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
2
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
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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
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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
18
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