a summary

7 essence without a lot of data. Gerald and I talked

8 about sort of what I was supposed to say.

9 [Slide.]

10 This is sort of the outline of what he

11 told me I was supposed to say which is I was

12 supposed to talk briefly about electrophysiologic

13 tests, their natural history in diabetes, the

14 correlation with outcomes, their use in clinical

15 trials, a few practical issues and then I could

16 give my own summary.

17 [Slide.]

18 So there are a number of

19 electrophysiological tests available. I have

20 changed the term briefly, as you will see here, to

21 neurophysiological tests and, in fact, I saw Joe

22 Arezzo, who is in the audience in the back, who is

23 really a world-class expert in this. I hope he

24 will correct me when I am wrong.

25 But there are a number of tests available

72

1 that can be used. I think one of the issues we

2 keep hearing about is nerve conduction, nerve

3 conduction, nerve conduction and, although that is

4 the most studies and what I will spend most of the

5 time talking about, you should be aware that there

6 are a number of other testing modalities available.

7 Not all have been as well studied but all are out

8 there, all have been looked at to some extent in

9 terms of reliability, validity and, in some cases,

10 change over time.

11 The main ones that you hear about are

12 sensory-motor-conduction studies and, in

13 particular, as I will mention later from the

14 Japanese, the use of F-waves in monitoring

15 long-term electrophysiologic change in diabetic

16 neuropathy, electromyography--that is, the actual

17 placing of a needle in the muscle because that is

18 viewed as minimally invasive, hasn't really been

19 used much--although it is possible to do it, it

20 hasn't been used much--quantitative sensory

21 testing, and there are number of devices out there

22 that can be used.

23 They are part of many of the composite

24 measures that you will hear about from Eva and is a

25 very nice and, i some cases, very simple highly

73

1 reproducible test that we shouldn't forget about.

2 Autonomic-function testing and QSART are,

3 in my view, much more advanced. They require a

4 degree of sophistication and expertise and don't

5 yet have the longitudinal multicenter experience

6 that I think we would like to bring these into

7 clinical trials currently.

8 [Slide.]

9 The most comprehensive data we have in

10 that we in the natural history of EDx studies in

11 diabetes is longitudinal studies of a large number

12 of diabetics who were tested very carefully using

13 the Mayo measures which, again, are highly

14 reproducible within their centers. They have

15 published and studied over a long time.

16 As Eva will tell you, this is what is

17 needed very dramatically with other measures and in

18 other centers and in other populations. Some of

19 that work is being proposed today. There is an

20 enormous need to look at other measures in other

21 populations over time. But this is the best data

22 that we have and I won't read the little numbers up

23 there. You can read them for yourselves. They are

24 printed.

25 But the data is very solid that if you do

74

1 the NIS(LL)+7, you have highly competent people to

2 do it, you are doing it at a center where

3 essentially it was invented, you can show that

4 there are these very precise changes over time and

5 everybody from industry knows that you can then use

6 these to say whether you want to, as was proposed

7 earlier, show that you can slow the rate of

8 progression, you can stop a disease of, in fact,

9 you can improve a disease.

10 There are a lot of other measures that

11 have been used. They all show the same thing; that

12 is, a worsening over time. But none have the sort

13 of extensive precision that the NIS(LL)+7 has.

14 [Slide.]

15 Again, the best data comes from Peter Dyke

16 and his colleagues at Mayo. It essentially shows

17 that nerve conductions, and, again, I am going back

18 to nerve conductions, are clinically meaningful if

19 you accept the statement, and it is hidden in

20 there, that a two-point change in the

21 neuropathy-impairment score is a clinically

22 meaningful measure. Again, I don't know how many

23 here are neurologists and have done this measure.

24 Two points is, in my view, sort of right at the

25 border of what probably two of us could get when we

75

1 are doing it based, side to side, the same

2 patients.

3 But at least, when it is done by Mayo

4 physicians at the Mayo Clinic, this is a very

5 reliable number and it is equal to a precise change

6 in nerve-conduction velocity of either a composite

7 number of nerves or a single nerve or a change in

8 the amplitude for either the composite nerves or

9 single nerves.

10 So, if you can get the nerve conductions

11 done, you can both look at amplitude and velocity

12 in these motor nerves and you can show that they

13 are equivalent to a change in the NIS score and two

14 points on the NIS score is a significant clinical

15 change.

16 [Slide.]

17 So where do we sort of stand? Again, this

18 is summarizing a lot of data that is out there in

19 terms of use, predominant, again, of

20 nerve-conduction studies. They have been used

21 forever. Probably the first one where it was used

22 was, in fact, Eliason's study of diabetic rats

23 where he made them diabetic and he could show that,

24 in the diabetic rats, nerve conduction worsened

25 compared to the controls. That was, I guess, in

76

1 the 50s. Since that time, nerve conductions have

2 been used time and time again, either primarily or

3 secondarily in this.

4 They clearly have shown in diabetes an

5 improvement when the change in the diabetic case is

6 very dramatic; the introduction in insulin therapy,

7 the introduction of pumps, or dramatic treatment in

8 children.

9 The third one is the one that has bothered

10 everybody. Mark has already mentioned it. All the

11 drugs have failed. Therefore, "all the composite

12 measures have failed." One of the difficult

13 questions that I think all of us around the table

14 are asked constantly from industry which is, is it

15 the drug or is it the measure.

16 I think that, for the moment, we can't be

17 certain except to know that both have failed. We

18 can say it is the drug and, therefore, the measures

19 couldn't have worked or we could say actually we

20 thought the drug was pretty good, but the measures

21 were not very good. It is sort of a cart and horse

22 question.

23 [Slide.]

24 So there are a number of practical issues

25 to consider when looking at these. The first is

77

1 what is the outcome that you are actually looking

2 for and what is the fiber population that you are

3 affecting.

4 So these nerve-conduction studies, as the

5 neurologists know, are predominantly large-fiber

6 measures. If you are looking for a drug that is

7 going to affect a small-fiber function, then you

8 wouldn't do nerve conductions because it is not

9 going to get at it. But you might do either skin

10 biopsies, which you will hear about, or

11 quantitative sensory-testing measure to look at

12 small-fiber function.

13 So this is an issue that comes up time and

14 time again. Think about the fiber population that

15 you want to affect, and then pick the endpoint

16 measure that you are interested in. What parameter

17 is going to get better? Is it a velocity parameter

18 which happens very quickly if you improve diabetic

19 control or is it an amplitude measure which is

20 going to be most likely to take a long period of

21 time and have a slower change because it is

22 fundamental property of nerve regrowth and

23 collateral reinnervation?

24 Last, as you can see, you fast will the

25 intervention work? If you improve glycemic

78

1 control, nerve-conduction will change very quickly

2 but then, after that, it is going to stay very

3 stable while amplitude won't change except very

4 late in the study.

5 That comes into the second issue here

6 which is what, really, will your drug do? What is

7 it going to affect? Is it going to affect

8 velocity? Is it going to affect large fiber, small

9 fiber, autonomic function and then you need to go

10 into the top issue to pick the outcome choice that

11 you want.

12 I think the last question comes up quite

13 frequently. The answer is an unequivocal yes. All

14 of these techniques can be done. With training,

15 you can get away from this issue of the test is too

16 complicated or the measure is so complex and there

17 is such variability that nobody could ever do it

18 and we have got to do something stupidly simple.

19 The answer is it has been done time and time again.

20 You can do nerve conductions. You can do

21 quantitative sensory testing in multiple sites.

22 You just need a little bit of training like you do

23 for a neurologic exam. I said here in the note

24 that there have been some multicenter Japanese work

25 that has been done looking at nerve conduction and

79

1 they have shown that F-wave is an extremely robust

2 measure and probably, in their hands, the best

3 measure in terms of reliability.

4 But, again, before accepting that, you

5 need to decide, is the F-wave going to change in

6 your trial and is that what you are interested in.

7 [Slide.]

8 Let me try and summarize because I think

9 we ought to leave more of the time for discussion,

10 clearly nerve conductions are the best studies and

11 the most accepted tests. They correlate with

12 measures. A change in time is real and that they

13 can look at both worsening and improvement.

14 The other electrophysiologic tests are

15 there. They are good, but a lot of them we need

16 more data. That is what this NIH report to

17 Congress is going to say in some respect. We have

18 got to figure out can these others be done and can

19 they be done in large populations over time.

20 That the nerve conductions are

21 particularly important in my view as we think about

22 disease-modifying agents, and, again, we will hear

23 more of this from Eva, I hope, in these composite

24 measures. The Peter Dyke one is the NIS(LL)+7. We

25 have done TNS and Eva has done her own. But they

80

1 are all useful because they look at a variety of

2 domains.

3 You can then begin to look the subdomains

4 essentially suggesting a little bit of what Mark

5 said, that there may be subpopulations or

6 submeasures of these larger domains that improve at

7 a time when the main domain may, in fact, not

8 improve.

9 [Slide.]

10 I have not really talked about the issue

11 as regards to symptom of neuropathic pain because I

12 view that as symptomatic treatment. The

13 electrophysiologic tests shouldn't be forgotten,

14 either nerve conductions or quantitative sensory

15 testing. Both we and Joe Arezzo and others have

16 shown that these are extremely valuable in toxicity

17 monitoring.

18 So, if you think your drug is going to

19 cause a problem, even though it may help symptoms,

20 these are very reliable measures to look at but

21 they really don't have a use in outcome criteria

22 for these kinds of pain studies because they look

23 at large fibers which are not going to be affected

24 and they are fundamentally not altering the

25 disease.

81

1 Thank you.

2 DR. KATZ: Thank you, Dr. Cornblath.

3 Any questions from around the table for

4 Dr. Cornblath?

5 DR. BRIL: I have a question.

6 DR. KATZ: Yes. Dr. Bril?

7 DR. BRIL: Thank you for that reminder of

8 the importance of nerve-conduction studies. I

9 guess my question had to do with the magnitude of

10 change which is the essential question because the

11 thing that we all see changing is conduction

12 velocities.

13 One of the problems with using nerve

14 conductions as a surrogate is what does it mean.

15 So I would challenge you to just tell us and share

16 with us the magnitude of change after

17 transplantation, the magnitude of change in

18 velocity or amplitude after a year or two after

19 transplantation or after the insertion of an

20 insulin pump because, although Peter Dyke has

21 developed those quantitative measures that say you

22 have to have 2 meters per second in order to detect

23 a clinical change, I would be surprised if you can

24 obtain that degree of change very easily in a

25 chronic disorder such as diabetic neuropathy.

82

1 So could you just clarify that?

2 DR. CORNBLATH: Yes. The data, and this

3 is one of these unfortunate things, that the kind

4 of comparative data that you would like, Navarro

5 has the best data from Minnesota on the degree of

6 change in nerve conduction but they are not doing

7 it in extent with NIS scores or NIS(LL) scores so

8 it is a little bit of apples and oranges.

9 But these kinds of values are very easy to

10 see after the several meter per second, after

11 implantation of pumps or the beginning of insulin

12 therapy. It is very common to see multimeter

13 changes in their hands.

14 Now, they didn't go back and look at the

15 change in terms of NIS(LL) or in terms of other

16 quantitative measures.

17 DR. BRIL: But I think if you follow them

18 out for five years, it may be a meter per second

19 but it is not that quickly, that rapidly. The

20 magnitude isn't that great in a short time after

21 transplant.

22 DR. CORNBLATH: It can be when the

23 diabetic control goes to normal.

24