1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE

NDA 21-431: ACAMPROSATE 333 MG TABLETS

LIPHA PHARMACEUTICALS, INC.

Friday, May 10, 2002

8:00 a.m.

Holiday Inn Bethesda

Versailles I

8120 Wisconsin Avenue

Bethesda, Maryland

2

PARTICIPANTS

Dan Oren, M.D., Acting Chairperson

Sandra Titus, Ph.D., Executive Secretary

MEMBERS

Edwin H. Cook, Jr., M.D.

Richard P. Malone, M.D.

Irene E. Ortiz, M.D.

Matthew V. Rudorfer, M.D.

Andrew Winokur, M.D., Ph.D.

STATISTICS SGES

Robert Hamer, Ph.D.

Andrew C. Leon, Ph.D.

PSYCHIATRIC SGE

Paul Keck, M.D.

ALCOHOLISM SGE

Richard Fuller, M.D.

GUESTS (Non-Voting)

John R. Hughes, M.D.

Charles O\'Brien, M.D., Ph.D.

Linda Porrino, Ph.D.

Alan Schatzberg, M.D.

INDUSTRY GUEST (Non-Voting)

Dilip J. Mehta, M.D., Ph.D.

FDA

Sandra L. Kweder, M.D.

Cynthia McCormick, M.D

Celia Winchell, M.D.

Sue Jane Wang, Ph.D.

3

C O N T E N T S

Call to Order, Introductions:

Dan Oren, M.D., Acting Chair 4

Conflict of Interest Statement:

Sandra Titus, Ph.D. 7

Welcome and Introductory Comments:

Cynthia McCormick, M.D. 11

Lipha Presentations

Introduction: Anita M. Goodman, M.D. 17

European Development Program and Current

Registration Status:

Silvie Chabac, M.D. 26

Acamprosate: Mechanism of Action, Preclinical

Effects and Pharmacokinetic Overview:

George F. Koob, Ph.D. 29

Efficacy Results from three Pivotal

Clinical Trials:

Karl F. Mann, M.D. 40

Analysis of the U.S. Study Results:

Barbara J. Mason, Ph.D. 50

Closing Remarks:

Anita M. Goodman, M.D. 77

Questions from the Committee to Lipha 82

FDA Presentations

Clinical Issues of Efficacy:

Celia Winchell, M.D. 113

Statistical Perspective of Acamprosate Experience:

Sue Jane Wang, Ph.D. 141

Questions from the Committee to FDA 166

Open Public Hearing

Victor Hesselbrock, Ph.D. 186

Steven Mirin, M.D. 192

Edward Eder, M.D. 197

Mark Publicker, M.D. 199

Charge to the Committee: Cynthia McCormick, M.D. 202

Continuation of Discussion 205

4

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

2 Call to Order, Introductions

3 DR. OREN: Good morning. My name is Dan

4 Oren. I would like to call to order this meeting

5 of the Psychopharmacological Drugs Advisory

6 Committee regarding NDA 21-431 for acamprosate 333

7 milligram tablets.

8 This committee is purely an advisory

9 committee so I have the distinct pleasure of being

10 an acting chair of a committee with no power. But

11 we have an important mission and that mission is to

12 make recommendations to answer questions to give

13 some guidance to the FDA to do with what they wish.

14 I would like the members of the panel to

15 each introduce themselves. We will go around. I

16 will start with the FDA representatives who are

17 from the Review Division and ask\--Sandy Kweder is

18 not here yet but we will start with Dr. Cynthia

19 McCormick.

20 DR. McCORMICK: How do you do. I am Dr.

21 Cynthia McCormick. I am the Director of the

22 Division of Anesthetic, Critical Care and Addiction

23 Drug Products at the FDA. Welcome.

24 DR. WINCHELL: I am Celia Winchell. I am

25 the Medical Team Leader for Addiction Drug Products

5

1 and I did the primary clinical review for this NDA

2 DR. WANG: Good morning, everyone. My

3 name is Sue Jane Wang. I am the Statistic Leader

4 in the Alcoholism Treatment Clinical Trials. I am

5 the statistical reviewer for this project.

6 DR. OREN: As we go around to the formal

7 members of our panel, I would introduce Dr. Leon is

8 who is a new member. I want to ask everyone, in

9 addition to telling us a little bit about what you

10 do, tell us where you are from.

11 DR. LEON: I am Andrew C. Leon, Cornell

12 University Medical College. I work primarily in

13 affective disorders and anxiety disorders.

14 DR. KECK: My name is Paul Keck. I am

15 Vice Chair for Research in the Department of

16 Psychiatry at the University of Cincinnati College

17 of Medicine.

18 DR. HAMER: I am Bob Hamer. I am

19 Professor of Psychiatry and Biostatistics at the

20 University of North Carolina.

21 DR. WINOKUR: Andy Winokur from the

22 Department of Psychiatry, University of Connecticut

23 Health Center. I am Director of Psychopharmacology

24 there.

25 DR. MALONE: I am Richard Malone from the

6

1 Department of Psychiatry at the Medical College of

2 Pennsylvania in Philadelphia. I am involved mainly

3 in child psychiatry research.

4 DR. RUDORFER: I am Matthew Rudorfer from

5 the National Institute of Mental Health. I am the

6 Associate Director for Treatment Research in the

7 Division of Services and Interventions Research.

8 DR. TITUS: I am Sandy Titus. I am with

9 the FDA. I am the Executive Secretary for PDAC.

10 DR. OREN: I am still Dan Oren. I am an

11 Associate Professor of Psychiatry at Yale

12 University.

13 DR. ORTIZ: I am Irene Ortiz. I am from

14 the Department of Psychiatry at the University of

15 New Mexico and the Albuquerque V.A. I am in

16 geriatric psychiatry and addiction psychiatry.

17 DR. FULLER: I am Richard Fuller. I am

18 Director of the Division of Clinical and Prevention

19 Research at the National Institute on Alcohol Abuse

20 and Alcoholism.

21 DR. PORRINO: I am Linda Porrino, a

22 Professor in the Department of Physiology and

23 Pharmacology at Wake Forest University School of

24 Medicine

25 DR. HUGHES: I am John Hughes. I am a

7

1 Professor in Psychiatry at the University of

2 Vermont.

3 DR. MEHTA: I am Dilip Mehta. I am the

4 industry representative on this committee.

5 DR. OREN: Drs. Porrino, Hughes and Mehta

6 are guests with the committee and we are delighted

7 to have you here.

8 The three questions that we have before us

9 for today are we are asked to consider the evidence

10 of efficacy of acamprosate in the treatment of

11 alcoholism and to provide advice on three key

12 questions.

13 One, how can the discrepant results

14 between the older European studies and the more

15 recently conducted American study be reconciled?

16 Two, do the data support any conclusions regarding

17 subgroups of patients more likely to benefit from

18 acamprosate? Three, given the conflicting results,

19 is there sufficient evidence of the efficacy of

20 acamprosate in the treatment of alcoholism to

21 warrant approval?

22 I will turn the podium over to Dr. Titus.

23 Conflict of Interest Statement

24 DR. TITUS: I am going to read the

25 conflict of interest statement dealing with

8

1 acamprosate for this meeting. The following

2 announcement addresses the issue of conflict of

3 interest issues associated with this meeting and is

4 made a part of the record to preclude even the

5 appearance of such at this meeting.

6 Based on the submitted agenda for the

7 meeting and all relevant financial interests

8 reported by the committee participants, it has been

9 determined that all interest in firms regulated by

10 the Center for Drug Evaluation and Research present

11 no potential for an appearance of a conflict of

12 interest with the following exceptions.

13 Robert Hamer has been granted waivers

14 under 18 USC 208(b)(3) and 21 USC 355(n)(4) for his

15 and his spouse\'s stock in the parent company of a

16 competitor. The stock is valued between \$25,000 to

17 \$50,000.

18 Richard Fuller has been granted a waiver

19 under 21 USC 355(n)(4) for his stock in the parent

20 company of a competitor. The stock is valued from

21 \$5,001 to \$25,000. Because 5 CFR 2640.202(a) de

22 minimis exemption applies, a waiver under 18 USC

23 208(b)(3) is not required.

24 Paul Keck has been granted a waiver under

25 21 USC 355(n)(4) for his stock in the parent

9

1 company of a competitor. The stock is valued at

2 less than \$5,001. Because 5 CFR 2640.202(a) de

3 minimis exemption applies, a waiver under 18 USC

4 208(b)(3) is not required.

5 A copy of the waiver statements may be

6 obtained by submitting a written request to the

7 Agency\'s Freedom of Information Office, Room 12A30

8 of the Parklawn Building. With respect to FDA\'s

9 invited guests, there are reported interests that

10 we believe should be made public to allow the

11 participants to objectively evaluate their

12 comments. Dr. Anthony Schatzberg consulted with

13 Bristol-Myers Squibb within the past year on a drug

14 which is unrelated to acamprosate or its competing

15 products.

16 Dr. Charles O\'Brien is Chief of Psychiatry

17 at the Philadelphia Veterans Affairs Medical

18 Center. Dr. O\'Brien was previously invited by

19 Forest Laboratories to a meeting concerning

20 acamprosate. However, he was unable to attend due

21 to other commitments. Dr. O\'Brien was the first to

22 initiate a study of naltrexone, a competing product

23 in alcoholism and his center participated in the

24 U.S. acamprosate trial. But he had no direct

25 involvement. His center is also participating in

10

1 the NIH-sponsored study of naltrexone and

2 acamprosate but he is not directly involved. Dr.

3 O\'Brien previously received consultant and speaker

4 fees from Dupont Pharmaceuticals. Lastly, he has

5 been invited to be a member of Forest Laboratories

6 Advisory Board but he had not yet accepted.

7 In addition, we would like to disclose

8 that Dr. Dilip Mehta is participating in this

9 meeting as an industry guest acting on behalf of

10 regulated industry. Dr. Mehta reported that he

11 owns stock in Bristol-Myers Squibb.

12 In the event the discussions involve any

13 other products or firms not already on the agenda

14 for which an FDA participant has a financial

15 interest, the participants are aware of the need to

16 exclude themselves from such involvement and their

17 exclusion will be noted for the record.

18 With respect to all other participants, we

19 ask, in the interest of fairness, that they

20 address any current or previous financial

21 involvements with any firm whose products they may

22 wish to comment upon.

23 Thank you.

24 DR. OREN: I will now call upon Dr.

25 Cynthia McCormick, Director of the Anesthetic

11

1 Critical Care and Addiction Drug Products at the

2 FDA.

3 Welcome

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

5 Advisory Committee Members, Invited Guests, members

6 of FDA and members of public, welcome to this

7 meeting of the Psychopharmacologic Drugs Advisory

8 Committee convened to discuss the efficacy of

9 acamprosate.

10 Chronic alcoholism continues to be a

11 widespread and debilitating disorder which places a

12 tremendous burden on society in healthcare costs,

13 lost wages and personal suffering. The need for

14 effective pharmacologic agents for this disorder

15 cannot be overstated. It has been estimated that

16 100,000 lives and \$184.6 billion annually are the

17 cost of chronic alcoholism in the United States.

18 Currently, there are only two

19 pharmacologic agents available for alcoholism in

20 the U.S. Antabuse was approved in 1951 and

21 marketed at times intermittently. Revia,

22 containing the opioid antagonist naltrexone, was

23 approved for this indication in 1994.

24 Despite the crying need for new and better

25 pharmacotherapies, it is very important that drugs

12

1 approved for this condition must meet the FDA

2 standards for safety and effectiveness. To approve

3 a drug with marginal effectiveness or no

4 effectiveness at all would have no more

5 public-health benefit than to approve no drug.

6 In December, 2001, the FDA received for

7 review a new drug application for the product

8 acamprosate. Acamprosate has been available in

9 Europe for the treatment of chronic alcoholism for

10 nearly fifteen years. The application, when filed,

11 was given a priority review status by the FDA

12 because this was hoped to have the potential to

13 affect the course of a disease with tremendous

14 morbidity and mortality.

15 The FDA team has completed the review of

16 the efficacy of this product and has struggled with

17 the contradictory efficacy results between the

18 European and United States study. The efficacy

19 data on which this application rests includes a

20 number of European clinical trials performed over

21 the last fifteen years, three of which are

22 considered pivotal studies, and a recently

23 completed U.S. multicenter trial.

24 The results of these studies on their face

25 paint a conflicting picture. The FDA team has

13

1 attempted to explore the apparent contradictions by

2 evaluating the differences between these studies

3 through a variety of analyses. The discussion of

4 these factors and how they contribute to our

5 understanding of the drug\'s efficacy will be the

6 primary focus of this meeting.

7 The three pivotal European trials, Pelc

8 II, Paille and PRAMA were of similar design,

9 methodology and outcomes. The trials have been

10 considered successful by the company and the review

11 team concurs with this assessment but with caveats

12 which the FDA team will be reviewing this morning.

13 The U.S. study, on the other hand, was not

14 successful in demonstrating superiority over

15 placebo on the primary outcome and most secondary

16 measures. Indeed, on some measures, the drug

17 appeared to perform less well than placebo.

18 Some differences between the European and

19 U.S. studies can be clearly delineated. The

20 European population was primarily one of pure

21 alcoholics. The U.S. population was largely

22 polysubstance abusers. The European patients had

23 either recently undergone detoxification and were

24 abstinent prior to randomization. The U.S.

25 patients were generally not abstinent prior to

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1 randomization.

2 The ascertainment of drinking data in the

3 European studies was essentially retrospective,

4 infrequent and the values were heavily imputed. It

5 was very methodical and rigorous in the U.S. study

6 using accepted methods for reconstructing drinking

7 data and information was obtained at frequent

8 intervals. There were also very tight follow-up

9 provisions in place in the U.S. study.

10 The review team has attempted to apply the

11 same conservative approach to analysis of the data

12 of the U.S. and the European studies but they have

13 obtained disparate results.

14 Finally, the studies differed in terms of

15 the formulation of acamprosate that was used and

16 the regimen of administration, although the total

17 daily dose was essentially the same.

18 It is not uncommon for an NDA database to

19 have both successful results and results which are

20 not considered positive. In general, the agency\'s

21 approach to such a situation is to consider the

22 totality of the evidence giving consideration and

23 weight to such factors as the quality of the data,

24 the strength of the effect size, statistical

25 significance and assessment of whether the effects,

15

1 even in the negative trials, are supportive or

2 trend in the right direction and are not

3 contradictory.

4 If a trial has truly failed\--that is,

5 demonstrated an effect that contradicts the

6 remainder of the evidence\--an attempt is made to

7 understand the reason for that contradiction and to

8 determine, on balance, which results are more

9 credible. Occasionally, further clinical work is

10 needed.

11 In this NDA, the differences between the

12 studies are clear. The questions that remain,

13 however, are whether these differences can

14 adequately account for the disparate results and

15 whether the failure of acamprosate in the U.S.

16 study was a function of the difference in

17 responsiveness of the U.S. alcoholic population or,

18 perhaps, a difference in manifestation of the

19 disease.

20 Stated differently, can the results of the

21 European trials be generalized to the U.S.

22 alcoholic population? There are other aspects of

23 the drug-approval decision which are not being

24 brought for discussion today. The drug\'s safety is

25 still under evaluation and is expected to be

16

1 completed at the end of this month.

2 Both clinical inspections and inspections

3 of the manufacturing site have not been conducted

4 and are expected to be conducted by the end of

5 June. These will both be weighed into the decision

6 for approval and also in the timing of approval.

7 For this reason, the advisory committee meeting

8 today will not be one in which a final approval

9 recommendation is being requested.

10 The FDA is seeking the advice of the

11 Psychopharmacologic Drugs Advisory Committee and

12 experts in clinical research in alcoholism on your

13 assessment of the evidence provided in support of

14 the efficacy of this product. We are inviting the

15 committee to discuss a series of questions probing

16 the issues surrounding the efficacy results and to

17 make recommendations that will ultimately aid the

18 FDA in making its determination once the other

19 aspects of the application are complete.

20 These will lead to the final decision

21 about the approvability of the product for the

22 maintenance of abstinence in chronic alcoholism.

23 Thank you.

24 DR. OREN: Thank you, Dr. McCormick.

25 I would like to ask three more members of

17

1 our panel who arrived to introduce yourselves, tell

2 us who you are, where you are from.

3 Dr. Cook?

4 DR. COOK: Dr. Cook, University of

5 Chicago.

6 DR. OREN: Dr. Schatzberg?

7 DR. SCHATZBERG: Dr. Schatzberg from

8 Stanford University.

9 DR. OREN: Dr. O\'Brien?

10 DR. O\'BRIEN: Charles O\'Brien, University

11 of Pennsylvania.

12 DR. OREN: We will now move on to the

13 presentations by Lipha. I would like to introduce

14 Dr. Anita M. Goodman, Executive Vice President and

15 Chief Operating Officer of Lipha.

16 Lipha Presentations

17 Introduction

18 DR. GOODMAN: Good morning.

19 \[Slide.\]

20 I am Anita Goodman of Lipha

21 Pharmaceuticals. I would like to introduce our

22 presentation on acamprosate, a new therapy for

23 maintaining abstinence in alcohol dependence.

24 \[Slide.\]

25 Alcohol dependence is a medical disorder

18

1 which afflicts at least 8 million Americans with

2 almost an equal number of alcohol abusers. The

3 cost to society of alcohol dependence are enormous,

4 both in terms of medical and hospitalization costs,

5 losses and economic potential from reduced

6 productivity and premature death, and costs related

7 to incarceration and judicial process.

8 Beyond the obvious economic implications,

9 costs cannot be attributed to the significant

10 emotional toll this disorder extracts from families

11 affected by alcohol dependence and for the loss of

12 lives, both the lives of patients often still in

13 their prime and the innocent lives of those killed

14 by drunk drivers.

15 Every person in this room knows and has

16 been touched by at least one person whose entire

17 life has been altered and all too often ruined by

18 alcohol dependence. The effect of that dependence

19 reaches out and extends to everyone who that loves

20 them, that cares about them and that works

21 alongside them.

22 The treatment of alcohol dependence is not

23 easy nor, in its current status, is it uniformly

24 successful. It requires the voluntary engagement

25 and time commitment of the patient, involvement of

19

1 family members and concerned friends, and a team

2 approach of care providers ranging from self-help

3 groups, social workers, to psychologists,

4 psychiatrists and internists.

5 \[Slide.\]

6 The role of pharmacotherapy in this

7 disorder continues to be limited by lack of

8 available approved medications and possibly also by

9 some resistance on the part of the treatment

10 community to consider alcohol dependence as

11 amenable to treatment by anything except intensive

12 behavioral and psychotherapy.

13 Furthermore, from a product-development

14 point of view, there is the additional lack of

15 universally accepted outcome parameters. This is

16 undoubtedly one of the areas we will touch on

17 today. In contract to diabetes or hypertension,

18 for example, where there are universally agreed to

19 and reliably measurable endpoints for the

20 regulatory assessment of the product\'s

21 efficacy\--for example, hemoglobin A1C and blood

22 glucose levels in diabetes, or blood-pressure

23 changes in hypertension\--the ideal parameter or

24 parameters for measuring outcome in trials or

25 therapies for alcohol dependence have not been

20

1 agreed to and, in fact, are still under active

2 discussion both by academicians as well as

3 regulatory agencies.

4 In the studies described in your briefing

5 documents, we have proposed and utilized a group of

6 related parameters linked to self-reported drinking

7 behavior but in the context of a platform of

8 abstinence. The FDA has expressed some concerns

9 about the methodologies in obtaining

10 outcome-related information and we will address

11 this today.

12 Unlike almost every other medical

13 disorder, as Dr. McCormick pointed out, there are

14 only two pharmacotherapies available which are

15 specific for alcohol dependence post-withdrawal,

16 the aversive agent disulfiram and the opioid

17 antagonist naltrexone. Both of these drugs,

18 however, have limitations in their general

19 applicability related to their mechanism of action

20 either because patients may have significant

21 hepatic dysfunction or may slip to drinking.

22 Thus, a medication such as acamprosate

23 that is more encompassing should be welcomed by the

24 treatment community.

25 \[Slide.\]

21

1 This morning, you will be hearing about

2 the development of acamprosate and its current

3 global registration status from my French

4 colleague, Dr. Silvie Chabac, who is based at

5 Lipha\'s headquarters in Lyon, France. Dr. Chabac

6 has been involved with acamprosate clinical

7 research for many years and brings considerable

8 knowledge and experience to today\'s meeting.

9 In her presentation, Dr. Chabac will

10 describe to you the core acamprosate studies which

11 comprise the registration dossier for this product

12 worldwide.

13 \[Slide.\]

14 Fourteen double-blind placebo-controlled

15 studies were conducted throughout Europe between

16 1989 and 1995. From these studies, thirteen of

17 which supported the efficacy and safety of

18 acamprosate in maintaining abstinence and only one

19 of which showed no significant treatment effect, we

20 selected three as pivotal for the following

21 reasons.

22 \[Slide.\]

23 All fourteen studies in the clinical

24 portion of the European dossier were conducted by

25 qualified experts who are alcohol specialists

22

1 working in specialized centers or departments. All

2 the studies were performed according to existent

3 standards of good clinical practice. They all

4 followed specific protocols and have existing

5 retrievable case-report forms as well as electronic

6 databases.

7 However, the three studies considered by

8 Lipha to further qualify as pivotal, had the

9 following additional characteristics. The study

10 centers were still active and the source documents

11 and other medical records were still largely

12 accessible, thereby permitting an on-site FDA audit

13 as is required for a new drug application.

14 You have to keep in mind that collectively

15 the archival requirements for retaining documents

16 had been exceeded for the majority of these

17 European studies.

18 \[Slide.\]

19 In addition, for these three studies, the

20 clinical research organizations or CROs which had

21 managed the trials were still active and also had

22 some of the original trial management

23 documentation. The final point would be that two

24 of these studies looked at two dose levels of

25 acamprosate and they also, thereby, provide some

23

1 suggestion of dose responsiveness.

2 \[Slide.\]

3 Following Dr. Chabac will be a

4 presentation by Dr. George Koob, Professor and

5 Director of the Neuropharmacology Division of the

6 Scripps Research Institute in La Jolla. Dr. Koob

7 is the recipient of this year\'s Distinguished

8 Investigator\'s Award of the Research Society on

9 Alcoholism and the recipient of this year\'s award

10 from the American Society on Addiction Medicine.

11 Dr. Koob has worked in the area of animal

12 models and mechanisms of alcohol dependence for

13 many years and has provided significant insight

14 into the way in which acamprosate exerts its

15 activity. He is the author of more than 500

16 peer-reviewed articles largely on addiction.

17 This morning, Dr. Koob will discuss

18 acamprosate\'s preclinical effects, its purported

19 mechanism of action and will also briefly cover

20 acamprosate\'s pharmacokinetic profile.

21 \[Slide.\]

22 Dr. Karl Mann, Professor and Chairman of

23 the Department of Addictive Behavior and Addiction

24 Medicine at the University of Heidelberg in Germany

25 and also an investigator in one of the pivotal

24

1 studies will then review for you the efficacy

2 results from the three pivotal European clinical

3 trials.

4 Dr. Mann has the unique distinction of

5 holding the only Chair of Addiction in Germany. He

6 is the European editor of the journal Alcoholism,

7 Clinical and Experimental Research and is the

8 author of more than 200 scholarly papers in the

9 area of clinical research on alcoholism.

10 Because, as Dr. McCormick has mentioned to

11 you, the safety review of acamprosate is still

12 ongoing, we cannot present safety data today, so

13 Dr. Mann\'s focus will be on efficacy only. As you

14 know from the documents you have received, the FDA

15 has convened this committee and its invited experts

16 to consider the persuasiveness of the data from

17 these European studies for the proposed indication.

18 I would like to point out that we, Lipha,

19 always intended to rely heavily on the substantial

20 European database for this new drug application in

21 our overall development strategy. But we also felt

22 that it was very important to conduct a safety and

23 efficacy study of acamprosate in alcohol-dependent

24 patients in the United States.

25 At the recommendation of the division,

25

1 very broad admission criteria were used. The

2 results of the American trial called U.S. 96.1 in

3 your document which may, at first, appear to be at

4 odds with the conclusions of the European studies

5 which Dr. Mann will describe has, however, afforded

6 us the opportunity to gain further insight into how

7 acamprosate works best.

8 \[Slide.\]

9 Dr. Barbara Mason, Professor of Psychiatry

10 and Behavioral Sciences and Director of the

11 Substance Abuse Division at the University of Miami

12 as well as overall principle investigator for the

13 American study, U.S. 96.1, will present data from

14 the study and the understanding that it has

15 brought. Again, at the division\'s request, the

16 discussion will focus on efficacy.

17 Dr. Mason has extensive experience in

18 clinical alcohol research and has been the

19 principle investigator of many NIH-funded clinical

20 trials involving medication development in

21 alcoholism. She serves on the Scientific Advisory

22 Council of the National Institute on Alcohol Abuse

23 and Alcoholism and is field editor for the Journal

24 of Neuropsychopharmacology.

25 Dr. Mason has published extensively

26

1 including in such journals as the Archives of

2 General Psychiatry and the Journal of the American

3 Medical Association.

4 \[Slide.\]

5 Following her presentation, I will then

6 make some concluding comments and answer or

7 redirect questions you may have.

8 \[Slide.\]

9 As Dr. McCormick has enumerated, we have

10 been asked by FDA to address the following issues.

11 Why were the efficacy results for the ITT

12 population in the U.S. trial inconclusive in

13 contrast to the consistently positive European

14 studies? Were the methodologies appropriate and

15 are European and American alcohol-dependent

16 populations comparable?

17 In the next hour, our presentations will

18 bring clarity to these issues.

19 Thank you. Dr. Chabac will now speak.

20 European Development Program

21 and Current Registration Studies

22 DR. CHABAC: Good morning.

23 \[Slide.\]

24 My name is Silvie Chabac. I was the

25 doctor responsible for the European Development of

27

1 Program of acamprosate. I would like to give you

2 an overview of these programs along with the

3 current registration status of acamprosate.

4 \[Slide.\]

5 The story of acamprosate began in France

6 in the early 1980s. The French pharmaceutical

7 company, Laboratoires Meram, decided to investigate

8 amino-acid neuromediators as a new research

9 project. During the screening tests, one compound

10 was particularly noted for its outstanding

11 pharmacological properties, calcium acetyl

12 homotaurine, now best known as acamprosate.

13 Based on animal work that Dr. Koob will be

14 describing shortly, Meram then decided to

15 specifically develop this compound for alcohol

16 dependence. In 1987, the 333 milligram acamprosate

17 tablet was authorized for marketing authorization

18 in France. It has been commercially available

19 there since 1989.

20 At that stage, Meram transferred the

21 license for acamprosate to its sister company,

22 Lipha, for worldwide development.

23 \[Slide.\]

24 The same year, Lipha began an extensive

25 clinical program throughout European for

28

1 registration purposes. Over 4000 alcohol-dependent

2 patients were randomized in fourteen double-blind

3 placebo-controlled studies conducted in ten

4 different European countries. This

5 clinical-development program included long-term

6 studies, two phase II and twelve phase III, with

7 the treatment period ranging from 3 to 12 months.

8 \[Slide.\]

9 Based on the solid efficacy and safety

10 results of this development program, Lipha began

11 the worldwide registration of acamprosate. Today,

12 it is registered in 30 countries on five continents

13 where alcohol dependence is recognized as a disease

14 and a major public-health problem. Since 1995,

15 worldwide registration has been ongoing, first in

16 Europe where it is now approved for marketing in

17 nineteen countries including Scandinavian countries

18 and Eastern Europe, then, in South and Central

19 America and in Mexico. Three years ago,

20 acamprosate was registered in Australia, Singapore

21 and Hong Kong, then last year in South Africa.

22 Finally, to complete the process, Lipha

23 submitted an NDA for acamprosate in the United

24 States of America last December. In every country

25 where it is marketed, acamprosate has a specific

29

1 labeling; maintenance of long-term abstinence in

2 patients with alcohol dependence who have been

3 withdrawn from alcohol.

4 Acamprosate should be prescribed in

5 conjunction with counseling for a recommendation

6 treatment duration of one year. To date, around

7 the world, there have been 1.5 million patient

8 years of exposure. This group of patients had the

9 opportunity to benefit from the treatment with

10 acamprosate for alcohol dependence.

11 Now, we would like to make that

12 opportunity available to patients in the United

13 States.

14 Thank you very much.

15 Acamprosate: Mechanism of Action,

16 Preclinical Effects and Pharmacokinetics

17 DR. KOOB: Good morning.

18 \[Slide.\]

19 I am George Koob. I have been consulting

20 with Lipha Pharmaceuticals since 1990,

21 approximately eleven or twelve years, on their

22 preclinical program.

23 \[Slide.\]

24 Acamprosate or calcium acetyl homotaurine

25 is the calcium salt of acetylated homotaurine.

30

1 Homotaurine is a homolog of the naturally occurring

2 amino acid taurine and does not readily cross the

3 blood-brain barrier. The acetylation of

4 homotaurine makes the compound more lipophilic and

5 allows penetration of the blood-brain barrier by

6 this compound.

7 I am going to discuss with you, very

8 briefly, this morning the neuropharmacological

9 mechanism of action of acamprosate, its

10 pharmacokinetics and its interactions with other

11 drugs or, shall I say, its lack of interaction with

12 other drugs.

13 \[Slide.\]

14 The neuropharmacological mechanism of

15 action of acamprosate has been elucidated by

16 extensive use of animal models. Animal models of

17 alcohol have evolved significantly over the past

18 twenty years and have a high degree of face and

19 predictive validity.

20 \[Slide.\]

21 The animal models for understanding the

22 actions of acamprosate can be understood in terms

23 of excessive drinking, excessive drinking that is

24 driven by dependence, abstinence and relapse. I am

25 going to give you one clear example of the actions

31

1 of acamprosate preclinically in an animal model of

2 excessive drinking.

3 \[Slide.\]

4 Before I do that, let me just review with

5 you very quickly the evidence that was accumulating

6 on acamprosate through animal models. It is

7 critical for you to understand that, in all of

8 these models, the animals were producing an

9 excessive amount of alcohol intake by a variety of

10 means. Acamprosate decreases alcohol drinking in

11 rats that were selected for excessive drinking. In

12 one of the earliest studies, acamprosate decreases

13 alcohol intake in dependent animals. This is

14 another one of the early studies done by Le Magnin

15 group. Acamprosate reverses the preference for

16 alcohol and the increase in drinking in dependent

17 animals during withdrawal.

18 I am going to show you an example from our

19 own laboratory where acamprosate eliminates the

20 alcohol deprivation effect in rats under

21 free-drinking operant limited-access conditions.

22 \[Slide.\]

23 Rodents, like human beings, and this

24 speaks to the face validity of the animal models,

25 don\'t like the taste of alcohol so, to induce a

32

1 rodent to drink alcohol, one starts with a sweet

2 solution. We, in our laboratory, use saccharine,

3 and fade in alcohol and ultimately fade out the

4 saccharine. These animals are in limited-access

5 situations where they drink alcohol once in the

6 evening. They have a lever that they press to

7 obtain 10 percent alcohol or water. By the end of

8 a two- or three-week period, these animals are

9 drinking pharmacological amounts of alcohol in this

10 30-minute session.

11 \[Slide.\]

12 You can see that the alcohol intakes range

13 from about 20 to 80 milligram percent which is

14 equivalent to what you or I would have from one

15 glass of wine. In doing this kind of a procedure,

16 you can reliably have a baseline drinking of

17 alcohol but you can also make manipulations that

18 will produce increases in drinking that at least

19 have face validity and some predictive validity for

20 the human condition.

21 \[Slide.\]

22 In this side, what I am showing you is if

23 you stop the animal\'s availability to alcohol for a

24 series of days, what you see is an increase in

25 alcohol intake that is quite dramatic when the

33

1 animal is reinstated. This is called the alcohol

2 deprivation effect in rodent models. It is

3 equivalent to the abstinence violation effect in

4 human alcoholics.

5 What you can see from this slide is that

6 the animals that have three, five, seven or

7 fourteen days of abstinence between their

8 self-administration show a dramatic increase in the

9 amount of alcohol. They show a dramatic increase

10 in their blood-alcohol levels, jumping from

11 30 milligram percent, on average, to approximately

12 80 milligram percent.

13 What you can also see is, that on a

14 baseline condition, the behavior is very stable in

15 this model. You can also see here that there is no

16 effect of the alcohol deprivation effect on water

17 intake.

18 \[Slide.\]

19 Acamprosate dose-dependently, as in other

20 animal models of excessive drinking, decreases the

21 alcohol deprivation effect. There are a couple of

22 very important points from this slide from the

23 point of view of the animal models and the

24 preclinical effects of acamprosate.

25 One is that acamprosate has no effect on

34

1 baseline drinking at these doses. Higher doses

2 will affect baseline drinking. The other issue is

3 that acamprosate has no effect on water intake.

4 Both of these argue to the selectivity of the

5 effect on excessive drinking and the selectivity of

6 the effect from the point of view of other

7 behavior.

8 \[Slide.\]

9 It is also important to note what

10 acamprosate does not do in animal models. What

11 this slide addresses is that acamprosate does not

12 produce what we would call anxiolyticlike effects

13 or anticonflict effects in animal models of

14 anxiety. The other points on this slide just

15 simply illustrate the fact that acamprosate has no

16 abuse potential in preclinical animal models.

17 Acamprosate does not substitute for

18 alcohol. It does not block the discriminative

19 stimulus properties of alcohol. It doesn\'t have

20 any reinforcing or aversive effects on its own and

21 it doesn\'t interact with other drugs of abuse.

22 \[Slide.\]

23 The neuropharmacological mechanism of

24 action of acamprosate is thought to focus on three

25 major areas as depicted in this slide. Acamprosate

35

1 is thought to modulate glutamate receptors as

2 illustrated by No. 1 here. Acamprosate is thought

3 to modulate voltage-dependent calcium channels and

4 acamprosate may also have long-term effects on

5 intermediate early gene products that can

6 ultimately change subunit expression of glutamate

7 receptors. Glutamate, as you know, is the major

8 excitatory neurotransmitter in the brain.

9 \[Slide.\]

10 More specifically, the

11 neuropharmacological effects of acamprosate can be

12 shown in the following way. Acamprosate has been

13 clearly shown to inhibit neuronal hyperexcitability

14 by decreasing presynaptic release of the excitatory

15 neurotransmitter, glutamate, and by decreasing

16 postsynaptic excitability of glutamate receptors.

17 Acamprosate, as I mentioned, inhibits

18 calcium influx through the NMDA glutamate receptor

19 possibly through an interaction with the polyamine

20 site on the NMDA receptor. This is very important

21 for understanding its action because this is a

22 modulatory effect. It is thought to be an

23 allosteric interaction. It is not a direct

24 receptor action. Acamprosate is not MK801, for

25 those of you versed in this. That means that it is

36

1 not a noncompetitive antagonist to the glutamate

2 receptor. It does not interact directly with any

3 receptor component of the glutamate receptor that

4 would lend it to toxicity.

5 Acamprosate also inhibits calcium influx

6 through voltage-dependent calcium channels. Just

7 to add to its profile as an antihyperexcitability

8 agent, acamprosate also increases the synaptic

9 availability of the inhibitory neurotransmitter

10 taurine, the work of Philip De Witte and his

11 colleagues.

12 \[Slide.\]

13 What does this mean? What it means, very

14 simply, is that acamprosate acts a partial

15 coagonist at the glutamate receptor through an

16 allosteric interaction with the polyamine binding

17 site on the NMDA glutamate receptor complex.

18 What does this translate to? It

19 translates to a normalization of the receptor

20 system that has become disregulated by the chronic

21 administration of alcohol. That statement, itself,

22 has all the key elements there. It is the

23 normalization of a disregulated receptor system and

24 neurotransmitter system that has been disregulated

25 by chronic alcohol and chronic withdrawal and

37

1 repeated alcohol and repeated withdrawal.

2 So neuropharmacological consequences are

3 to enhance activation of the glutamate receptor

4 when endogenous levels of the activators such as

5 glutamate are low but, most critically, to inhibit

6 activation when levels of the endogenous activators

7 are high such as during alcohol withdrawal.

8 \[Slide.\]

9 This lead to further observations of great

10 scientific interest that acamprosate also has

11 neuroprotective actions. I am not going to go

12 through the details but simply to say that, in a

13 number of in vitro and preclinical models,

14 acamprosate has been shown to have

15 neuroprotective-like effects.

16 \[Slide.\]

17 From the point of view of the

18 pharmacokinetics, I thought I would go through this

19 and spend a little time on this. Acamprosate does

20 have bioavailability and that has been adequately

21 demonstrated presumably because of the

22 modifications of the molecule to make it more

23 lipophilic. That is 11 percent in humans, 16

24 percent in rodents.

25 It has an elimination half-life of 18

38

1 hours in humans. Similar, a little longer, in

2 rodents. The time-to-steady-state plasma levels is

3 five to seven days, a critical issue in regards to

4 the design of preclinical studies and clinical

5 studies. There is no protein binding of

6 acamprosate in the blood.

7 The most critical point on this slide is

8 that the elimination of acamprosate is by renal

9 excretion. It is not metabolized and, thus,

10 hepatically compromised patients do not have to

11 worry about taking acamprosate.

12 The lethality in humans, there is no known

13 lethality. In rodents, the dose that has produced

14 lethality is 6 grams per kilogram. This is several

15 log units higher than the effective dose. It is

16 way out there.

17 \[Slide.\]

18 Acamprosate has basically no interactions

19 with any alcohol. Other drugs that are used for

20 the treatment of alcoholism and other

21 psychotherapeutic drugs with the exception that

22 there is data in press\--Dr. Mason has a paper in

23 press in Neuropsychopharmacology showing that

24 naltrexone actually increases plasma levels of

25 acamprosate by about 25 to 30 percent depending on

39

1 what measure you are using.

2 The mechanism for that increase in plasma

3 acamprosate levels by naltrexone is not known but

4 probably has something to do with its pericellular

5 mechanism of absorption.

6 \[Slide.\]

7 So I would like to stop now just with this

8 slide to reiterate the neuropharmacologic mechanism

9 of action of acamprosate. This

10 neuropharmacological action of acamprosate, as I

11 said earlier, has three major components. The

12 bottom line is that acamprosate normalizes the

13 hyperexcitability in the brain associated with

14 alcohol dependence, notably alcohol withdrawal and

15 protracted abstinence.

16 Acamprosate does this by modulating the

17 glutamate receptor as a partial agonist which is a

18 very effective pharmacological way of returning the

19 brain to a normal state. It also modulates

20 voltage-dependent calcium channels and it also

21 interacts with the taurine neurotransmitter which

22 is an inhibitory neurotransmitter also decreasing

23 neuronal hyperexcitability.

24 Thank you.

25 Efficacy Results from Three Pivotal Clinical Trials

40

1 DR. MANN: Good morning. I\'m Karl Mann.

2 I am working at the University of Heidelberg. It

3 is my pleasure to share some of the data that we

4 gained about ten years ago in these European trials

5 with acamprosate. Apart from my academic

6 affiliation, I also run a hospital with inpatient

7 and outpatient treatment for alcoholics where we do

8 treat patients with acamprosate on a day-to-day

9 basis so we could share also some of the

10 experiences that we have been gaining there with

11 you today.

12 \[Slide.\]

13 I am going to talk about these three

14 studies which were done in Europe about ten years

15 ago. Their objective was to look at the safety and

16 efficacy of acamprosate versus placebo in

17 maintaining long-term abstinence in alcoholics

18 following alcohol withdrawal.

19 \[Slide.\]

20 These studies were done in Belgium, in

21 Germany and in France. They were all multicenter,

22 like twelve centers in this study and twelve

23 centers in the German study, 31 centers in the

24 French study with a large number of patients

25 included which wound up to almost 1,000 patients in

41

1 these three studies.

2 \[Slide.\]

3 As I said, they were double-blind

4 randomized and placebo-controlled, all three of

5 them. They were multicenter. Two of them used two

6 dosage levels like the Pelc study and the Paille

7 study in France. They had one arm with a medium

8 dose of acamprosate and one arm with about 2 grams

9 of acamprosate per day whereas the German study had

10 only one arm of medication versus placebo.

11 The Pelc study was done over a period of

12 three months, twelve weeks, and there was no

13 after-care after that whereas the other two studies

14 were over a period of a whole year, so a whole year

15 of study. Then, in the German study, another

16 twelve months of investigation of looking how the

17 patients did afterwards. In the Paille study in

18 France, this was six months.

19 It is also important to note that the

20 psychosocial therapy that was provided to the

21 patients was site-specific. There was not one

22 psychosocial treatment for everybody across all

23 sites. But, of course, within the sites, those

24 patients who received acamprosate or placebo also

25 received the same kind of psychosocial treatment.

42

1 \[Slide.\]

2 We had male and female patients, of

3 course, in these studies. We had a lower and an

4 upper age limit so no patients who were older than

5 65 years were allowed. They were all DSMIII or

6 DSMIII-R, positive alcoholics. They all, and this

7 is another important point, had detoxification

8 prior to the entry into this study.

9 This is something you can see here. The

10 Pelc study required at least five days of clear

11 abstinence before they could enter the study. In

12 the German study, this was between two weeks and

13 four weeks, the window in which they could enter

14 the study. In the French study, this was one week

15 up to about four weeks, also.

16 \[Slide.\]

17 Here are the methods for collecting data,

18 drinking data, in these three studies in Europe.

19 Of course, there is self-report on alcohol

20 consumption at each visit done by the patient.

21 Then, of course, also, there is confirmation

22 looking at biological markers such as gamma GT,

23 liver-function test, MCV, CDT and also

24 breathylizing at each single visit. So each most

25 of these things were done at each of these single

43

1 visits.

2 Then, of course, the investigator who

3 either was a trained psychologist working in this

4 field or who was a doctor working in this field,

5 they had to make and give their clinical global

6 impression about the drinking status of the

7 patient.

8 These were in addition to their

9 professional training. They were also trained

10 prior to the studies in collecting the data using

11 the interviews and the material that was provided

12 in these studies.

13 Then, finally, family members or other

14 caretakers such as the private doctor or the family

15 doctor of the patient was also involved in trying

16 to find out what the drinking status of this

17 patient was. This was done, the integration of all

18 this material, or all this information, by the

19 investigator who had then to say, well, he is

20 abstinent or he is drinking and he did resume

21 drinking ten days ago, for instance.

22 Whenever there was a discrepancy between

23 those variables, then we said, okay, we are going

24 the conservative way. Then we say he was drinking.

25 \[Slide.\]

44

1 Here is the number of patients. You can

2 see we had about 1,000 who were randomized. This

3 is the ITT population. Then the completion of the

4 study you can see here. That is, to me at least, a

5 very important point. You can see that in the

6 acamprosate arms, we retained much more, or many

7 more, patients than we did in the placebo arm.

8 Also this is not, and was not, an outcome

9 criteria in the first place. To me, as a

10 clinician, as a psychiatrist, this is a very

11 important issue because as long as I have and see

12 the patients, I can do something about them. So,

13 for me, clinically, this is a very meaningful and

14 positive figure here.

15 So then, conversely, of course, we have

16 these figures of the patients who discontinued the

17 study.

18 \[Slide.\]

19 The reasons for discontinuation were

20 different. We had, as you have seen already, 46

21 percent who discontinued while being on acamprosate

22 and 60 percent being on placebo, for instance,

23 because of lost-to-follow-up or treatment failure

24 or other reasons such as patient refusal, et

25 cetera. So, there again, we meet these figures

45

1 that I have shown to you before. More patients

2 stay in treatment when they are treated with

3 acamprosate.

4 \[Slide.\]

5 Here are the demographics of these

6 studies. Of the patients in these studies, we had

7 85 or 80 percent males, more or less. We had a

8 mean age of 42, 43 years, 70 kilograms of body

9 weight. We had a mean duration of alcohol

10 dependence of about ten years throughout these

11 studies.

12 Then these are the consumption data from

13 which you can see that many of those people, like

14 around 80 percent or 70 to 80 percent, had had,

15 like, ten shots of whiskey a day, which is a lot,

16 or 40 ounces of wine a day or 80 ounces of beer a

17 day.

18 All of them had been detoxified prior to

19 the entry of the study. That is, again, something

20 we have already touched upon. So almost all were

21 abstinent at baseline. So that was the same across

22 all three European studies which I am presenting to

23 you here.

24 \[Slide.\]

25 Here are the treatment exposures in weeks

46

1 within these studies. You can see the Pelc study

2 which lasted 13 weeks, the average was 10 to 11

3 weeks on treatment. The German study\--by the way,

4 this acronym stands for Prevention of Relapses in

5 Alcoholics with Acamprosate. That is what PRAMA

6 stands for\--48 weeks, and we had about 32 weeks on

7 treatment in the acamprosate group and less on

8 treatment in the placebo group, and then, again,

9 the Paille study, 35 in the low-dose acamprosate,

10 37 in the high-dose and 31 in the placebo group.

11 \[Slide.\]

12 Compliance. This was based on pill count,

13 the pills that were turned in by the patients when

14 they came to the visits. So we have about 97

15 percent in the Pelc study. Because these are much

16 longer, of course, we have a lower but still

17 satisfactory compliance of 81 percent in the German

18 study, 82 to 88 percent in the French study.

19 \[Slide.\]

20 Here are the outcome criteria that were

21 used throughout these three European studies.

22 First of all, of course, was time to first drink.

23 So whenever someone had a relapse, we counted, or

24 we measured the time when this occurred and this

25 was entered into this analysis. Then we did a

47

1 Kaplan-Meier statistics on this.

2 Then, the second outcome criterion was

3 rate of rate of complete abstinence which meant the

4 percent of patients completing the study without

5 consuming any alcohol. Of course, these two are

6 very conservative measures and you certainly\--or,

7 let\'s put it another way. There is more

8 information in this data than just the time when

9 someone had his first relapse because these are

10 relapses to drinking at all. That is different

11 from the studies which were done at the same time

12 in the U.S. where you had return to heavy drinking.

13 This is return to the first drink.

14 If you do this, you might lose someone who

15 had one drink or maybe two days of drinking and

16 then he was abstinent again and he is always

17 counted as a failure.

18 So, what we did in order to try to pick up

19 this additional information is we looked at

20 something that was called cumulative abstinence

21 duration in percent. That is the time on the study

22 where a patient is reported to be abstinent no

23 matter whether they had a relapse or not at some

24 time during the study.

25 \[Slide.\]

48

1 So here are the results. First, the

2 Kaplan-Meier for the first drink in the Pelc study.

3 You see the placebo group in blue. They are having

4 relapses. Of course, the other patients have

5 relapses. The difference between the two groups is

6 statistically significant if you take dropouts as a

7 failure.

8 There is no difference between the two

9 dosages. The low and high dosage of acamprosate

10 did not produce a significant difference between

11 those two but the other one compared with placebo

12 was clearly significant.

13 \[Slide.\]

14 The same is true for the PRAMA in Germany,

15 again, time to first relapse. Those on placebo,

16 they tended to relapse earlier than the patients on

17 acamprosate.

18 \[Slide.\]

19 The Paille study; again, we have a

20 difference between placebo and the two treatment

21 arms with acamprosate which, again, between the two

22 arms, there was not a difference in the Paille

23 study time to first relapse.

24 \[Slide.\]

25 The second outcome criterion, you

49

1 remember, was complete abstinence or rate of

2 complete abstinence. Here is the Pelc study,

3 again, after only three months of treatment. Those

4 on placebo had about 14 percent whereas the others

5 who were treated with acamprosate were at about 40

6 percent abstinent after twelve weeks.

7 After one year in the German study, we

8 have here 12 percent versus 29 percent, again a

9 very clear-cut 2.4-fold advantage for acamprosate.

10 In the Paille study, there is a significant

11 difference between placebo and the high dosage of

12 acamprosate, also. So, I think, also they are

13 clear results.

14 \[Slide.\]

15 Now this percentage of abstinent days, or

16 the CAD percent. Again, in the Pelc study we have

17 a difference between placebo and the two treatment

18 arms. In the German study, we have the same. In

19 the Paille study, placebo also is different from

20 the high-dosage of acamprosate.

21 \[Slide.\]

22 Here is the summary. First outcome

23 criterion, time to first relapse, a clear

24 indication that acamprosate works better with about

25 a factor of two to three times longer stay with

50

1 relapse than in the placebo group.

2 The complete abstinence rate, it is the

3 same result, between 1.7 and 2.7 times greater or

4 better with acamprosate compared with placebo.

5 Also, for this third outcome criteria, we have an

6 advantage in favor of acamprosate versus placebo.

7 These were the results of these three pivotal

8 studies which were done in Europe.

9 \[Slide.\]

10 With my final slide, I would like to show

11 you again where I work and I might see you again at

12 one of these occasions. Thank you.

13 Analysis of the U.S. Study Results

14 DR. MASON: Good morning.

15 \[Slide.\]

16 I am Dr. Barbara Mason and I served as

17 overall principle investigator for the U.S.

18 acamprosate trial.

19 \[Slide.\]

20 In this section, I am going to first be

21 covering these points for the U.S. multicenter

22 trial. I will conclude by integrating the U.S. and

23 European acamprosate clinical trial experience in

24 outpatients with alcohol dependence.

25 \[Slide.\]

51

1 The U.S. multicenter trial had two

2 overarching and somewhat competing objectives. The

3 first objective was to provide FDA with the

4 requested reassurance about the safety of

5 acamprosate in the typical American outpatient with

6 alcohol dependence who was considered to be more

7 likely to abuse other drugs and have less access to

8 inpatient detoxification services than their

9 European counterparts.

10 Additionally, because acamprosate is not

11 metabolized and it is eliminated unchanged by the

12 kidneys, there was interest in examining the safety

13 of acamprosate without any restrictions on study

14 admission because of serum-creatinine level or

15 liver-function-test abnormalities or patient age as

16 opposed to the European studies.

17 One implication, of course, of no upper

18 age limit is greater chronicity in a progressive

19 disorder and, likewise, no upper limit for

20 liver-function test may admit patients with more

21 severe alcohol dependence.

22 \[Slide.\]

23 The second objective related to the

24 sponsor\'s interest in evaluating the efficacy of

25 the standard therapeutic 2 grams per day dose of

52

1 acamprosate but given as two 500 milligram tablets

2 twice a day in contrast to the European dosage

3 schedule of two 333 milligram tablets three times a

4 day.

5 These two dosing schedules had previously

6 been shown to be bioequivalent in the multidose

7 crossover pharmacokinetic study. In addition,

8 given the safety and tolerability of the standard 2

9 gram dose of acamprosate, there was interest in

10 evaluating a higher 3 gram daily dose on an

11 exploratory basis in a smaller group of subjects.

12 \[Slide.\]

13 We developed two strategies specified in

14 the study protocol and case-report form to control

15 for factors generally associated with reduced

16 alcoholism treatment efficacy. The study was

17 particularly vulnerable to the influence of these

18 factors because of the broad admission criteria

19 which had been requested by the FDA for their

20 safety evaluation.

21 First, as in many pharmacologic studies

22 involving drugs with prolonged time to steady

23 state, an efficacy evaluable population was defined

24 that included those subjects who took medication

25 for the seven days needed to reach acamprosate

53

1 steady state and who were at least 75 percent

2 compliant with medication thereafter.

3 Additionally, this efficacy evaluable

4 population excluded those whose urine tested

5 positive for elicit drugs at any study visit. A

6 second strategy was to include standardized

7 baseline measure of variables identified in the

8 alcoholism-treatment literature as reliably

9 associated with poor outcome such as severity of

10 dependence or comorbidity or treatment goal of

11 nonabstinence.

12 These variables were to be examined in

13 relation to outcome as potential covariates in

14 order to reduce residual variation in the analyses

15 and to off set the influence of random imbalances

16 of baseline variables, particularly for subgroups

17 of interest.

18 \[Slide.\]

19 As in the European pivotal trials, the

20 U.S. study was double-blind, placebo-controlled

21 with random assignment to treatment and all

22 subjects met DSM criteria for alcohol dependence.

23 Unlike the European pivotal trials, the U.S. study

24 did not exclude substance abusers or those over

25 65 years of age and did not require detoxification

54

1 nor an abstinent interval prior to randomization.

2 In the European pivotal trials, as Dr.

3 Mann mentioned, all subjects received whatever

4 supportive psychosocial therapy was routinely used

5 by the center or investigator. Conversely, in the

6 U.S. trial, a standardized behavioral therapy

7 program that included a scripted therapist manual

8 and patient handout materials was provided to all

9 study participants.

10 \[Slide.\]

11 There is no gold standard for determining

12 drinking occurring between study visits or office

13 visits. Therefore, self-report with multiple

14 sources of corroboration whenever possible is the

15 current state of the art, both for alcoholism

16 pharmacotherapy trials as well as in treatment

17 settings.

18 European pivotal and U.S. trials all

19 relied on self-reported drinking gathered under

20 specific conditions shown to enhance accuracy of

21 self-report including eliciting the drinking data

22 by an alcoholism expert and providing written

23 assurance of confidentiality of the data.

24 All data were collected in clinical or

25 research settings which encouraged honest reporting

55

1 as opposed to probation offices or other settings

2 which might have legal or punitive ramifications

3 for disclosure of drinking.

4 Three of the four trials provided diaries

5 that were collected at each study visit either to

6 aid recall or to provide information on general

7 clinical status. Only the U.S. study included a

8 daily drinking calendar using standard drink icons

9 to enhance precision of self-reported quantity and

10 frequency of drinking, as shown in the next slide.

11 \[Slide.\]

12 Standard drinks were defined on the basis

13 of alcohol content with a beer equal to a glass of

14 wine equal to a shot of hard liquor. Although

15 standard drinks in the U.S. study contained

16 approximately 15 grams of pure alcohol, a bit more

17 generous than shown here, I am showing you these

18 12-gram icons because for today\'s presentation and

19 for your briefing document, all drinking

20 information is based on the smaller European

21 12-gram standard drink.

22 \[Slide.\]

23 All pivotal trials included multiple

24 biochemical measures to confirm validity of

25 self-report of abstinence or drinking. All trials

56

1 used gamma GT. Both the PRAMA and U.S. studies

2 breathylized patients at each study visit, and Pelc

3 II and U.S. trials tested for alcohol in urine as

4 well.

5 Additionally, PRAMA, Paille and the U.S. trials

6 verified patient self-report with a close friend or

7 relative specified by the patient at multiple time

8 points.

9 In all trials, if there were discrepancies

10 between patient self-report and the corroborating

11 information, typically the most negative outcome

12 would be assumed accurate. The drinking intervals

13 assessed in each trial were of sufficient duration

14 to capture infrequent drinkers and were consistent

15 with methodologic studies confirming the validity

16 of self-report for intervals of these durations.

17 \[Slide.\]

18 The primary study outcomes in the European

19 pivotal trials were informed by an

20 abstinence-oriented treatment tradition with all

21 patients undergoing detoxification and beginning

22 study participation in an abstinence state.

23 Therefore, the first information obtained from

24 participants in these trials at each visit was did

25 they or did they not drink since their last study

57

1 visit.

2 Four patients who did report drinking, an

3 effort was made in all three European pivotal

4 studies to categorize the amount of alcohol

5 consumed and the number of drinking days since

6 their last study visit as per a case-report form.

7 However, all study primary outcomes, time to first

8 drink, complete abstinence rate, point prevalence

9 of abstinence, were related to abstinence or

10 nonabstinence.

11 Consistent with clinical practice and

12 research involving alcoholism, patients who

13 discontinued prematurely due to alcohol-related

14 reasons, or patients for whom follow-up information

15 was not available were considered treatment

16 failures and as nonabstinent for the remaining

17 treatment period.

18 \[Slide.\]

19 Conversely, the time-line follow-back

20 method used for data collection in the U.S. trial

21 was a research tool originally developed to assess

22 continuous variables associated with controlled

23 drinking as a study outcome as opposed to the

24 categorical outcome of abstinence/nonabstinence.

25 It involves a more rigorous emphasis on

58

1 retrospective estimates of daily drinking through

2 the use of calendar-based memory aids and standard

3 drink icons to enhance recall.

4 The tradeoff for the increased precision

5 of the time-line follow-back method is that it

6 requires more time to administer thereby increasing

7 the burden on the subject in clinic personnel.

8 This may result in increased attrition rates and

9 may be inappropriate in a clinical setting where

10 time is at a premium unless more precision on

11 drinking behavior is needed.

12 In U.S. clinical practice, the time-line

13 follow-back is not used for these reasons. U.S.

14 clinical practice more directly reflects the

15 drinking data collection methods of the European

16 studies.

17 Additionally, the time-line follow-back

18 method used in conjunction with the daily drinking

19 diary, as in the U.S. study, may, in itself, reduce

20 drinking. This impact on outcome has been shown

21 for self-monitoring techniques and other

22 indications; for example, Weight Watchers.

23 One can note that, in a double-blind,

24 placebo-controlled trial, the impact of study

25 procedures should be equally distributed across

59

1 treatment groups. Nevertheless, if study

2 procedures have a therapeutic influence, then the

3 study is actually comparing background treatment

4 plus placebo to background treatment plus

5 acamprosate and the presence of the background

6 treatment might reduce the effect size for

7 potential improvement that acamprosate could

8 provide.

9 \[Slide.\]

10 The U.S. study was a three-armed trial

11 with subjects randomized in a 3 to 3 to 1 ratio to

12 placebo, acamprosate 2 grams a day or acamprosate 3

13 grams a day. 741 patients were screened and, of

14 these, 601 outpatients with alcohol dependence

15 representing 81 percent of those screened were

16 randomized to 6 months of treatment.

17 After the treatment phase, patients were

18 followed for an additional two months

19 off-treatment. In my discussion of the U.S. study,

20 I am going to focus on the comparison between

21 acamprosate 2 grams and placebo since that

22 comparison forms the basis of the sponsor\'s NDA.

23 The 3-gram group was an exploratory dose group of

24 smaller size, as you can see and I won\'t address it

25 further this morning.

60

1 \[Slide.\]

2 As I mentioned before, in comparing the

3 methodologies of the U.S. and European studies, in

4 the U.S. study, all patients were provided with a

5 brief standardized behavioral-therapy program at

6 every study visit. The program was based on

7 principles of motivation enhancement with the goals

8 of abstinence and methodology compliance and was

9 delivered by experienced nurses or counselors with

10 a bachelor\'s degree or higher.

11 Patients were provided with informational

12 handouts about alcohol and acamprosate. There were

13 also tips for quitting drinking and ongoing

14 self-assessment and interactive exercises

15 pertaining to their drinking behavior such as the

16 treatment goals work sheet and the treatment

17 progress summary.

18 The components of this program are

19 currently used in conjunction with acamprosate in

20 Europe\--I have some of the materials here and am

21 happy to share them\--and will shortly be available

22 on line at Acoweb, the Lipha website. In the U.S.

23 trial, the behavioral therapy was implemented

24 across psychiatry, alcoholism-specialty and

25 internal-medicine settings.

61

1 \[Slide.\]

2 The 21 participating treatment centers

3 were located throughout the United States as shown

4 in this map.

5 \[Slide.\]

6 As in the European pivotal trials,

7 patients were in their mid-40s at their time of

8 study entry although, in the U.S. trial, the age

9 ranged from 22 to 72 years with about 10 percent of

10 patients in their 60s and early 70s. Compared to

11 the three pivotal trials in Europe, there was

12 somewhat greater representation of females in the

13 U.S. trial. Racial distribution was roughly

14 equivalent to U.S. population norms.

15 The 2 gram acamprosate group included more

16 individuals living alone with fewer subjects

17 employed full-time and more individuals with a

18 significant psychiatric history than the placebo

19 group.

20 \[Slide.\]

21 Just to orient you, the clinical global

22 impression was a summary by the investigator of the

23 patient\'s current alcohol dependence severity with

24 7 being most severe. A score of 22 or greater on

25 the alcohol dependence scale indicates subjects

62

1 with substantial to severe lifetime alcohol

2 dependence severity.

3 For the measures shown here and the

4 measures of psychosocial support shown on the

5 previous slide, although generally comparable

6 across the two treatment groups, you might notice

7 that, for each variable, the 2 gram group has

8 evidence of slightly greater severity of alcohol

9 dependence than the placebo group.

10 \[Slide.\]

11 There was a higher proportion of patients

12 in the placebo group having a baseline goal of

13 total abstinence and a higher proportion in the 2

14 gram group requiring medicated detoxification prior

15 to study entry. Accordingly, in the aggregate,

16 subjects assigned to the 2 gram group appear to

17 have entered the trial relatively disadvantaged.

18 \[Slide.\]

19 As you can see, approximately

20 three-quarters of the sample reported lifetime

21 experience with illicit substances with

22 approximately one-third reporting illicit substance

23 abuse in the year prior to randomization.

24 \[Slide.\]

25 Slightly less than half of the population

63

1 were current smokers and between 6 and 8 percent

2 had positive urine for cannaboids at screening.

3 \[Slide.\]

4 You have seen the formal patient

5 disposition in your briefing document. I would

6 like to highlight certain features of patient

7 participation that may be relevant for

8 understanding efficacy. You will note high rates

9 of methodology compliance across all treatment

10 groups. However, the 2-gram group had fewer weeks

11 on study and a lower rate of study completion than

12 the placebo group. In an effort to understand this

13 further, a blinded panel of experts evaluated all

14 premature terminations in terms of alcohol

15 relatedness taking into account all available

16 information.

17 Of those patients terminating early, the

18 reason was more likely to be alcohol-related in the

19 placebo group than in contrast to the 2 gram

20 acamprosate group. There was no difference in the

21 percentage of patients across the groups for

22 terminations due the adverse events.

23 \[Slide.\]

24 As the FDA pointed out in their

25 information package, in contrast to the European

64

1 studies, half the U.S. study population was still

2 drinking at randomization. Therefore, the plan for

3 European-based variables such as time to relapse

4 and rate of complete abstinence became relatively

5 meaningless.

6 Similarly, as pointed out earlier, the

7 fact that the 2 gram group had briefer time on

8 study would negatively impact on their cumulative

9 abstinence duration with missing time accounted for

10 as drinking time. Furthermore, the unfavorable

11 baseline imbalances for the 2 gram group were also

12 found to meaningfully influence study outcomes.

13 \[Slide.\]

14 The variables that we chose to measure in

15 a standardized manner at baseline in the

16 case-report form included a brief screen of major

17 psychopathology as greater psychiatric severity has

18 been reliably associated in the literature with

19 poor alcoholism treatment outcome.

20 Although subjects with current dependence

21 in illicit substances were excluded from study

22 admission, subjects with substance abuse including

23 those with urines positive for cannabis at

24 screening at baseline were admitted to the study.

25 Given the well-known association of drug abuse with

65

1 premature treatment termination and poor alcoholism

2 treatment outcome, the illicit drug use index

3 developed by the National Institute on Drug Abuse

4 was used to characterize severity of substance

5 abuse.

6 Additionally, the Fagerstrom test of

7 nicotine dependence was used to capture current

8 severity of nicotine dependence.

9 As with psychiatric and substance-abuse

10 comorbidity, greater severity of alcohol dependence

11 has generally been associated with poor treatment

12 response especially for outpatients. In the

13 American study, current severity of alcohol

14 dependence was assessed with the investigator\'s

15 clinical global impression and lifetime severity

16 with the Alcohol Dependence Scale.

17 \[Slide.\]

18 Fewer social supports result in worse

19 treatment response generally but especially in the

20 case of outpatient treatment of alcoholism.

21 Readiness to change emerged as the strongest

22 predictor of long-term drinking outcome in Project

23 MATCH and, as in Project MATCH, was measured, in

24 this study with DiClementi\'s stages of readiness to

25 change.

66

1 Initial commitment to complete abstinence

2 has been shown to predict higher rates of

3 abstinence among alcoholics, opiate users and

4 cigarette smokers. In contrast, subjects having a

5 goal of minimizing a slip or having other drinking

6 goals are typically more likely to relapse.

7 Treatment goals were assessed at baseline

8 in the U.S. study with a standardized treatment

9 goals check list which I will be showing you.

10 Compliance with prescribed treatment has been

11 significantly associated with drinking outcome in

12 both behavioral and pharmacological clinical

13 trials.

14 In the U.S. study, methodology compliance

15 was estimated on the basis of pill count from

16 returned blister packs at every study visit.

17 Ingestion of acamprosate was verified by plasma

18 acamprosate levels at week 1 and end of study

19 although results were not available until after

20 study unblinding.

21 Importantly, and finally, as Babour and

22 colleagues have pointed out, these factors may be

23 most meaningfully used in combination to create a

24 multidimensional model to understand alcoholism

25 treatment outcome.

67

1 \[Slide.\]

2 The FDA has requested that we provide an

3 analysis to reconcile the findings of the U.S. and

4 European trials and to further our understanding of

5 how acamprosate would be beneficial in American

6 alcoholics. Given that missing data are attributed

7 to relapse in study-outcome calculations, in order

8 to better understand the efficacy of the 2 gram

9 group, a standard panel of covariates relating to

10 baseline measures of psychosocial support and

11 alcoholism severity and treatment exposure were

12 uniformly applied to all outcome measures.

13 Statistical modeling associated early

14 termination with baseline variables relating to

15 psychosocial support and disease severity rather

16 than to treatment group assignment.

17 \[Slide.\]

18 The actual chest list used in the case

19 report form to capture patients treatment goals at

20 baseline is depicted in this slide. In the FDA\'s

21 analysis, patients with the goal of abstinence were

22 grouped together with those acknowledging that they

23 could have a slip and the difference in results may

24 serve to emphasize the importance of complete

25 commitment to abstinence at treatment onset to

68

1 optimize acamprosate efficacy.

2 \[Slide.\]

3 Because the first dose of study

4 methodology was an observed dose given in a clinic,

5 all 601 randomized patients were included in the

6 safety population. The intention to treat, or ITT,

7 population represented all randomized patients for

8 whom any follow-up efficacy data were available. I

9 have already described to you the a priori defined

10 efficacy evaluable population.

11 As Sharon Hall and colleagues at the

12 University of California and Stephanie O\'Malley and

13 colleagues at Yale University have reported,

14 commitment to total abstinence is related to a

15 lower risk of returning to use of alcohol as

16 opposed to goals that include slips, controlled

17 drinking or other levels of alcohol consumption.

18 One of the DSM-IV diagnostic criteria for

19 alcohol dependence specifically relates to the

20 tendency to drink more than originally intended.

21 Consequently, complete abstinence is the treatment

22 goal recommended by NIAAA and other expert groups.

23 Because a treatment goal of abstinence was

24 so strongly associated with positive U.S. study

25 outcomes, subjects within the ITT and efficacy

69

1 evaluable population who, at baseline, identified

2 their treatment goal as total abstinence were

3 looked at as additional subpopulations in order to

4 better understand acamprosate efficacy in the U.S.

5 population.

6 We have called these subpopulations

7 respectively the motivated ITT population and the

8 motivated efficacy evaluable population.

9 \[Slide.\]

10 Cumulative abstinence duration or percent

11 of abstinence time on study was the only original

12 outcome parameter which was still applicable to the

13 U.S. study population since it does not involved

14 censoring of data at the time of the first drink.

15 In the original European-based analysis plan for

16 the calculation of this outcome parameter, the

17 number of abstinent days were divided by the total

18 duration of the trial.

19 Given the precision of the U.S. data

20 collection and follow-up methods in the revised

21 analysis the denominator remained the total trial

22 duration unless patients were censored for leaving

23 the trial for reasons unrelated to alcohol.

24 Also, as stated earlier, in order to

25 better understand the efficacy of acamprosate in

70

1 the U.S. population, a standard panel of baseline

2 and treatment exposure covariates would uniformly

3 applied across outcome measures in order to reduce

4 residual variation and offset the imbalances in

5 comparisons between acamprosate and placebo.

6 This adjustment enables the supportive

7 identification of trends with p less than 0.05 in

8 favor of acamprosate 2 grams relative to placebo in

9 the ITT group. The extent of these favorable

10 trends increases as one moves to the more defined

11 populations mainly because of the larger increase

12 in cumulative abstinence duration percent in the

13 acamprosate group than in the placebo group.

14 Abstinence time was about 6 percent longer

15 with acamprosate 2 grams in the ITT population

16 while for patients in the efficacy evaluable

17 population who had total abstinence as their

18 treatment goal, abstinence time was about 16

19 percent longer with acamprosate 2 grams relative to

20 placebo.

21 This supports the premise that motivation

22 to be abstinent merits consideration in the

23 interpretation of acamprosate efficacy in the U.S.

24 population.

25 \[Slide.\]

71

1 Furthermore, the previously noted trends

2 with acamprosate were maintained in the 2 gram

3 group relative to placebo during the two months

4 post-treatment follow-up phase again most markedly

5 in those subjects with a baseline motivation of

6 total abstinence.

7 \[Slide.\]

8 As support analyses of cumulative

9 abstinence duration, covariate adjusted odds ratios

10 were calculated for the likelihood of good response

11 with acamprosate relative to placebo. Good

12 responders were defined as those subjects with a

13 cumulative abstinence duration of 90 percent or

14 more. This is highly relevant from a clinical

15 point of view.

16 For the motivated efficacy evaluable

17 population, the adjusted odds ratio for good

18 response with acamprosate versus placebo

19 supportively had p less than 0.05 and corresponded

20 to about three times higher odds for good response

21 with acamprosate 2 grams than with placebo.

22 Conversely, poor response was defined as those

23 subjects having a cumulative abstinence duration of

24 10 percent or less.

25 The adjusted odds ratio for poor response

72

1 for acamprosate 2 grams relative to placebo had p

2 less than 0.05 and showed a decreasing pattern of

3 lower odds for poor response for acamprosate 2

4 grams across the subgroups.

5 \[Slide.\]

6 A final support analysis of abstinence

7 looked at the likelihood of a subject being

8 abstinent during the interval prior to their last

9 treatment-phase visit. This outcome may have

10 clinical relevance in that a subject\'s behavior at

11 the end of study may be predictive of behavior off

12 study.

13 There was a trend for subjects treated

14 with acamprosate 2 grams to have a high odds for

15 being abstinent at the end of study participation

16 compared to placebo with compliant and motivated

17 patients having more than twice the odds to be

18 abstinent at this key time point in the 2 gram

19 group.

20 \[Slide.\]

21 Now I am going to turn to a secondary

22 outcome that involves quantity of drinking on

23 study. The calendar method of drinking data

24 collection in the U.S. study permitted the most

25 detailed examination to date of whether acamprosate

73

1 reduces alcohol consumption in nonabstinent

2 subjects during the study.

3 You will recall that all subjects received

4 a standardized alcohol-specific behavioral therapy

5 and, as this slide shows, all patients, including

6 the placebo group, showed substantial reductions on

7 study from baseline levels of drinking. However,

8 particularly in those subjects motivated to be

9 abstinent, the covariate adjusted analysis showed a

10 larger reduction with acamprosate 2 grams than with

11 placebo.

12 Again moving from ITT to the more defined

13 subpopulations, there was a further reduction of

14 only approximately 3 percent in the placebo group

15 compared to almost 20 percent in the acamprosate 2

16 gram group. This provides further support for an

17 association between motivation to be abstinent and

18 trends in favor of acamprosate relative to placebo

19 in the U.S. population.

20 \[Slide.\]

21 As seen in this slide, all treatment

22 groups showed an improvement in mean levels of GGT

23 at study endpoint relative to the elevations in

24 mean values seen at baseline. Mean endpoint values

25 were normal or near normal in this predominantly

74

1 male study population further attesting to the

2 improved status of patients in all groups and the

3 validity of self-report in this study.

4 \[Slide.\]

5 As requested by the FDA, the U.S. study

6 population was much more inclusive than seen in

7 most clinical trials in alcohol dependence in order

8 to assess the safety of acamprosate in patients

9 with polysubstance abuse, hepatic and renal

10 dysfunction and the elderly.

11 As a result of the U.S. study\'s broad

12 admission criteria, 81 percent of screened patients

13 were randomized supporting the external validity of

14 the study. I want to emphasize that, in contrast,

15 in an ongoing large multicenter trial in

16 alcohol-dependent patients, only about 25 to

17 30 percent of screened patients were randomized.

18 The rate of compliance with medication

19 exceeded 88 percent in all treatment groups lending

20 support to the acceptability of both acamprosate

21 and the divided dosing schedule.

22 \[Slide.\]

23 Controlling for baseline variables in

24 treatment exposure, the U.S. study results support

25 the efficacy of acamprosate 2 grams relative to

75

1 placebo particularly in patients with a baseline

2 goal of abstinence. This treatment group had

3 increased cumulative abstinence duration and

4 increased likelihood of good response, a decreased

5 likelihood of poor response and an increased

6 likelihood of being abstinent at study termination.

7 In addition, although all groups showed

8 improvement in drinking behavior on study relative

9 to baseline, the 2 gram group had a greater

10 decrease in both the quantity and frequency of

11 alcohol consumption compared to placebo.

12 Self-reported drinking were confirmed by

13 accompanying changes in GGT. A consistent

14 association was found between trends in favor of

15 acamprosate and a baseline goal of total abstinence

16 across study outcomes.

17 This observation has implications for

18 healthcare providers prescribing acamprosate for

19 their outpatients with alcohol dependence.

20 \[Slide.\]

21 Integrating the U.S. and European

22 pivotal-trial exposure with acamprosate, overall,

23 acamprosate 2 grams per day showed significant

24 effects on abstinence outcomes in almost 2000

25 alcohol-dependent outpatients participating in

76

1 double-blind, placebo-controlled trials up to one

2 year in duration.

3 Additionally, acamprosate showed continued

4 efficacy during off-treatment follow-up periods of

5 as long as one year.

6 \[Slide.\]

7 European and U.S. data suggest that

8 acamprosate does not induce abstinence in

9 unmotivated drinkers. In Europe, patients had to

10 make a commitment to abstinence-oriented treatment

11 that began with formal detoxification typically

12 inpatient. Thus, their treatment goal at the onset

13 of the clinical trial was implicitly total

14 abstinence and treatment effects may have been

15 easier to discern because of the resultant

16 homogeneity.

17 In contrast, the U.S. study population did

18 not typically undergo detoxification and was quite

19 heterogeneous in their expressed baseline treatment

20 goals. Through examination of subpopulations,

21 defined by the presence of total abstinence as a

22 treatment goal, the U.S. data suggest that it is

23 not necessary to undergo formal detoxification in

24 order to obtain therapeutic benefit from

25 acamprosate provided patients are motivated for

77

1 total abstinence.

2 \[Slide.\]

3 Uniformly, high rates of compliance across

4 the pivotal trials support the acceptability of

5 acamprosate in the twice daily and three times

6 daily dosing schedules used in these studies. The

7 pivotal trials spanned a range of countries and

8 clinical settings. You may also recall that the

9 European studies, by design, did not include any

10 uniform behavioral therapy. Thus, the efficacy of

11 acamprosate is supported across a broad range of

12 treatment orientations.

13 Closing Remarks

14 DR. GOODMAN: Ladies and gentlemen,

15 members of the committee, I would like to spend

16 these final few minutes of our presentation on the

17 issues set forth by the division for your

18 consideration.

19 \[Slide.\]

20 In our briefing document and in our

21 presentations this morning, we have described to

22 you three European double-blind, placebo-controlled

23 studies of acamprosate that meet all the FDA

24 criteria for approvability. As we are all aware,

25 the process of drug development is a long one, more

78

1 often than not. The European studies on which we

2 are relying as evidence of efficacy were conducted

3 starting in 1989 and were completed for the most

4 part by 1995.

5 Although the FDA has characterized these

6 studies as older, in fact, the trials were

7 conducted by qualified clinical experts in the

8 field of alcoholism. They meet the FDA criteria of

9 being clinically generalizable to the target

10 population in the United States and the trials were

11 conducted in a manner consistent with good clinical

12 practice and are auditable.

13 \[Slide.\]

14 Despite differences of opinion about the

15 most appropriate methodology for assessing outcome

16 in clinical trials of alcohol dependence, and, in

17 fact, despite the actual methodologies applied,

18 those of Lipha or those of the FDA, the three

19 European pivotal trials showed consistently

20 significant and clinically relevant effects both on

21 parameters selected as primary, as shown here, as

22 well as various secondary parameters described in

23 your briefing document.

24 These studies, along with the others

25 described in the documents provided to you, served

79

1 and continue to serve as the basis of regulatory

2 approvals around the world, most recently in

3 Australia and South Africa. The results of the

4 European trials are applicable to approvability for

5 the United States because there is no biologic or

6 pharmacokinetic reason to believe that drug

7 response in alcoholic patients will differ between

8 Europe and the United States.

9 As Dr. Koob has pointed out, the drug is

10 not metabolized. Nor is there any reason to

11 believe that the nature of alcohol dependence

12 differs in European and American alcoholic

13 patients.

14 \[Slide.\]

15 In a letter to the FDA, at their request,

16 from the National Institute on Alcohol Abuse and

17 Alcoholism specifically addressing this issue, the

18 concluding comments from NIAAA are the core illness

19 of alcohol dependence is similar in the United

20 States and Europe.

21 The conclusion is based on several

22 considerations. First, the diagnostic methods for

23 coding alcohol dependence are very similar in the

24 United States and Europe. Most of the clinical

25 trials of acamprosate in Europe used the Diagnostic

80

1 and Statistical Manual of Mental Disorders III-R,

2 the DSM III-R, for verification of alcohol

3 dependence, the version which was available and

4 used in both Europe and the United States at the

5 time these studies were conducted.

6 Second, an international conference, held

7 in Germany in September of 1999 to determine if

8 cross-national studies could be conducted,

9 concluded that, while there are cultural

10 differences between the U.S. and Germany,

11 cross-national collaboration was feasible because

12 the alcohol-dependent populations were similar.

13 Finally, a comparison of the cardinal

14 symptoms of the alcohol dependence syndrome in U.S.

15 and Soviet populations revealed virtually identical

16 characteristics.

17 \[Slide.\]

18 Dr. Barbara Mason has shown you, through

19 analyses using an informed set of baseline

20 variables and treatment exposure that the American

21 study results are not in conflict with the European

22 experience when baseline differences among the

23 treatment groups are controlled for. In fact,

24 these analyses have led to a further understanding

25 of the sorts of patients who might ultimately

81

1 benefit from acamprosate, namely patients who are

2 motivated to total abstinence without a slip.

3 These data are offered to you not as a

4 justification of the methods and the results but,

5 instead, as an explanation for what happened in the

6 very broadly inclusive U.S. trial and as a means of

7 assuring you that the populations are, indeed,

8 similar.

9 Dr. Mason has presented to you the

10 interpretation of these additional analyses which

11 showed that acamprosate increased the percentage of

12 abstinent time on study, increased the likelihood

13 of remaining abstinent for 90 percent or more of

14 the time on study and, as shown in your briefing

15 document, also impacted favorably on alcohol

16 consumption in those patients who did drink.

17 \[Slide.\]

18 Taken as a whole, the acamprosate clinical

19 data submitted to the FDA for the indications shown

20 here which are being considered in the context of

21 an accelerated review more than meet the FDA\'s

22 criteria for approval and do not warrant additional

23 safety and efficacy trials.

24 It would unduly penalize that percentage

25 of alcoholic patients who may benefit from

82

1 acamprosate as well as their families and the

2 community in general if approval were to be delayed

3 while we all await further studies and analyses.

4 We acknowledge that acamprosate is not the

5 magic bullet we all seek for just about any medical

6 condition you could describe. However, the overall

7 picture is, indeed, clear enough both from the

8 perspective of acamprosate\'s efficacy and safety to

9 proceed further with the approval process.

10 \[Slide.\]

11 The FDA agreed that acamprosate deserved

12 an expedited review when our NDA was filed and

13 their ongoing review of the extensive data

14 submitted has been very thorough in this

15 therapeutic area in which they are practically

16 pioneers.

17 The paucity of available therapies for the

18 treatment of alcoholism and the continued enormity

19 of the personal and economic costs of alcoholism

20 mitigate, however, for action now rather than

21 later.

22 Thank you very much.

23 Questions from the Committee

24 DR. OREN: We now turn to the portion of

25 meeting where the members of the committee have the

83

1 opportunity to question Lipha about their

2 presentation or anything else with regard to

3 today\'s questions.

4 Given that there are millions of Americans

5 who may be affected by our recommendation, I

6 encourage our committee members not to be shy but

7 to be very vocal in coming up with questions.

8 Anyone wish to begin?

9 Dr. Keck?

10 DR. KECK: I know our task is mostly

11 around efficacy today but I have some questions

12 just about safety. It is likely that a lot of

13 people, say, with bipolar disorder who have high

14 rates with alcoholism could take this drug. What

15 do we know about drug interactions with lithium or

16 NSAIDs or other drugs that are renally cleared?

17 DR. GOODMAN: I can tell you that, from a

18 formal point of view, we have not conducted any

19 pharmacokinetic interaction studies with those

20 classes of drugs and there could be some reason to

21 suspect, mechanistically, that they might interact.

22 But we don\'t have the information to date.

23 I don\'t know, Dr. Chabac, if you are aware

24 of any patients in our postmarketing

25 pharmacovigilence database that might have been

84

1 exposed to lithium?

2 DR. CHABAC: As I told you, we have 1.5

3 million patient year exposure. You know well that

4 those patients probably have high comorbidity and

5 were treated with these kinds of products. On

6 postmarketing surveillance, we had no specific

7 problem, specific interaction with those drugs.

8 But, as Dr. Goodman told you, we didn\'t investigate

9 all possible drugs to be associated with

10 acamprosate.

11 DR. GOODMAN: I might add one thing, but I

12 don\'t want to go out of the boundaries of our

13 restricted discussion of efficacy. But we did look

14 at NSAIDs or analgesics in general in terms of

15 adverse-event occurrence in the U.S. study. My

16 recollection is that there was no difference in

17 pattern of adverse events or increased incidence.

18 But that is just based on\--we have been focussing

19 on efficacy both for the preparation of this

20 meeting and so I would want to verify that. It\'s a

21 good point.

22 DR. KECK: Just one other basic

23 pharmacokinetic question. It was unclear to me in

24 how many of the studies the recommendation was that

25 the drug be taken with food. But that struck me as

85

1 curious since, if I am reading the data correctly,

2 food decreases the absorption and bioavailability

3 of a drug that already has limited bioavailability.

4 Can you help me understand that?

5 DR. GOODMAN: It\'s a good point. My

6 interpretation of that would be, again, that this

7 is not a drug that you are taking acutely such as

8 you might use an NSAID for a headache or joint pain

9 or whatever. It is something that is chronically

10 administered.

11 So I think the food effect really is of

12 minimal importance over the long haul once a person

13 is at steady state. Dr. Porte may have some

14 thoughts about that as well. She is our

15 pharmacokineticist from Lyon.

16 DR. PORTE: To answer your question, the

17 food interaction study was performed for a single

18 dose administration. This does not correspond to

19 the dosing schedule recommended in the labeling.

20 So we expect that this food interaction will not

21 impact on the clinical efficacy of this compound

22 even thought the bioavailability is already

23 limited.

24 DR. GOODMAN: As far as the clinical

25 trials are concerned, and Karl Mann may have some

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1 comments on that, in many instances, the drug was

2 taken with meals as a reminder for taking\--

3 DR. OREN: Dr. Winokur?

4 DR. WINOKUR: I wanted to ask a question

5 related to difference between the populations

6 included in the European trials and the U.S. trial.

7 If I remember data from the packet, which I don\'t

8 think was commented on, a considerably higher

9 percentage of subjects in the European trials had

10 histories of very high drinking histories, for

11 example greater than ten drinks a day. I just

12 wondered if some additional comment about that

13 aspect of different profiles\--we have talked about

14 differences, for example, that there was other drug

15 use in the U.S. trial but I was interested in the

16 analysis of the history of drinking frequency in

17 the U.S. trial.

18 DR. GOODMAN: I will just comment. It

19 was, I won\'t say misrepresented in the briefing

20 document, but, in fact, the calculations presented

21 for the European data were based on drinks per day

22 for patients who did drink whereas the U.S. data

23 was shown as drinks per day for all patients,

24 whether they drank or not. So the data that Dr.

25 Mason presented in her demographics, in fact, was

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1 the correct representation for the purposes of

2 comparison because they are basically they same.

3 DR. HUGHES: First of all, before I make

4 my comments, I just want to clarify that the

5 University of Vermont was the site of the U.S.

6 study but I did not participate in that.

7 What I wanted to ask was if there is a

8 subset of more motivated patients that acamprosate

9 works in, two things to judge post hocs on are

10 reproducibility and plausibility. So the two

11 questions I have are are there any instances,

12 either with alcoholism or other drug dependencies,

13 where a subset of more motivated patients changes

14 not the outcome but the odds ratio. That is the

15 first question. So is there a precedence for this.

16 The second question is what would you

17 maintain is the behavioral or biological mechanism

18 by which being more motivated would change, again,

19 not the outcome but, by being more motivated, it

20 would change the relative efficacy of acamprosate

21 to placebo. So, again, what is the reproducibility

22 of this and what is the mechanism?

23 DR. MASON: John, the two papers that I

24 pulled which Sharon Hall and colleagues at the

25 University of California and Stephanie O\'Malley\'s

88

1 naltrexone study didn\'t calculated odds ratios.

2 They just are descriptive statistics. So I don\'t

3 know that I have information that would be helpful.

4 DR. HUGHES: My recollection of those

5 papers was that the more motivated did better but,

6 by being more motivated, it didn\'t change your

7 response to the treatment. Is that correct?

8 DR. KOOB: The more motivated did better

9 without changing their response to the treatment

10 DR. HUGHES: If you had some measure of

11 active to placebo in a study, I agree with you,

12 being more motivated is going to take your

13 abstinence rates up. But my worry is it going to

14 take them both up and not change the relative rates

15 of outcome because active and placebo.

16 I am trying to think of a prior study in

17 which, if you took a more motivated group, it

18 changed the differences between active and placebo.

19 I was wondering if you know of one.

20 DR. MASON: In the O\'Malley study, which I

21 am more familiar with, it depends on what outcome

22 you look at because in the group that had the

23 behavioral therapy in which a slip was considered

24 likely, permissible, et cetera, they did have more

25 days on which drinking occurred as opposed to

89

1 patients in the behavioral therapy group that were

2 told, you must be completely abstinent.

3 Then that was crossed with naltrexone. So

4 you did have the influence of the instruction to be

5 abstinent or have a slip interacting with an

6 outcome parameter and drug. Does that help?

7 DR. HUGHES: Any thoughts about mechanism?

8 DR. MASON: George has a thought. Good.

9 DR. KOOB: I think the animal data

10 suggests that acamprosate\--and this is part of the

11 pharmacokinetic issue as well. Acamprosate takes a

12 while to reach steady state. It is five to seven

13 days. Any mechanism, whether it is cognitive or

14 whether it is induced by the European studies where

15 a person had the detox, that lengthens the time

16 between when an individual has stopped drinking and

17 the onset of steady state blood levels of

18 acamprosate is going to facilitate the

19 normalization of the neurotransmitter systems that

20 it works on.

21 So my answer to that question would be

22 anything that lengthens the time that the organism

23 is without alcohol, and in that alcohol deprivation

24 study where we see a large effect, those animals

25 are not allowed to drink during the period that

90

1 they are getting acamprosate, you see a bigger

2 effect of acamprosate.

3 DR. OREN: Dr. Ortiz?

4 DR. ORTIZ: My question is Dr. Mann

5 mentioned that the European studies all had

6 psychosocial treatment programs. Dr. Mason just

7 briefly mentioned something about behavioral

8 treatment in the American study, and I am wondering

9 if we can get a little bit of elaboration on that.

10 DR. MANN: In the European studies, there

11 were not psychotherapies or psychosocial treatment

12 which was manual based. It was the treatment that

13 was, at that time, given at these different centers

14 and this might have different\--within the study,

15 from center to center. So it was the center-based

16 treatment approach like counseling or, in some

17 centers, behavioral treatment. In others, it might

18 have been something else.

19 So there was not a manual-based treatment

20 in the European studies and that was different in

21 the U.S. study.

22 DR. MASON: In the U.S. study, there was a

23 manual that actually had a script in it for the

24 therapist to model and there was a training video.

25 It was based on principles of motivation

91

1 enhancement, particularly the manual developed by

2 the National Institute on Alcohol Abuse and

3 Alcoholism from Project MATCH and it also included

4 elements of the National Institute on Alcohol Abuse

5 and Alcoholism brochure for primary-care providers

6 in their approach to treating alcoholism.

7 It was really conceptualized as something

8 that could fit easily into a variety of treatment

9 settings. In fact, we deliberately included

10 internal-medicine sites. It was brief. It was

11 about twenty minutes. It could be delivered by a

12 nurse or an experienced counselor with a bachelor\'s

13 degree.

14 It involved handouts to the patients that

15 gave them information, let them do self-monitoring

16 exercises and really built on the patient\'s own

17 experience, what has worked for you in the past,

18 what hasn\'t worked. Then, if there is a report of

19 a drinking episode, what worked, what didn\'t work,

20 what do you see as the obstacles to your meeting

21 your treatment objectives.

22 Also, information like GGT levels were

23 shared with the patient so that they received

24 feedback about the progress that their efforts were

25 having in terms of the effect on their health. For

92

1 example, one of the motivation-enhancing

2 strategies, the time-line follow-back, quantifies

3 the amount of drinking that occurs in a week, for

4 example

5 Each standard drink roughly is equivalent

6 to 100 calories and people were drinking, on

7 average, about 40 drinks a week. So, when you do

8 that multiplication, people are kind of horrified

9 about how many calories are being consumed in

10 alcohol.

11 Also, another strategy is multiplying the

12 number of drinks per week by the cost. If you are

13 drinking in a bar and paying, like, \$5.00 a drink,

14 people then get thunderstruck at how much they are

15 paying for alcohol. So those are some of the

16 motivation-enhancement characteristics of the

17 standardized therapy that are tracked in the

18 treatment progress summary at each visit which

19 occurs on a monthly basis.

20 Initially patients are seen one week after

21 starting medication, then, in two weeks, and then

22 they switch to the monthly schedule.

23 DR. OREN: Dr. Schatzberg.

24 DR. SCHATZBERG: This is a question for

25 Barbara Mason and George Koob. When you are

93

1 looking at the U.S. study versus the European

2 studies and you are going to a new formulation, and

3 the fact that if you look at the average weight in

4 the U.S. study, it is about 10 percent higher than,

5 let\'s say, in the German study that Dr. Mann talked

6 about.

7 Are we sure that we just haven\'t

8 underdosed in the U.S. and have you looked at

9 acamprosate levels to ascertain whether, in fact,

10 we have an effective dose in Europe in 1998 that

11 may not be effective in the U.S.

12 DR. GOODMAN: I am going to just intervene

13 even though I am not Dr. Mason. I do want to

14 correct one thing that might be a misperception on

15 the part of the committee members. These are not

16 different tablets. The only thing that is

17 different\--there is no difference in the

18 formulation. They are identically formulated

19 except for the tablet strength. So there is no

20 difference in the tablet formulation.

21 As I believe Barbara pointed out in her

22 talk, there was a pharmacokinetic study,

23 multiple-dose pharmacokinetic crossover design, of

24 these two schedules which were shown to be

25 bioequivalent. So we feel, from the basis of that,

94

1 that the dosing is equivalent.

2 With regard to the question about the

3 heavier, huskier American population, I would say

4 that the Germans probably aren\'t too far off from

5 the American population. If you noticed in the

6 demographics, they weighed a bit more, on average,

7 certainly, than the French. So there could be a

8 comparability there.

9 We did do blood levels of acamprosate,

10 blinded of course, in the U.S. study one week after

11 starting treatment and then again at the time of

12 termination. Those blood levels were consistent

13 with steady-state levels in PK studies in our

14 dossier.

15 DR. OREN: Dr. O\'Brien?

16 DR. O\'BRIEN: My question also concerns

17 psychotherapeutic intervention. One of the

18 difficulties in interpreting efficacy studies in

19 any behavior disorder, whether it is depression,

20 anxiety or alcoholism is that the patients are

21 always getting two effective treatments; namely,

22 psychotherapy and a potentially effective

23 medication.

24 We have some evidence from other evidence

25 from other forms of substance abuse that there is a

95

1 dose-response curve for psychotherapy. In other

2 words, if you randomly assign people to various

3 levels of psychotherapy, it doesn\'t matter very

4 much which type of psychotherapy, so it is not

5 specific to, say, supportive-expressive versus

6 cognitive-behavioral. But the quantity is a

7 factor.

8 In clinics, there is a tendency, when a

9 patient is doing badly, you don\'t know whether they

10 are on drug or placebo but to enhance the amount of

11 time that is given to them, more frequent visits,

12 perhaps, or spending a little more time with them

13 or helping them a little bit more because you are

14 trying to help the patient.

15 I just wonder whether in either the

16 European, or any of the European studies or the

17 American study, whether there was an effort to

18 measure the quantity of psychotherapeutic

19 interaction.

20 DR. GOODMAN: I think I can answer and say

21 yes, there was. But, Barbara, maybe you want to

22 address it more specifically and Karl as well.

23 DR. MASON: I will just tell you that, in

24 the U.S. study, patients were allowed only two

25 emergency visits in addition to their monthly

96

1 visits. That was the protocol. If they required

2 more help than that, they were terminated as

3 treatment failures.

4 The treatment was proscribed to be twenty

5 minutes. It was very defined in the manual, the

6 procedures, and involved completing things and

7 reviewing things together. That was the parameter

8 of the therapy. It was adhered to.

9 DR. MANN: I think that is a very, very

10 important point which may, indeed, help to

11 understand the differences because, in the European

12 studies, the doses of psychosocial treatment was

13 extremely low. We gave very little, only a few

14 visits throughout the whole year; for instance, in

15 Germany, I think eight or nine visits.

16 So one per month in the first three months

17 and then only one every third month which is really

18 very little. So the doses which we applied were

19 really small. If you give much more\--we have seen

20 this in other studies, at least we have the

21 impression that if you have a very high placebo

22 response because you give a lot of psychosocial,

23 then the drug has a harder time showing an effect.

24 If I may add something to the other

25 question earlier about the difference between the

97

1 treatment sites or the centers, we have looked,

2 because there were different forms of psychosocial

3 treatments, the differences in outcome between

4 these centers and we didn\'t find any difference

5 there.

6 Also, there was a difference maybe in the

7 approach psychosocially. It didn\'t affect the

8 overall treatment outcome. I forgot this earlier.

9 DR. GOODMAN: Barbara may want to address

10 something about the phase IV European studies, the

11 Need Project.

12 DR. MASON: There was a large

13 multinational open-label study of acamprosate that

14 was conducted specifically to look at acamprosate

15 efficacy across five major types of psychotherapy,

16 group therapy\--Silvie, do you remember what some of

17 the other components were? This was in Europe.

18 There was no change, no significant difference in

19 acamprosate efficacy across the five major models

20 of psychosocial treatment that were studied.

21 This involved approximately 1200

22 outpatients with alcohol dependence all of whom

23 received acamprosate. The varying factor was the

24 co-occurring psychosocial therapy.

25 DR. OREN: Dr. Rudorfer?

98

1 DR. RUDORFER: If I could go back to the

2 pharmacokinetics for a second, given acamprosate

3 18-hour half-life, I wonder why some of the

4 European studies used three times a day dosing.

5 DR. PORTE: Actually the absorption

6 process of acamprosate is very slow so when you

7 measure the half-life, it corresponds to the end of

8 the plasma profile. Indeed, it does not correspond

9 in the case of acamprosate to pure elimination but

10 there is still some remaining absorption of

11 product. Therefore, to find a dosing regime for

12 acamprosate, we should more look at the elimination

13 half-life for the intravenous dose which is from

14 five to seven hours.

15 DR. OREN: Dr. Leon?

16 DR. LEON: In designing and implementing a

17 clinical trial, we typically take many safeguards

18 to minimize the bias of the treatment effect. What

19 we usually focus on are randomization and blinding

20 and statistical strategies. What I am struck by

21 here is it appears another strategy that is very

22 important in minimizing bias is that we prespecify

23 our primary dependent variable, our efficacy

24 measure, and prespecify our primary data analytic

25 technique.

99

1 I don\'t see any examples of that in these

2 four trials. It looks as if the primary data

3 analytic technique that was specified in the

4 protocol was not adhered to nor was the primary

5 efficacy measure.

6 If those measures and techniques are

7 prespecified, then anyone who looks at the data

8 will get the same answer. But when they are not

9 prespecified and changed after the data have been

10 collected, that objectivity or agreement across

11 independent assessors is jeopardized.

12 I wondered if you have a comment on that.

13 DR. G. COOK: Gary Cook. I am a

14 consultant to Lipha. I will probably need Dr.

15 Goodman\'s help on this. I believe that for the

16 European studies there was some type of reasonable

17 statistical plan and that the analyses that were

18 done to support the efficacy of those studies was

19 reasonably consistent with that plan.

20 There might be some further clarification

21 as to exactly what the plans were, but my

22 understanding is that there was a plan, that the

23 results were consistent with that plan and then a

24 variety of additional analyses have been done to

25 further support the robustness of the analyses of

100

1 those studies.

2 Now, the U.S. study, the issues are

3 totally different. But we need to sort of deal

4 with this in two steps so could you first clarify

5 what would have been the response to this question

6 with respect to the European studies.

7 DR. GOODMAN: I would make two points, and

8 there may be additional members of our group

9 especially from Europe who could say other things.

10 But, first of all, with regard to the total

11 protocol design, as the FDA has pointed out in

12 their document as well, the design requirements are

13 not as detailed and specific and uniform as they

14 are now with the international harmonization

15 guidelines.

16 So, if the European studies were to be

17 done today, there would be very detailed analytical

18 statistical analysis plans included in the

19 protocol.

20 I believe, as Dr. Chabac also pointed out,

21 that the purposes of the studies globally were for

22 registration purposes so there was a common plan

23 for analysis of the data and that is why these

24 variables, all of which we consider to be related

25 because they are all another way of looking at

101

1 abstinence or drinking that these are appropriate.

2 DR. CHABAC: I just want to add something.

3 Remember that we designed all our European studies

4 using a core protocol. That means the same study

5 design. In our protocol, we specified which were

6 our primary criteria, mainly time to first relapse

7 since we were seeking for an indication to maintain

8 long-term abstinence. So it was our primary

9 criteria very well described in our protocol and it

10 is in the NDA.

11 DR. LEON: Can I just follow up? In my

12 reading of the documents, it looked like the time

13 to alcohol was not specified as a primary dependent

14 variable either in Pelc or in the second one,

15 Paille.

16 DR. GOODMAN: Right; I think that is

17 correct. They varied slightly between the studies

18 but what I am saying is that the information that

19 was obtained allowed one to do an integrated type

20 of analysis where you could use the information and

21 look at it for a similar outcome parameter. As I

22 said earlier, and I think we all agree, there is

23 not really a methodology, a statistical

24 methodology, people certainly agree on but the

25 outcome measures for this, especially when Lipha

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1 was working with acamprosate, naltrexone was not

2 available in Europe and just became available there

3 recently. So Lipha was really pioneering this area

4 and the types of outcome parameters that were used

5 were, by that very nature, something that could be

6 gleaned from the information gathered.

7 I think probably each country had their

8 own kind of slant on what they thought, more or

9 less investigator-driven types of endpoints.

10 DR. G. COOK: The primary objective,

11 relatively clearly abstinence.

12 DR. GOODMAN: Yes; exactly.

13 DR. G. COOK: So, even though there may

14 have been variations on how abstinence was looked

15 at, whether it was time to first drink or complete

16 abstinence or number of abstinent days, the focus

17 was on abstinence and the conclusions across those

18 multiple criteria were pretty much the same.

19 I think the analyses the FDA has done

20 pretty much agrees with that so there are not

21 really any major inconsistencies that I have seen

22 if you basically say the real objective of those

23 studies was abstinence.

24 DR. LEON: But I still haven\'t heard you

25 say that the data analyses that were presented

103

1 today corresponded directly with that that was

2 described before the data were collected. It seems

3 like the primary efficacy measure and the data

4 analytic techniques in all four of the studies are

5 different than those specified in the protocols.

6 DR. G. COOK: But, for the three European

7 studies, your earlier point, which is consistency

8 of findings across a variety of ways of looking at

9 the data, was, indeed, supported. Now, the U.S.

10 study is going to be a totally different phenomenon

11 which we will get to shortly.

12 Essentially, the structure of the European

13 studies, particularly at the time they were done,

14 had a reasonably clear objective of abstinence and

15 the criteria that were looked at were all criteria

16 that were relevant to abstinence. The conclusions

17 across those criteria by the different ways of

18 looking at them, whether by the sponsor or the

19 agency, were pretty much the same.

20 It would be important that they were the

21 same because if it had turned out that the analyses

22 of abstinence in the Europeans had varied according

23 to measure or method, that would be an issue with

24 respect to the European studies. So, the fact that

25 there is consistency across those different ways of

104

1 looking at the data, even though they have

2 different conventions for how you deal with

3 intervals between visits, is important to the

4 robustness.

5 With respect to the U.S. study, I think

6 there was, at one time, interest in the time to

7 first drink or abstinence. That was a goal of the

8 U.S. study. But that was basically defeated

9 because the patients weren\'t abstinent at baseline.

10 In other words, unlike the European studies, you

11 did not have abstinent patients at baseline. So

12 the notion of looking at time to first drink or

13 total abstinence broke down. That is why other

14 things had to be looked at.

15 Now, the role of the U.S. study here is to

16 try to understand consistency; is there information

17 in the U.S. study that more or less fits with what

18 was proven in the European studies. The U.S. study

19 doesn\'t prove anything. It is possibly

20 inconclusive. It possibly raises doubt about what

21 was seen in the European studies.

22 So the role of all of the explanatory

23 analyses\--we don\'t call them confirmatory anymore

24 for the U.S. study; we call them explanatory\--is to

25 try to understand whether there is information or

105

1 trends in the U.S. study that fits with what was

2 proven in the European studies. That is what Dr.

3 Mason tried to share with you all.

4 So the original planned analyses didn\'t

5 work because we didn\'t have an abstinent population

6 at baseline.

7 DR. OREN: Dr. Hamer?

8 DR. HAMER: Actually, I have a related

9 question. I have very little experience in

10 substance abuse but I do have a great deal of

11 experience in depression studies and schizophrenia

12 studies and a variety of other psychiatric studies.

13 If a sponsor came in with four depression

14 studies of which three were positive and one

15 wasn\'t, basically, I think both the FDA and this

16 committee would tend to sort of shrug our shoulders

17 and say, you know, we have failures in depression

18 studies. Three out of four is not bad. Sounds

19 like a good drug to me.

20 So, as a statistician, I never want to

21 underestimate the pure properties of randomness.

22 So I may not feel as compelled as the FDA seems to

23 feel to seek explanatory reasons for why the U.S.

24 study, unfortunately, failed.

25 Now, there are other issues with the

106

1 European studies having to do with the time frame

2 and conditions under which they were designed and

3 the fact that they didn\'t have this rigid

4 prespecified endpoints and analyses as the ones we

5 would design now are.

6 But I do agree with Dr. Cook that what we

7 really should be pulling out of the

8 nonprotocol-specified reanalyses of the U.S. data

9 is that these analyses are possibly explanatory.

10 They are hypothesis-generating. They are not

11 hypothesis-confirming. I hope that the sponsor is

12 not claiming that these hypotheses in the U.S.

13 study indeed confirm that acamprosate promotes

14 abstinence in patients who are already abstinent

15 and I would hope we don\'t interpret it that way.

16 So I would say that our task, in some

17 sense, is, using the standards that we are

18 accustomed to using, in a sense, to look at the

19 European studies and decide whether those provide

20 sufficient evidence of safety and efficacy.

21 DR. OREN: If I could just ask you, since

22 we just have a few more minutes for this

23 segment\--we will have an afternoon discussion

24 section to weigh all the different points. So if

25 we could just focus on the specific questions for

107

1 the company to answer.

2 DR. HAMER: In that case, I will postpone

3 things.

4 DR. OREN: Okay. Dr. Keck?

5 DR. KECK: This is a belated follow up to

6 Dr. O\'Brien\'s point about psychosocial influence on

7 outcome. I am just, again, trying to understand

8 the many reasons why the U.S. study failed. In a

9 way, it doesn\'t surprise me that a study in which

10 you had ambivalently motivated people many of whom

11 were not abstinent to participate in the trial with

12 poly drug abuse didn\'t do so well in this study.

13 But one other embedded reason I wonder

14 about in the design is it seems to me that patients

15 had not only one but potentially two psychosocial

16 treatments here because of the\--I\'m getting the

17 terminology here\--the time-line follow-back method

18 which, again, coming not as a substance-abuse

19 researcher but doing research in other

20 impulse-control disorders, any time you put a diary

21 into a study as a treatment-outcome measure, you

22 invariably introduce, I think, subtly, a form of

23 behavioral therapy by completion of the diary,

24 itself.

25 So I guess I am saying it seems to me you

108

1 had two psychosocial interventions or behavioral

2 therapy interventions which I think made it even

3 more difficult to find a drug-placebo difference.

4 Does that sound fair to say?

5 DR. MASON: It sounds quite fair and

6 accurate, and the placebo response rate was high in

7 the U.S. study. I completely agree with you that

8 the data-collection methods, in themselves,

9 probably raised the threshold of what was perceived

10 by the patient as therapeutic activity, in addition

11 to the twenty minutes that they were officially

12 assigned.

13 DR. OREN: Dr. Hughes

14 DR. HUGHES: I wonder of you could respond

15 to my rationale here. The notion is that, with

16 increased psychosocial treatment, you decrease the

17 odds ratio between active and placebo. That is the

18 notion I hear being proposed.

19 If increased psychosocial is\--the typical

20 way you test that is you take the response of the

21 placebo group and does it correlate with the odds

22 ratio. It is a standard metaanalytic treatment.

23 So the notion is studies that have high placebo

24 responses should have low odds ratios.

25 I did this before I came down. When I

109

1 look across the fourteen studies, that is not the

2 case in the fourteen acamprosate studies. So my

3 rationale is the data don\'t suggest that high

4 placebo rates lead to lower odds ratios. But maybe

5 I am thinking wrong.

6 DR. GOODMAN: I am certainly far from a

7 statistician but I would just comment that, if you

8 are looking across the European studies and, if I

9 understood your comments correctly, you were

10 talking about behavioral therapy and I gathered

11 something rather substantial that was, as Dr. Mann

12 has pointed out, that was not the case in Europe.

13 It was not consistent and it varied and it was

14 more\--the term that was used in the European

15 dossier was \"naturalistic.\"

16 Maybe I didn\'t understand what you were

17 saying.

18 DR. G. COOK: This is Gary Cook, again. I

19 am not sure how to answer your question. I think

20 when the placebo rate is higher, that can make it

21 more difficult to show a difference in rates

22 because the amount of room for change may be

23 affected.

24 Odds ratios are complicated kinds of

25 things, so their ability to be large or small is

110

1 related to the base rate that you are working with

2 so an odds ratio of 90 percent versus 95 percent is

3 2. If you have 90 percent compared to 95 percent,

4 the odds ratio there is about 2 whereas if you are

5 comparing 50 percent to 67 percent, the odds ratio

6 is 2.

7 So I think it is very difficult to try to

8 actually project what you think an odds ratio might

9 do as you change the base rate. If you do have

10 high placebo rates, it may make it more difficult

11 to show a substantial difference in response rates

12 because the amount of room for improvement may be

13 less.

14 But I think, really, it is uncertain in

15 these kinds of things. Also, again, the U.S.

16 population and European populations were different

17 from one another, so extrapolating across the two

18 populations will have its difficulties.

19 DR. OREN: To conclude this segment, Dr.

20 Rudorfer and then I will ask one question after

21 that.

22 DR. RUDORFER: Thanks. It certainly can

23 be challenging to do an effectiveness study such as

24 the U.S. study where one broadens inclusion

25 criteria to try to better reflect real-world

111

1 populations. I think the American investigators

2 did a very good job of responding to the FDA

3 request to, say, have a broad age range and include

4 cormorbidities.

5 But what concerns me is they are sort of

6 going back to basics. If we are discussing the

7 efficacy of a drug for \"maintenance of long-term

8 abstinence from alcohol,\" I still don\'t understand

9 why abstinence was not an inclusion criterion.

10 DR. GOODMAN: I will let Barbara address

11 that, but I think our assumption in designing the

12 protocol was that patients would understand that

13 they were to be abstinent at the study onset. It

14 was not explicitly stated, but that was our

15 expectation. So, of course, it was quite a

16 surprise to find out that half these people were

17 not abstinent.

18 I think we had been quite\--what would I

19 say\--just really tuned into the European

20 populations as starting from this abstinence

21 without appreciating that that would not be the

22 case in our study.

23 But, Barbara, you might\--we also had the

24 steady-states idea.

25 DR. MASON: Your point is well taken. The

112

1 behavioral therapy was abstinence oriented,

2 complete abstinence. The admission criteria was

3 people had to have a minimum period of time with no

4 hazardous drinking, which is no more than one drink

5 a day for women, two drinks a day for men, so that

6 they would have decreased to that level so we

7 wouldn\'t have to deal with withdrawal symptoms on

8 study.

9 But, because acamprosate takes the time

10 that it does to reach steady state, and the animal

11 literature was indicating that there may be some

12 benefit in alcohol withdrawal, our idea was to

13 start drug as soon as possible in the process to

14 help these patients become and stay abstinent.

15 That is why the admission criteria were

16 what they were. We did no interim analyses or

17 peaks or anything and so that is why it was the

18 surprise that it was in terms of the rate of

19 nonabstinence.

20 DR. OREN: My question is for Dr. Mann.

21 In the European studies in support of the efficacy

22 of acamprosate, you mentioned that the completor

23 rates were higher in the active group than in the

24 placebo group. Was that a statistically

25 significant difference and what kind of statistic

113

1 was used?

2 DR. MANN: It was a significant

3 difference. I think we could pop up one of these

4 extra slides, but I know there was a significant

5 difference between those two groups but I don\'t

6 recall what kind of statistics we did. But we

7 could find out and then deliver that information

8 later if you want. Sure.

9 DR. OREN: We will now take a ten-minute

10 break and then reconvene to hear from the FDA.

11 \[Break.\]

12 DR. OREN: We are now at the point for FDA

13 presentations. I will call upon Dr. Celia

14 Winchell, Medical Team Leader for Addiction Drug

15 Products.

16 FDA Presentations

17 Clinical Issues on Efficacy

18 DR. WINCHELL: I am Celia Winchell from

19 the FDA and I am going to speak to you this morning

20 about the clinical review of the efficacy of

21 acamprosate.

22 \[Slide.\]

23 I want to let you know that we approached

24 this data hopefully. We knew before the

25 application came in that the American trial hadn\'t

114

1 worked out. But it isn\'t unusual for an

2 application to contain some trials that worked and

3 some trials that weren\'t able to show a difference

4 from placebo.

5 But this time, we had some older, perhaps

6 less rigorous, foreign studies that worked against

7 a recent domestic and really good study that

8 didn\'t. It was hard to overlook that.

9 We had some reservations about the conduct

10 of the European trials but we looked at them at

11 them a few different ways and we were able to find

12 encouraging results. Then both the statistical

13 reviewer, Dr. Wang, and I dug into the American

14 trial data. We really hoped there would be some

15 explanation for the outcome that would have some

16 face validity and could tell us something about

17 circumstances in which acamprosate works and

18 circumstances in which it doesn\'t and that would

19 give us confidence that we could accept the

20 European studies.

21 For about the next half hour, I am going

22 to take you through the process of looking at the

23 efficacy data and show you where it led us.

24 \[Slide.\]

25 The questions on this slide are the ones

115

1 you have been asked to consider this morning. You

2 have heard some comments from Lipha on the matter

3 and, before I begin, I will point out that there

4 are two ways of casting the questions.

5 It was suggested in the materials that we

6 reviewed that the reason the European trials were

7 able to demonstrate the effect of acamprosate and

8 the American trial wasn\'t is primarily that the

9 populations differed. The European subjects, as we

10 have heard, all randomized to treatment after

11 completing an inpatient detox. There were few

12 polysubtance abusers in the European studies and

13 the European studies either assumed or required a

14 high level of motivation for abstinence.

15 Lipha was able to identify a subset of the

16 American population they presented to us as being

17 most like the European subjects and they feel that

18 this group did demonstrate the effect of

19 acamprosate. So you could put the questions on the

20 slide this way. Given the positive findings

21 throughout Europe, how would we weigh the results

22 of the United States trial upon consideration of

23 our explanatory analyses based on population

24 differences?

25 But, on the other hand, I found a number

116

1 of the aspects of the European data presentation

2 that gave me pause during my review and I was

3 completely unable to find a way to explain the

4 results of the American trial.

5 As you saw in the materials provided in

6 the backgrounder, I defined a number of population

7 subsets that I thought could account for the

8 differences. For statistical reasons, I restricted

9 myself to use of prerandomization characteristics

10 and, no matter how I sliced it, there was no

11 treatment effect of acamprosate at the proposed

12 dose. It was not a matter of failure to reach

13 statistical significance due to small sample size.

14 There was really no difference and occasionally

15 there were differences that trended in the wrong

16 direction, in the direction of favoring placebo.

17 So I would be inclined to put the

18 questions this way. In view of the failure of the

19 carefully conducted American trial, which we are

20 unable to explain through analyses directed at

21 various subpopulations, can we accept the findings

22 of the European studies knowing the data was

23 collected less systematically.

24 \[Slide.\]

25 In the next few minutes, I am going to

117

1 take you through the review of the efficacy data

2 that was submitted to the FDA for review. The

3 emphasis in the material submitted to us for the

4 purpose of an integrated efficacy analysis was on

5 the cumulative abstinence duration. So I will

6 cover how we concluded that this outcome variable

7 identified for the European pivotal trials couldn\'t

8 really be viewed with confidence.

9 Then I will give you the good news about

10 what we were able to make out of those trials and

11 then I will walk you through the American trial

12 which wasn\'t able to show an effect of acamprosate

13 and our attempts to resolve the discrepancies

14 between these bodies of data.

15 \[Slide.\]

16 So, first, what is my problem with

17 cumulative abstinence duration. As I mentioned,

18 the primary outcome variable emphasized in the

19 integrated analyses in the European pivotal trials

20 was cumulative abstinence duration, which is

21 measured in days, or what was called corrected

22 cumulative abstinence duration which amounts to

23 percent days abstinent.

24 In your briefing book, you read that we

25 rejected this variable on review. I will remind

118

1 you that these studies were complete at the time

2 the IND was open. We never discussed the design

3 and analysis of these trials prospectively, so

4 there wasn\'t an opportunity to comment prior to the

5 NDA review.

6 Let me make the point that I have no

7 problem with these measures in theory. They are

8 attractive because they capture the picture of

9 drinking behavior even for those subjects who don\'t

10 abstain for the entire observation period which we

11 know is most of them.

12 The problem with the use of these measures

13 in analyzing the European studies is that they

14 amount to a false precision. These studies

15 collected the drinking data in a somewhat

16 nonsystematic way at widely spaced visits and used

17 various data-handling rules to convert the data so

18 collected into number of days of abstinence and

19 days of drinking.

20 On examining the protocols, the

21 case-report-form fields and the data-handling

22 rules, I concluded that the CAD in the three

23 pivotal European trials, actually in all the

24 European trials, the ten additional ones other than

25 the British study, seem to be a highly imputed

119

1 value that went beyond the precision of the data

2 actually collected.

3 I will walk you through the three pivotal

4 studies to show you what I mean.

5 \[Slide.\]

6 We have already heard about these studies.

7 The first study is Pelc II. This was a short-term

8 study with 90 days of treatment. This study had

9 seven on-treatment visits. These visits were close

10 together, one to two weeks. At each visit, the

11 investigator estimated the subject\'s average daily

12 consumption on drinking days and average frequency

13 of consumption. It wasn\'t a systematic approach to

14 this, like the time-line follow-back method.

15 The real problem, though, is in the

16 data-handling rules. Anyone who had any number

17 other than 0 listed for frequency and amount for

18 the purposes of the CAD calculation was considered

19 to have been drinking during the entire inter-visit

20 interval. So any number between one drinking day

21 and 15 drinking days was transformed to 15 drinking

22 days.

23 If a visit was missed, drinking days were

24 imputed all the way back to the previous visit. So

25 this method collapses a fairly wide range of

120

1 responses into two possibilities, 0 or 15. I find

2 this troubling because the result was then

3 mathematically summed, a mean was calculated to the

4 tenth place and comparisons were made

5 statistically.

6 \[Slide.\]

7 The Paille study, somewhat more

8 problematic, had a one-year treatment period but

9 only nine visits on treatment so the interval was

10 as much as 60 days between visits. At these

11 visits, the investigator again came up with an

12 estimate of the number of days of nonabstinence and

13 the drinks per drinking day without a systematic

14 technique for reconstructing the data.

15 But, unlike the Pelc study which used this

16 very conservative approach, the Paille study

17 handling rules took that estimate on its face and

18 put it into the calculations of CAD. I am just

19 skeptical about the precision.

20 \[Slide.\]

21 The PRAMA study had only six visits over

22 48 weeks of treatment. For half the visit, the

23 intervisit interval was three months. At these

24 visits, there was a global assessment by the

25 physician and then the physician was also supposed

121

1 to determine if a relapse occurred, classify it as

2 short-term or long term, try to figure out when it

3 happened, and then there were data-handling rules

4 for the calculation of CAD which are so complex

5 that I have put them on a separate slide which is

6 still too small to read.

7 \[Slide.\]

8 I know you can\'t read this but I am just

9 trying to make the point that there is such a

10 complicated set of mathematical rules here to

11 transform what is a rough estimate about what has

12 happened for the past three months into a specific

13 number of days of drinking versus abstinence. I

14 just felt that is a false precision that goes

15 beyond what was really known. That was the bad

16 news.

17 \[Slide.\]

18 But the good news was we looked at the

19 datasets and tried to see what we could conclude

20 based on the data collected. You have heard that a

21 considerable amount of effort went into

22 establishing abstinence versus nonabstinence.

23 There were blood-alcohol levels taken,

24 breathylizers. There were collateral informants.

25 There were other external informants. There was a

122

1 lot of effort here. So we could place some

2 credibility on that.

3 I considered how many people were assessed

4 by the investigator as continuously abstinent. I

5 realize that is a very high standard and doesn\'t

6 really capture all of the clinical effect that

7 would be considered relevant so I wanted a way

8 other than CAD to look at periods of abstinence

9 even if they were interrupted by periods of

10 drinking.

11 So I went through and I counted how many

12 people had zero visits at which they were assessed

13 as abstinent, how many had two, and so on, and

14 compared across treatment groups. Now, with an

15 intervisit interval of 90 days, binary assessment

16 of abstinence versus nonabstinence, maybe a little

17 suspect but we talked about all the effort that

18 they went to do this; right?

19 If the subject can convince the

20 investigator he hasn\'t had a drink in three months,

21 that probably does mean something.

22 \[Slide.\]

23 Here I have laid out the results of the

24 continuous abstinence analysis. This lists the

25 number of percent of subjects in each treatment arm

123

1 who were assessed as continuously abstinent

2 throughout the treatment period. In each of these

3 studies, acamprosate, at the dose proposed for

4 marketing, was superior to placebo and the

5 differences were statistically significant.

6 Here Pelc is clear. Here this one is kind

7 of marginal and it depends on what analysis you do.

8 Mine came out with a p-value of 0.042 for this

9 pairwise comparison. Then here I will just

10 clarify. This says 1998 per day. Actually these

11 patients were allocated by weight so that heavier

12 patients got 1998 per day and later patients got

13 1332 per day. But it turns out there were only

14 thirteen people who got 1332 a day. So, for

15 convenience, I am just calling it 1998 a day and

16 this is also statistically significant.

17 \[Slide.\]

18 I also wanted to look at the results that

19 included noncontinuous abstinence as clinically

20 relevant. So I tabulated for each study how many

21 subjects were assessed by the investigator as

22 abstinent at zero visits, one visit, two visits and

23 so on. I am going to show the tables for each

24 study one-by-one on the next few slides. I will

25 just tell you that the differences come out

124

1 statistically significant in favor of acamprosate

2 1998 milligrams per day in all the studies.

3 If you look very closely, it seems that,

4 for the most part, the superiority in this analysis

5 continues to be driven primarily by the subjects

6 who were continuously abstinent. But there is, in

7 some studies, a little greater tendency for the

8 placebo subjects to have very few abstinent visits.

9 In other studies, the subjects who have many but

10 not all abstinent visits strengthen the finding.

11 So this first slide shows you the results

12 from Pelc II. There were supposed to be nine

13 visits but, for some reason, there are no subjects

14 with nine abstinent visits. But these numbers

15 here, this 26, 26, 9, these are the same numbers

16 that come up for the continuously abstinent

17 analysis. I haven\'t been able to explain this. It

18 may have to do with handing of missing data.

19 In any case, you will see here that there

20 is a greater tendency for placebo subjects to have

21 zero, one or two abstinent visits as compared to

22 people assigned to active condition.

23 Of course here you will see this is

24 consistent with the continuous abstinent analysis.

25 There are just a lot more people assigned to active

125

1 who had eight visits compared to placebo.

2 \[Slide.\]

3 Here is the analysis for the Paille study.

4 There were nine visits, these 85 people here.

5 These are 85 people who were continuously

6 abstinent. They are shown as having nine visits

7 assessed as abstinent.

8 This study was the one that had the most

9 marginal results when you look at continuous

10 abstinence. But you can see that if you add in the

11 people who had eight abstinent visits, that

12 strengthens the finding because you end up with 44

13 in each of these groups which is 24 to 25 percent.

14 In the placebo group, you end up with 22,

15 which is only 12 percent. At the other end of the

16 spectrum, the least successful end, the difference

17 is less obvious. 54 percent of the placebo group

18 has two or fewer abstinent visits\--I am adding

19 these together\--compared to 47 percent of the

20 acamprosate low-dose group and 40 percent of the

21 acamprosate 1998 milligram group.

22 \[Slide.\]

23 Here is the data from PRAMA. There were

24 only six visits in this one-year study and, as Dr.

25 Wang will discuss, there were many dropouts and

126

1 dropouts occurred at different rates across

2 treatment groups. Missing visits couldn\'t be

3 assessed as abstinent visits. They were missing.

4 So this analysis is vulnerable to the dropout

5 problem. We understand that many fewer placebo

6 subjects actually attended six visits so,

7 obviously, they have many fewer opportunities to be

8 assessed as abstinent.

9 So we have to look at this analysis with

10 caution in view of that phenomenon. But here you

11 see that the superiority of acamprosate over

12 placebo at the most successful end of the spectrum

13 is clearly driven by the subjects with six

14 abstinent visits. There is no difference at four

15 or five.

16 But the difference between treatments is

17 also apparent at the other end of the success

18 spectrum. 63 subjects, or 46 percent in placebo

19 group, had zero or one visit at which they were

20 assessed as abstinent as compared to 39 which is

21 just 29 percent of the acamprosate group.

22 \[Slide.\]

23 So, in summary, it does look as if the

24 three European studies indicate an effect of

25 acamprosate in maintaining abstinence after

127

1 detoxification.

2 \[Slide.\]

3 Let\'s turn to the American study. As you

4 have already heard, this was a multicenter study

5 involving 601 subjects at 21 centers throughout the

6 United States, 260 subjects randomized to placebo,

7 258 on acamprosate 2000 milligrams a day and 83 to

8 the exploratory arm, acamprosate 3000 milligrams a

9 day.

10 We have discussed that the study used a

11 different formulation from the one in the European

12 trials. In those studies, there was a 333

13 milligram tablet. Subjects took two tablets three

14 times a day with meals. This study used a

15 compositionally proportional 500 milligram tablet.

16 The subjects actually took three tablets

17 QAM and QHS3. So everybody, including the 3 gram

18 exploratory arm, would have to take three tablets,

19 the 2 gram got two active and one placebo and the

20 placebo arm got three placebo.

21 We have already discussed the

22 pharmacokinetics and the TID dosing isn\'t essential

23 to maintaining steady state. So BID is not a

24 concern. And we have already touched on the food

25 effect. The effect of food is to lower systemic

128

1 exposure so, if anything, we think that the dosing

2 schedule in the American study would have exposed

3 the American subjects to a higher total daily dose

4 even though the nominal dose, 2 grams and 1998

5 milligrams, are essentially the same.

6 This was a carefully conducted and closely

7 monitored study. The features included six months

8 of treatment with eight on-treatment visits most of

9 which were at four-week intervals. Subjects

10 brought drinking diaries to each visit which were

11 used to help reconstruct day-by-day drinking data

12 using the time-line follow-back method.

13 Breath alcohol was measured at each visit

14 and collateral informant data was also collected at

15 intervals. This information was used to modify the

16 drinking data when it conflicted with the subject\'s

17 information and, in addition, as we have heard, the

18 subjects received a standardized brief psychosocial

19 therapy oriented to reinforcing medication

20 compliance.

21 \[Slide.\]

22 The primary outcome measure was the

23 percent of study days which were non-drinking days

24 referred to in the study report as corrected

25 cumulative abstinence duration. The number of

129

1 non-drinking days was calculated from the time-line

2 follow-back data as modified by other information

3 in the breath alcohol collateral informant and

4 there was an algorithm prespecified for assigning

5 values to missing days that occurred prior to

6 discontinuation or lost to follow up.

7 There was also a fairly rigorous protocol

8 for locating subjects to minimize the amount of

9 data that had to be imputed. My understanding is

10 that, in the calculation of a CCAD,

11 discontinuations were evaluated by a blinded panel

12 of raters and, if they were related to drinking,

13 all the days after discontinuation were considered

14 drinking days. But if a discontinuation was not

15 considered related to drinking, the denominator was

16 then adjusted so that the days after dropout were

17 not considered in this calculation of percent days

18 abstinent.

19 You might think that that is very

20 conservative and unfair to people who drop out

21 early as the result of drinking, so we actually

22 looked at people\'s baseline level of drinking to

23 see, if they got worse, maybe they would go back to

24 how bad they were before they came into the trial.

25 It does probably overestimate but over

130

1 half the subjects were drinking six or seven days a

2 week. About a quarter of them were drinking four

3 or fewer days a week. So it is an overestimate but

4 it is not horrendous.

5 \[Slide.\]

6 These are the results that I get from the

7 sponsor\'s datasets that were submitted to us for

8 review. Considering the entire intent-to-treat

9 population, the mean percent days abstinent for the

10 placebo group was 51 percent. The small group that

11 was randomized to 3 grams a day, about the same, at

12 50 percent. And the group that got the recommended

13 dose of acamprosate 2 grams a day had a mean

14 percent days abstinent of 46 percent.

15 Looking at the medians, placebo also

16 outperformed acamprosate. Why did this happen? If

17 acamprosate worked in the European studies why

18 didn\'t it seem to work here?

19 \[Slide.\]

20 Here were the simplest and most attractive

21 explanations presented to us from even before the

22 NDA was submitted. First, the European subjects

23 had been detoxed and were abstinent at baseline but

24 the American subjects were not required to undergo

25 detox probably as a consequence of the current

131

1 climate in our medical-care delivery system. Only

2 about 10 percent of them got it.

3 Furthermore, by the time the

4 study-medication treatment began, about half the

5 subjects were already actively drinking. So, the

6 first idea that springs to mind to all of you is

7 that acamprosate is just a relapse-prevention

8 agent. It keeps alcoholics from taking the first

9 drink but it can\'t seem to put the brakes on if

10 someone is actively drinking.

11 So, of course, I looked at the subset that

12 was abstinent at baseline which is about half the

13 subjects.

14 Now, the second difference was level of

15 motivation. Some of the European studies actually

16 required, as a condition of entry, that the subject

17 be committed to abstinence. Others didn\'t, but it

18 has been assumed the subjects must have been

19 motivated because they were willing to go through

20 detox.

21 Now, I am not sure about that because I

22 don\'t know about the healthcare delivery system in

23 Europe, either now or at the time these studies

24 were done over ten years ago. It is possible

25 inpatient detox was pretty standard and readily

132

1 available and that willingness to go into the

2 hospital for three days wasn\'t really a marker for

3 a high level of motivation.

4 But let\'s say it was. In the American

5 study, as you heard, subjects were asked to

6 indicate at screening what their goal was for

7 treatment and they could choose from a list that

8 ranged from total abstinence to no goal. You saw

9 that it included temporary abstinence, controlled

10 drinking. You also saw there was another option on

11 there; total abstinence, but I realize a slip is

12 possible.

13 This wasn\'t, \"I think a slip is okay,\" or,

14 \"My therapist has told me, you will probably slip.\"

15 That\'s okay. Let\'s talk about what we are going to

16 do about it. This was just, my goal is total

17 abstinence but I realize a slip is possible. It

18 was multiple choice.

19 I regard that as just as motivated but a

20 little more realistic. And I put those two

21 together. That is actually 72 percent of the

22 subjects and evenly distributed once you add them

23 together, evenly distributed across treatment arms.

24 Finally, the high rate of polysubstance

25 abuse in the American trial was striking,

133

1 especially given that a positive urine tox for

2 anything other than marijuana was exclusionary.

3 Now, only PRAMA of the European studies gave us

4 information about other substance-abuse history

5 and, in that study, on 20 percent of the subjects

6 had any history of other substance abuse.

7 In contrast, the United States population,

8 only 20 percent did not have a history of illicit

9 drug use.

10 \[Slide.\]

11 As you have heard, Lipha was able to find

12 a subset they thought resembled the European

13 population. It was defined by some

14 post-randomization variables, post-randomization

15 compliance with visits and medication. In

16 addition, a treatment goal of complete abstinence.

17 In this group, the acamprosate arm had 70

18 percent days abstinent and the placebo group had 63

19 percent. But the problem here is that it appears

20 to be that this is the only population that

21 demonstrates an effect of acamprosate. It is

22 defined primarily by post-randomization behavior

23 such as medication compliance and observed use of

24 substances. All post hoc analyses make us

25 uncomfortable because if you do enough of them, you

134

1 are bound to find one that comes out significant

2 which actually makes it particularly troubling that

3 we couldn\'t.

4 But subset analyses, whether post hoc or

5 planned, that rely on groups defined by

6 post-randomization factors are particularly

7 troubling. Finding that a drug was particularly

8 effective in a group with a certain set of

9 post-randomization behaviors really doesn\'t give us

10 any information that we can use for patient

11 selection.

12 What\'s more, this population definition

13 doesn\'t even take into account the issue of

14 abstinence at baseline which the proposed label

15 indication now indicates is the important feature

16 of patient selection. So I am not convinced by

17 this finding. I am not convinced by this

18 population definition.

19 As you read, I conducted a series of

20 subset analyses of my own using populations that

21 seemed to make sense to me.

22 \[Slide.\]

23 I am going to go over for you my analysis

24 populations and how I hit upon them. I analyzed a

25 subset of subjects that were abstinent for at least

135

1 five days at baseline. That is fairly

2 straightforward. The subset that identified a goal

3 of abstinence, whether or not they indicated that

4 they realized a slip was possible. And I tried to

5 figure out the best way to define the

6 nonpolysubstance-abusing population. So let me

7 take you through some of the things I considered.

8 First, there was something called an

9 illicit drug use index calculated for each subject.

10 If they had no history whatsoever of illicit drug

11 use, that was zero. So I looked at that group, but

12 it was very, very small. It was 20 percent of the

13 randomized population.

14 So then I thought, well, maybe past-year

15 drug use was probably a reasonable indicator of

16 current active polysubstance abuse. So I looked at

17 the group with no illicit drugs in the past year

18 which enlarged the subset to about 40 percent of

19 the randomized population.

20 But, because subjects were allowed to

21 enter the study if they had a tox screen positive

22 for marijuana, if I looked at the group that had no

23 past-year drug use other than marijuana, I actually

24 got as many as 80 percent of the randomized

25 population. Now, I will acknowledge that that is

136

1 our fault. We asked Lipha to broaden the inclusion

2 criteria to allow for a positive tox for marijuana

3 at entry because we are concerned that the actual

4 target population has a pretty high prevalence of

5 polysubstance abuse and it seems like we were

6 right.

7 Even though people were screened out, if

8 they had current dependence on any other substance

9 and screened out if they had a positive urine tox

10 at screening for anything other than marijuana, the

11 enrolled population still has a 14 percent history

12 of opiate use and 49 percent history of cocaine

13 use. This is what American alcoholics look like.

14 I also looked at the group defined by the

15 results of urine toxes during the study. But I am

16 actually not at all convinced that this is useful.

17 With monthly study visits, tox screens are unlikely

18 to pick up all the illicit drug use in the study

19 and also nothing can be predicted about the results

20 of urine-tox screens that weren\'t done because the

21 subject dropped out of the study.

22 So if you select subjects who just don\'t

23 have urine-tox evidence of drug use, it doesn\'t

24 mean you have a population that didn\'t use drugs.

25 It also especially means you don\'t have a

137

1 population that is prone to use drugs after they

2 drop out. Also, there were only urine-tox data for

3 525 subjects, so I didn\'t use this.

4 Ultimately, I decided to focus on the

5 subjects whose only illicit drug use in the past

6 year had been marijuana. So, from now on when I

7 say no past-year illicit drug use, what I am

8 talking about is actually the subjects who had no

9 past-year illicit drug use other than marijuana.

10 Then I put together the subset that was

11 abstinent at baseline, motivated and had no

12 past-year illicit drug use, a very small group,

13 only 20 percent of the randomized population.

14 \[Slide.\]

15 These are my results. This is using the

16 sponsor\'s corrected cumulative abstinence duration

17 in the dataset. Here is motivated. I don\'t have a

18 slide for this but I did look. I looked at

19 motivated, total abstinence versus total

20 abstinence, but I believe a slip is possible. And

21 they are exactly the same. They are the same.

22 Here is abstinence. Here is the no

23 history whatsoever of drug use. These are very

24 small numbers. No illicit drugs and here is not

25 illicit drugs other than marijuana. This is the

138

1 last time you are going to see these guys. You

2 will see that these are all actually going the

3 wrong way.

4 I have to say that, going into this, I was

5 really hoping that the rubber was going to meet the

6 road somewhere. I was going to be able to say,

7 ah-ha, it only works in pure alcoholics, or, see,

8 as long as you are abstinent at baseline, it works.

9 But these analyses just don\'t bear out any

10 conclusion about patient selection that suggests

11 why acamprosate didn\'t work in this study.

12 \[Slide.\]

13 Looking at the subset that was abstinent

14 and motivated and the subset that was abstinent,

15 motivated and had no past-year illicit drug use, I

16 still could not find an effect of acamprosate.

17 \[Slide.\]

18 I looked at other measures, too. Complete

19 abstinence wasn\'t very useful because there were so

20 few subjects, 33 to be exact, who were abstinent

21 for the entire trial and 20 of them were on

22 placebo.

23 There was a categorical analysis of good

24 response which looked at how many subjects had 90

25 percent days abstinent or more. This was

139

1 interesting because the motivation ITT population

2 defined by the sponsor did show the acamprosate

3 group tied with the placebo group and then the

4 sponsor defined motivated efficacy evaluable

5 population showed acamprosate beating placebo, but,

6 as it turned out, my analysis populations do not

7 fare as well and the placebo group did better than

8 the acamprosate group in all the populations that I

9 tried.

10 \[Slide.\]

11 So next I looked at fairly liberal

12 definition of success. There was a dataset in

13 which relapse was flagged if the patient relapsed

14 into having at least five drinks a day for five of

15 the next seven days.

16 So we looked at how many subjects never

17 had a relapse as so defined. Obviously, success by

18 this criterion is fairly common. In this slide,

19 you will see the ITT population looks a little bit

20 promising but neither the abstinent subset, the

21 motivated subject, the no-past-year-illicit drugs

22 or the group that met all three criteria show an

23 effect of acamprosate on this measure. But the

24 sponsor motivated efficacy evaluable does.

25 \[Slide.\]

140

1 Just in case I missed something, I pored

2 over the demographics from the different trials to

3 find another explanation. I was so enthusiastic

4 about this that I misinterpreted this data and I

5 confused the number of drinks per drinking day with

6 the average number of drinks per week and I was

7 under the misimpression that there were more heavy

8 drinkers in the European data.

9 But, just in case you were wondering, this

10 analysis doesn\'t work either.

11 \[Slide.\]

12 In summary, the European studies indicate

13 an effect of acamprosate on either a continuous

14 abstinence or noncontinuous abstinence while the

15 American study does not demonstrate the efficacy of

16 acamprosate in any subset defined by

17 prerandomization variables that would be useful for

18 patient selection.

19 \[Slide.\]

20 So I will put the questions back up here.

21 I have gone through some of the concerns about the

22 data from the European trials; relatively

23 nonsystematic data collection, low frequency of

24 study visits and then some of the ways in which the

25 European-trial populations differed from the

141

1 American population.

2 Then I went through the exploratory

3 analyses I undertook to try to select the subgroup

4 from the American study who resembled the European

5 population on important measures such as level of

6 motivation, baseline drinking status and

7 polysubstance abuse and I showed you that I was not

8 able to identify any population that demonstrated

9 the effect of acamprosate on measures including

10 percent days abstinent, categorical good response,

11 or even the fairly low bar of surviving the trial

12 without five heavy drinking days in a single week.

13 So I will reiterate my way of looking at

14 the questions we have posed to you. In view of the

15 failure of the carefully conducted American trial

16 which we were unable to explain through analyses

17 directed at various subpopulations, can we accept

18 the findings from the European studies knowing that

19 the data was collected less systematically?

20 I am going to turn the microphone over to

21 Dr. Sue Jane Wang for the statistical presentation.

22 Statistical Perspective of Acamprosate Experience

23 DR. WANG: Good morning, everyone. I am

24 Sue Jane Wang from Statistical Discipline of FDA.

25 \[Slide.\]

142

1 In this presentation, I would focus on the

2 statistical perspective of my acamprosate review

3 experience. \[Slide.\]

4 Here is the outline of today\'s

5 presentation. First, I will discuss the dropout

6 issue in the three European trials followed by

7 proper interpretation of the efficacy results. I

8 will spend most of the time on the U.S. trial

9 because the drinking data was much more credible in

10 this well-controlled study but knowing that the

11 differential dropout problem still exists in the

12 U.S. trial making it very difficult to interpret.

13 Finally, I would bring to your attention

14 on the conflicting analytical issues we faced

15 during review in the U.S. trial and the European

16 trials.

17 \[Slide.\]

18 Since you have heard several

19 presentations, I will just use the following

20 notations for the four dose arms that consist of

21 these four different studies: first, the placebo

22 arm; acamprosate, low dose, only studied in the

23 European; acamprosate, medium dose studied in both

24 different places; and the high dose, 3 grams per

25 day.

143

1 \[Slide.\]

2 The Pelc trial was a multicenter

3 double-blind, randomized, placebo-controlled

4 three-arm study. The objective of this study was

5 to explore the effectiveness and tolerance of

6 acamprosate in helping to maintain abstinence in

7 the weaned alcoholic patient population. Although

8 the main criteria of judgment was the consumption

9 of alcohol, the drinking data was based on

10 respective collections from clinicians. The Pelc

11 II study was the shortest, about three months study

12 duration.

13 \[Slide.\]

14 The number of patients in this study was

15 about 60 for each treatment arm. Among this

16 percent of patients who discontinued study early

17 was the highest with placebo, 48 percent, and lower

18 but similar for the low-dose and medium-dose

19 acamprosate, about 30 percent. Time to

20 discontinuation from the study was similar among

21 the three groups.

22 To analyze the percent of patients with no

23 relapse, two analysis results are presented. Let

24 me explain the two analyses first. For the dropout

25 of this analysis, patients who did not complete the

144

1 study and did not relapse will be considered as a

2 good outcome or a success. So the numerator is the

3 number of patients who did not relapse but who may

4 or may not complete the study.

5 This is the traditional

6 last-value-carried-forward analysis. Often, the

7 additional trial considers dropout patients as a

8 bad outcome. However, in light of very different

9 dropout patterns between the U.S. and the European

10 trials, we think it is important to show these

11 analysis results.

12 The other one, see the row of as relapsed.

13 Only patients who completed the study and did not

14 relapse is considered as a good outcome. Although

15 a patient may discontinue the study and did not

16 have any relapse at the time of discontinuation,

17 but in this analysis they would be considered as

18 relapsed.

19 As shown in this table,

20 acamprosate-treated patients had more than twice on

21 the percent of no relapse as compared to placebo

22 using either the dropout-as-is analysis or the

23 as-relapsed analysis. In addition, the finding of

24 the time to first relapse was consistent with the

25 percent of no-relapse rates. All showed convincing

145

1 evidence of acamprosate effect.

2 \[Slide.\]

3 The Paille was a multicenter double-blind,

4 randomized, placebo-controlled study with three

5 arms. Although the low dose and medium dose were

6 included in this trial, the main objective was

7 really to study the low dose not the medium dose in

8 the alcohol patients who were followed as

9 outpatients after withdrawal.

10 In this 360-day trial, patient size was

11 about 180 per arm. Similar to the Pelc II trial,

12 significantly more dropouts occurred in the

13 placebo-treated patients compared to the two

14 acamprosate groups, 65 percent versus 55 and 48

15 percent. But the treatment exposure time was the

16 shortest with the placebo, about eight months,

17 followed by the low-dose acamprosate of 10.5 months

18 and the high dose, 11.8 months.

19 When the LVCF type analysis was

20 performed\--that is, the dropout-as-is

21 analysis\--there was no statistically significant

22 percent of complete abstinence between acamprosate

23 and placebo although a numerical trend was

24 observed, 23 percent in placebo, 27 in acamprosate

25 low dose and 20 percent in the high dose. The

146

1 p-value was 0.285, not significant.

2 In contrast, when the as-relapsed analysis

3 was performed, twice higher in the percent of

4 complete abstinence was observed with acamprosate

5 as compared to placebo with a nominal p-value of

6 0.044. Interestingly, the sponsor reported that

7 the percent of complete abstinence using 340 days

8 as the cutoff instead of 360 days of the trial

9 period possibly related to the visit window in

10 counting the number of days.

11 \[Slide.\]

12 In this analysis, as you can imagine, it

13 lies between the dropout-as-is analysis and the

14 as-relapsed analysis giving a nominal p-value

15 somewhere in between, in this case, 0.096, not

16 significant.

17 A closer look using the time to first

18 relapse outcome showed that the time to first

19 relapse was twice longer with the medium dose but

20 not the low dose when compared to placebo, two

21 months versus one month. It is noted again that

22 the trial objectively planned to study the low dose

23 but not the medium dose. Thus the low-dose effect

24 cannot be conclusively shown and the medium-dose

25 effect observed was exploratory but was consistent

147

1 with the Pelc II trial.

2 \[Slide.\]

3 This is the third study for the European

4 trials. The PRAMA trial was a 48-week multicenter

5 double-blind randomized placebo-controlled two-arm

6 study studying acamprosate versus placebo. The

7 objective here again is to help maintain abstinence

8 after detoxification in the alcoholic patient

9 population.

10 \[Slide.\]

11 I would like to point out here that the

12 primary efficacy outcome for this study was

13 prespecified and that was time to first relapse.

14 Here, the relapse included short-term relapse,

15 long-term relapse and continuous relapse.

16 \[Slide.\]

17 In this 48-week trial comparing

18 acamprosate versus placebo, there were 136 patients

19 per group. Again, significantly higher dropout

20 rates were observed in placebo, 60 percent, versus

21 42 percent in acamprosate and had about half the

22 time on trial. It appeared that more placebo

23 patients dropped out because of patient refusal.

24 The percent of abstinence was higher in

25 acamprosate, 51 percent, versus 40 percent in

148

1 placebo when using the dropout-as-is approach. The

2 rates were significantly smaller using the

3 as-relapsed approach as this is more conservative,

4 29 percent in acamprosate and 12 percent in

5 placebo. Note that, in this study, the primary

6 efficacy endpoint prespecified was the time to

7 first relapse. Using the sensory indictor based on

8 either dropout-as-is or as-relapsed, the results,

9 based on time to first relapse clearly showed a

10 significant acamprosate effect.

11 \[Slide.\]

12 In summary, the three European trials had

13 the drinking data retrospectively collected and the

14 dropout rates were higher in placebo than in drug.

15 The effect of the medium dose was shown in percent

16 complete abstinence in Pelc II, in PRAMA,

17 confirmatory. In Paille, though, exploratory.

18 By the way, the medium dose is the

19 sponsor\'s proposed to-be-marketed dose. The effect

20 of the low-dose acamprosate was not shown in the

21 Paille trial. I would like to point out that these

22 trials were planned and conducted in the late \'80s

23 and early \'90s, about a decade ago.

24 \[Slide.\]

25 Now I would like to turn to the U.S.

149

1 trial. Subjects who were alcohol-dependent or who

2 had been withdrawn from alcohol or who had

3 completed medicated detoxification within two to

4 ten days of study entry were studied. This was a

5 multicenter, double-blind, randomized,

6 placebo-controlled study.

7 I would like to point out that the

8 randomized allocations of patients to the three

9 treatment arms were well balanced. The alcohol

10 measurements were rigorously collected according to

11 alcohol time-line follow-back schedule.

12 \[Slide.\]

13 For the U.S. trial, the primary objective

14 was to confirm the safety and efficacy of this

15 medium-dose acamprosate. The secondary objective

16 was to explore the efficacy and safety of the high

17 dose. The exploration was only planned for

18 one-third of the patients; that is, 83 patients

19 compared to 260 patients of the other two treatment

20 groups.

21 The treatment phase was 24 weeks or six

22 months and was conducted much more recently,

23 between \'97 and \'99.

24 \[Slide.\]

25 There was an apparent difference in the

150

1 percent of patients who dropped out of the study

2 early. Noticeably, the medium dose, or, say, the

3 to-be-marketed dose proposed by the sponsor,

4 appeared to have about 60 percent of patients who

5 discontinued study early but less so in the other

6 two arms, 45 percent placebo, 48 percent in the

7 high dose. The difference was primarily that the

8 medium-dose acamprosate group had more patients

9 dropped out due to patient decision, due to

10 patients lost to follow up.

11 There was also a difference in the time to

12 treatment discontinuation, about one month shorter

13 in the medium-dose acamprosate compared to the

14 other two arms.

15 \[Slide.\]

16 Here are the protocols specified by

17 primary efficacy outcomes that you are now familiar

18 with.

19 \[Slide.\]

20 Here are the results of the five primary

21 efficacy endpoints extracted from the sponsor\'s NDA

22 report and confirmed by us. For the comparison

23 between the medium-dose acamprosate and the

24 placebo\--that is, the main objective\--the percent

25 of patients who relapsed to drinking were similar,

151

1 92 percent with medium-dose acamprosate and 89

2 percent with placebo.

3 The median time to first drink was four

4 days in both groups and the median time to first

5 heavy drinking days was only a two-day difference.

6 For these three outcomes, the p-value were between

7 0.85 to 0.9 as for the cumulative abstinence

8 duration outcome, or the percent of cumulative

9 abstinence duration.

10 I would like to make a point of this

11 notation here that the sponsor used because I will

12 be referring to that later. CAD, cumulative

13 abstinence duration, in days; CCAD, percent of days

14 abstinence\--in other words, alcohol free. As you

15 can see from this table, it appeared that the

16 medium dose had borderline evidence of fewer days

17 of acamprosate, of complete abstinence based on

18 either the mean days or the median days.

19 Using the median as an example, you have

20 56 days for the medium dose compared to 78 days for

21 placebo having cumulative abstinence duration.

22 Similarly, for the percent of that, 38, much lower

23 compared to placebo. I will refer to these numbers

24 later.

25 Taken together, the total evidence based

152

1 on the five efficacy endpoints, there was no

2 evidence of medium-dose acamprosate effect on any

3 of the endpoints nominally although the high-dose

4 acamprosate appeared to perform better numerically

5 in the time to first heavy-drinking days.

6 \[Slide.\]

7 Thus, based on the prespecified primary

8 efficacy outcome, the result indicated that there

9 was no statistical evidence of this medium-dose

10 acamprosate. There were exploratory or supportive

11 analyses prespecified in the protocol. We

12 performed these analyses and could not find an

13 acamprosate medium dose effect.

14 \[Slide.\]

15 Right before the NDA, new drug

16 application, submission, the sponsor met with the

17 agency and acknowledged that the medium-dose

18 acamprosate failed to show a statistically

19 significant effect and submitted a new statistical

20 analysis plan. The highlight of this new plan

21 included the definition of the CAD was modified

22 post hoc. The algorithm of imputation on the

23 dropout patients was changed and the newly

24 considered outcome was percent abstinence duration.

25 Interestingly, the endpoint actually used

153

1 in the NDA submission was percent abstinence

2 duration but adjusted for treatment discontinuation

3 which appeared to be shorter in this medium-dose

4 acamprosate; that is, the variable, ALCCAD. This

5 endpoint was not included in the revised

6 statistical analysis plan although it was presented

7 at the pre-NDA meeting with the agency.

8 \[Slide.\]

9 What you have seen presented by the

10 sponsor is based on this Model No. 1. It contains

11 the seven covariates that Dr. Mason had explained.

12 I would like to just point you to the one

13 particular problematic variable, treatment

14 exposure. This model was discussed at the phase II

15 pre-NDA meeting but this model was not part of the

16 revised statistical analysis plan submitted at that

17 time.

18 \[Slide.\]

19 The sponsor was asked to also analyze the

20 data without that treatment exposure for Model No.

21 1, we just saw. The sponsor labeled it as Model

22 No. 2. Let\'s call it the six-covariate model.

23 Here, the treatment exposure was

24 calculated by multiplying the treatment compliance

25 and the treatment duration and then normalizing

154

1 into percent. It is worthwhile to note that the

2 treatment exposure so defined is potentially

3 treatment-related because that medium dose had a

4 higher percent of dropout rate and a shorter time

5 to discontinuation compared to the other two

6 groups.

7 In addition, such defined treatment

8 exposure variable is different from the baseline

9 variable and is not affected by the treatment

10 administration and the treatment outcome. But the

11 treatment exposure defined here would heavily

12 depend on when the treatment administration is

13 ended and whether patients comply with the

14 treatment assigned and why patients discontinue the

15 study.

16 \[Slide.\]

17 The CCAD outcome was the endpoint

18 discussed at the pre-NDA meeting. It was

19 prespecified but post defined. Of the two models

20 presented here, Model No. 1 and Model No. 2, using

21 the CCAD modified outcome, there were no

22 statistically significant findings of medium-dose

23 acamprosate.

24 Even if you don\'t do any adjustment, you

25 don\'t find anything either. Let us see how these

155

1 results can be drastically changed using the

2 post-hoc-defined primary-efficacy endpoint, ALCCAD.

3 Again, percent abstinence duration but adjusted for

4 treatment discontinuation.

5 \[Slide.\]

6 Here are the results using the

7 post-hoc-defined statistical model, the No. 1 and

8 No. 2 row, versus this model without further

9 covariate adjustment, the other four rows. Let\'s

10 look at the row labeled as mean No. 1 which was

11 based on seven covariates including the treatment

12 exposure, the problematic variable.

13 A nominal borderline statistical

14 significance was observed for the medium-dose

15 acamprosate compared to placebo, a p-value of

16 0.044. But when excluding that treatment exposure,

17 which is Model No. 2, such an acamprosate effect

18 disappeared, a p-value of 0.296. In contrast,

19 without this covariate adjustment, the unadjusted

20 mean showed a numerical trend of increased percent

21 abstinence duration from placebo to medium dose to

22 high dose, the third row here.

23 That is an adjusted mean. You can also

24 see on an adjusted median, the percent is

25 essentially the same between the medium dose and

156

1 the placebo of 59 percent.

2 I would like to bring to your attention

3 and clarify what the sponsor called an adjusted

4 mean or an adjusted median really is. As I just

5 mentioned, both the mean and the median was

6 adjusted for treatment discontinuation. In other

7 words, it rests strongly on treatment

8 discontinuation. Particularly, it was differential

9 among the three arms.

10 The truly unadjusted outcome was the CCAD,

11 the last two rows. As you can see, both the raw

12 mean and the raw median for acamprosate medium dose

13 was worse compared to placebo.

14 Let\'s put the high-dose acamprosate.

15 There was a numerically higher percent of

16 abstinence duration after adjustment for treatment

17 discontinuation. The high-dose effect appeared to

18 be shown nominally with the six covariate model and

19 was evident using the seven covariate model. These

20 better results did not hold up when we use the CCAD

21 outcome for the modeling.

22 \[Slide.\]

23 The sponsor considered four patient

24 populations to demonstrate the post hoc model. So

25 chosen, they were very consistent across the

157

1 patient population defined. As you have heard,

2 these are the four different patient populations;

3 the ITT, evaluable, multivariate ITT and

4 multivariate evaluable.

5 By showing this table, the nominal p-value

6 based on the seven covariate No. 1, all showed

7 statistical significance ranging from 0.044

8 borderline evidence to 0.008 significant evidence.

9 However, such evidence could not be supported when

10 the six covariate model No. 2 was applied to all

11 the four patient populations. None of them showed

12 statistical significance.

13 If a post hoc model is to be chosen

14 between Model No. 1 and Model No. 2, a less biased

15 analysis or a more persuasive analysis will

16 consider Model No. 2 without the treatment-exposure

17 variable. In addition, if these covariates are

18 really prognostic, including a fewer number of

19 covariates should still demonstrate some kind of

20 acamprosate medium-dose effect and should be

21 consistently reported in the literature cited by

22 the sponsor. But it did not.

23 \[Slide.\]

24 One might wonder what was the rationale

25 for the Model No. 1 chosen by the sponsor which was

158

1 not provided a priori. As previously shown, it was

2 the model with seven covariates that demonstrated

3 an acamprosate medium-dose effect but not the other

4 which excluded treatment exposure.

5 \[Slide.\]

6 This, of course, makes our job tougher.

7 We performed a few exploratory analyses. The idea

8 here was to understand how robust the results were

9 based on Model No. 1 chosen by the sponsor in the

10 NDA submission but not in the original protocol

11 analysis plan.

12 The exploration went on to include models

13 that always have the center in there or having one

14 variable at a time, or some combination of those.

15 This consisted of more than 30 models that we

16 tried. Other than the one model that the sponsor

17 identified, we found that there was no

18 statistically significant acamprosate medium-dose

19 effect from these various reasonable explorations

20 but there was one that works, which is the one that

21 included the abstinence goal and the

22 treatment-exposure variable together but not

23 individually.

24 \[Slide.\]

25 I would like to show you that, of the

159

1 seven covariates chosen by the sponsor, two of them

2 indicated potential imbalance between the three

3 treatment arms, namely treatment exposure and

4 abstinence goal.

5 As shown in this table, median exposure

6 was shorter in acamprosate medium-dose group

7 compared to the other two. This was consistent

8 with the shorter time to treatment discontinuation,

9 15 versus 20 or 21. In addition, there was a trend

10 in patient\'s baseline abstinence goal for the

11 treatments received as mentioned by the sponsor.

12 It appeared that numerically,

13 placebo-treated patients was more desirable to be

14 complete abstinence than acamprosate-treated

15 patients, 45, 40, 32. In contrast, if one

16 considered a more realistic goal of a slip is

17 possible versus others, the reverse numerical trend

18 was observed, 28, 31 to 39. It is the reverse

19 trend of the complete abstinence goal.

20 As pointed out by Dr. Winchell, when one

21 does not distinguish between complete abstinence

22 goal and the goal of allowed a slip is possible,

23 then there was essentially no imbalance among the

24 three treatment arms, as you can see, 73 percent,

25 71 percent.

160

1 \[Slide.\]

2 Here is a different way to look at the

3 data. In the following two figures, I will be

4 using green color to represent the medium dose,

5 darker blue for placebo and coral color for high

6 dose. For heavy drinking days, when the data was

7 summarized at each visit alone on the observed

8 data, as shown in this figure, it appeared that

9 acamprosate medium-dose group, the green color on

10 the top, showed a consistently larger number of

11 mean heavy-drinking days as compared to placebo.

12 Although the high dose had only one-third

13 of the patient size compared to the other two, an

14 apparent fewer number of heavy drinking days across

15 all the visits appeared to be evident and the

16 separation of the curve was consistent from Week 8

17 to Week 24, the end of the trial.

18 \[Slide.\]

19 In contrast, the distribution of any

20 drinking days at each visit was comparable among

21 the three treatment arms.

22 \[Slide.\]

23 From these various results shown, can we

24 conclude that the medium-dose acamprosate is

25 effective? First of all, the U.S. trial was

161

1 sufficiently powered to study the efficacy of this

2 dose but, clearly, there was no evidence of

3 medium-dose acamprosate when only one covariate was

4 accounted for. Even suppose that one covariate is

5 the potential outcome-related treatment exposure

6 alone. It didn\'t reach any statistical

7 significance.

8 To appropriately account for the

9 covariates, that should be unrelated to treatment

10 or outcome; that is, when that treatment-exposure

11 covariate is excluded from the model, we have shown

12 from a few example models, out of a total possible

13 128 models, the medium-dose acamprosate effect was

14 not found.

15 In addition, a numerically higher number

16 of heavy-drinking days relative to placebo at each

17 visit was observed.

18 \[Slide.\]

19 In fact, the 10 percent medium-dose effect

20 was highly dependent on post hoc selection of

21 covariates that were included in the model; for

22 example, a model including just two covariates, the

23 abstinence goal and the treatment exposure, or that

24 one model having all the seven covariates

25 coexisting in that model.

162

1 We have pointed out the problem with

2 models including the treatment-exposure covariate

3 because it could not be obtained until after

4 randomization of treatment assignment, after

5 treatment compliance and after treatment

6 discontinuation. An even more serious concern in

7 this exercise is the potential multiplicity

8 problem. In other words, could it be that the

9 sponsor performed analysis using only this

10 post-hoc-defined seven covariates or using many

11 more models to pick up this specific Model No. 1;

12 namely, what is the chance that one is going to

13 find a statistical significance after analyzing the

14 data using so many different models.

15 We all know that if one tests the same

16 parameter 100 times, five times are going to show

17 statistical significance simply based on chance

18 alone. Here, we found two out of 128.

19 \[Slide.\]

20 In this U.S. trial, the study was not

21 sufficiently powered to study this high-dose

22 effect. Rather, this dose was included to explore

23 the efficacy and safety. In a previous slide

24 showing mean heavy-drinking days, you have noticed

25 a numerically superior effect of acamprosate high

163

1 dose relative to placebo was seen at the later

2 visit of the treatment period and was consistent

3 throughout the end of the trial.

4 In addition, this high-dose effect

5 appeared to be seen if the adjustments always

6 included the abstinence goal but not otherwise. If

7 a model was performed using ALCCAD but not the

8 CCAD, we could not tell whether such finding was

9 real or by chance alone since the sample size was

10 only one-third of those powered for studying an

11 acamprosate effect.

12 \[Slide.\]

13 Here I would like to summarize the U.S.

14 experience. The medium-dose acamprosate appeared

15 to have worse dropout characteristics. The effect

16 of this medium dose was not shown based on the

17 protocol-specified primary efficacy outcome

18 although post-hoc-defined primary efficacy endpoint

19 of CCAD.

20 For the acamprosate medium dose, the

21 sponsor\'s post hoc chosen Model No. 1 or, for that

22 matter, Model No. 2, can be problematic as

23 statistical significance must rely on which

24 particular post hoc baseline defined covariates

25 and/or post randomization defined variables were

164

1 included in the model. The finding was very

2 fragile because the carefully chosen model showing

3 statistical significance could not hold its

4 significance after multiplicity adjustments.

5 \[Slide.\]

6 As for the high-dose acamprosate, the

7 exploratory analysis is suggested in the effect in

8 the time to first heavy drinking days and in the

9 mean heavy drinking days at each study visit over

10 the treatment period. Such heavy drinking days do

11 not adjust for treatment discontinuation like

12 ALCCAD.

13 It is emphasized, however, that the

14 finding in the high-dose acamprosate is simply

15 hypothesis generation as it didn\'t have sufficient

16 sample size for the study and had lack of safety

17 information for the dose level. The small sample

18 size prevented us from better understanding this

19 high-dose acamprosate treatment effect.

20 \[Slide.\]

21 So what is the difference between the

22 European and U.S. trials in terms of efficacy

23 outcomes? Why are we getting conflicting evidence

24 given randomizations were properly done. From the

25 statistical perspective, the biggest problem, in my

165

1 view, is the issue of differential dropout from the

2 study in terms of the time to discontinuation, in

3 terms of percent of dropouts and also in terms of

4 the distribution of reasons of dropouts.

5 We immediately face the problem of

6 differential dropouts in the opposite direction.

7 In other words, what have we found on the proposed

8 to-be-marketed acamprosate 2-grams-per-day effect?

9 We saw in the European trials, patient treatment

10 with acamprosate tended to stay in the trial longer

11 and less dropouts, but it was reversed in the U.S.

12 trial.

13 The sponsor had defined how they would

14 handle the missing data or data needed for the

15 dropout patients a priori but realized that it

16 didn\'t work and modified the definition after the

17 data had been collected when meeting with the

18 agency at the pre-NDA meeting and then modified

19 this outcome again as ALCCAD further by adjusting

20 for patient discontinuation.

21 Further data dredging was to include

22 treatment compliance and treatment duration to

23 create a variable called treatment exposure. That

24 can only be collected after the treatment

25 randomization. We believe that it is important and

166

1 there is a need to have a well-thought prespecified

2 algorithm for handling dropout patterns rather than

3 post hoc defined and redefined.

4 This concludes my review experience.

5 Thank you.

6 Questions from the Committee

7 DR. OREN: It is now time for the

8 committee to ask questions of the FDA regarding the

9 previous two presentations. Does anybody wish to

10 begin?

11 Dr. Rudorfer?

12 DR. RUDORFER: A question for Dr.

13 Winchell. We heard that about 10 percent of the

14 U.S. patient sample had undergone medical detox

15 before enrollment. Did you look at that subgroup

16 specifically?

17 DR. WINCHELL: I didn\'t because there were

18 so few of them. But I think that that was one of

19 Lipha\'s prespecified analyses so they may be able

20 to address that.

21 DR. GOODMAN: The statisticians can

22 correct me if I\'m wrong, but I don\'t believe that

23 we had a prespecified plan for looking at the detox

24 patients. What we plan to do, patients were

25 stratified according to whether or not they had

167

1 undergone detox before they were randomized. But,

2 again, this was a surprising finding to us. We

3 expected that at least a third of the patients, if

4 not more, would undergo detox but, in fact, it was

5 only, as you saw, about 10 percent of patients.

6 DR. OREN: Dr. Hughes.

7 DR. HUGHES: Does anybody know, of all the

8 patients who come in for alcohol treatment, how

9 many of them are already abstinent at the time they

10 come in? Is there any kind of health-resources

11 database on that? Celia, do you know of any or do

12 the Lipha people know? Is that 90 percent of the

13 patients or 20 percent?

14 DR. WINCHELL: The best data I have ever

15 seen on that question was from Dr. Mason who

16 presented some very interesting data, I think from

17 this study, showing that people are really bad off

18 until they make the call to enter treatment and

19 then, between making the call and actually entering

20 treatment, they seem to do a little better.

21 But I think we have got lots of experts

22 here from NIAAA and Dr. Mason who may know

23 something about that.

24 DR. OREN: Dr. O\'Brien?

25 DR. O\'BRIEN: I think Dr. Winchell alluded

168

1 to the fact about the current American healthcare

2 system. In fact, it has really changed. We began

3 studying discontinuation in the 1970s and, at that

4 time, there were a lot of inpatient alcohol

5 detoxification programs and we actually did random

6 assignment between inpatient and outpatient in a

7 randomized clinical trial.

8 Nowadays, it is very difficult for us to

9 study this because it is so expensive. We have to

10 get an NIH grant to pay for the inpatient days

11 because there aren\'t any available through any

12 other system. So I think that things have really

13 changed and the modal method now is for alcoholics,

14 in the United States, at least, to come to us with

15 blood-alcohol levels fairly significant, sometimes

16 incredibly high because they are so tolerant and

17 they just walk in or drive up despite huge alcohol

18 levels.

19 Then we have to figure out how to get them

20 detoxed. Depending on what the protocol is, we may

21 have to find an inpatient program which is, as I

22 said, difficult or we do an outpatient detox.

23 DR. OREN: Any further questions from the

24 committee to the FDA? Dr. Schatzberg?

25 DR. SCHATZBERG: I have a question for Dr.

169

1 Winchell and Dr. Wang. It seems that, on your

2 reanalysis, that the European data are pretty

3 convincing in terms of what you would agree would

4 be a reasonable criterion for efficacy, I gather

5 from what you concluded.

6 But just as something for the committee or

7 for my edification, these studies were done a long

8 time ago, obviously. How do you feel about, in a

9 way, changing what is the specified outcome

10 criterion in a post hoc analysis in that way. In a

11 sense, are we doing something contradictory? We

12 are sort of, on the one hand, saying, in the U.S.,

13 we are going to throw out the EFF data because it

14 is post hoc, and whatever.

15 There are issues, there, granted. Yet we

16 are still sort of doing that except it is our own,

17 or the FDA\'s, reanalysis. What kind of criteria

18 would you use or would you recommend for what

19 should constitute a reanalysis and is part of it

20 just that these are so old in terms of the studies?

21 DR. WINCHELL: I will start and then I

22 will let Dr. Wang respond. First of all, the

23 difference between an efficacy evaluable post hoc

24 analysis and some of the other types of subset

25 analyses we did, as I mentioned, it has to do with

170

1 whether the subsets can be defined by

2 prerandomization variables.

3 The real problem with post hoc analysis,

4 the reason people tend to dismiss it, it that there

5 is the risk of multiplicity, the risk that, simply

6 by chance, if you do enough of them, you will get

7 one coming out statistically significant, as you

8 know.

9 Nevertheless, we do these types of

10 analyses to see whether there is differential

11 effect in women and men, differential effect by age

12 or by race. Usually, the studies are not powered

13 to generate a statistically significant difference

14 in any type of subset. They are powered just big

15 enough to demonstrate and effect in the ITT

16 population.

17 So we don\'t expect these analyses to come

18 out with a statistically significant result. We

19 expect them to give us some trends or some

20 understanding or just to shed some light on who in

21 the population is particularly prone to benefit of

22 not to benefit.

23 We do these routinely. Rarely one might

24 take as the body of evidence supporting an

25 application some type of post hoc reanalysis of

171

1 data as supportive. If you had one or two very

2 strong studies, you might look retrospectively at

3 existing datasets in a way that was not anticipated

4 at the time the data was collected and say that

5 this analysis generates supportive, confirmatory

6 evidence that helps to complement the other results

7 and complete the body of evidence necessary for

8 regulatory decision making.

9 So it is not uncommon to look

10 retrospectively at older sets of data. Usually, we

11 get a little uncomfortable if that is the only

12 basis on which the efficacy can be concluded. I

13 think of this, and I know Dr. Wang maybe thinks of

14 this differently because she is a statistician and

15 I am a medical officer, but I think, in some ways,

16 of approaching this European data the way one might

17 approach a literature-based application where there

18 is this large body of data. I have got the actual

19 data. I can look at it various ways.

20 I think what we hoped to get when we first

21 met with Lipha was what I described, that we would

22 have one American trial that was successful but

23 that could not stand alone\--it was not

24 replicated\--and that we would accept as

25 confirmatory evidence analysis of older European

172

1 data notwithstanding the fact that it was a

2 different dose and a different dosage regimen and

3 that those pieces together would form the basis of

4 our decision.

5 Ultimately, we were faced with going

6 forward without that successful American study and

7 we still tried to make what we could out of the

8 European data.

9 I don\'t know if that addresses your

10 question. I will also ask Dr. Wang to talk about

11 how she sees it statistically and I see that my

12 boss wants to tell you what she thinks of it. So I

13 will let her go first.

14 DR. McCORMICK: Thank you. I guess,

15 really, the crux of your question is how is it that

16 we can go into the U.S. dataset and do these post

17 hoc analyses ourselves and not accept what the

18 sponsor has given us in terms of their post hoc

19 analyses, and yet we are taking the European

20 dataset and saying we are all going to do a post

21 hoc analysis here, and that is going to be the

22 basis of our regulatory decision.

23 Yes, that does give us some discomfort.

24 Let me first say that, as far as the U.S. post hoc

25 analyses are concerned, I think both on the part of

173

1 the sponsor and ourselves, is that these are purely

2 hypothesis-generating. We are looking to try to

3 understand this information, not to draw any

4 conclusions about it, because we feel quite

5 comfortable that we cannot use the United States

6 study in making a regulatory decision.

7 That leaves us with the bulk of the data

8 from Europe, or all of the data from Europe, to

9 make our decision about. Yes; it does give us some

10 discomfort in seeing trials in cases where we

11 haven\'t had prespecified primary-outcome measures

12 and we have to reconstruct them based upon what the

13 trial objectives were.

14 Yet, when we take the most conservative

15 approach, even more conservative than what was

16 probably originally intended, looking at complete

17 abstinence, it is consistent across all the

18 studies.

19 This, truly, is something that we would

20 like to bring to the table, though. But I think

21 even beyond having done that and taking the more

22 conservative approach, looking at complete

23 abstinence as an outcome, our even greater level of

24 discomfort and, really, the reason for having this

25 meeting is not so much have we chosen a post hoc

174

1 analysis to do on this dataset but what is the

2 credibility of the dataset, itself.

3 Can we rely upon, for example, a one-year

4 study in which there have been only six visits,

5 where the data is largely imputed? Can we believe

6 that and can we base our regulatory decision on

7 these studies? That is the crux of the matter.

8 DR. WANG: I am going to talk about from

9 the statistical perspective. In terms of the

10 timing of the European trials versus the U.S.

11 trial, yes, we are going to say these are all post

12 hoc analyses. What you see from the European

13 studies, you have all the consistencies across all

14 the outcomes that you looked at.

15 When there is a problem of differential

16 dropout between the acamprosate and the placebo, it

17 is in the direction, you believe the drug works.

18 However, in the U.S. trial, the troubling thing is

19 the post hoc nature of it.

20 First of all, if the drug works, if the

21 prespecified analysis works, we don\'t need to talk

22 about the post hoc. So, going to post hoc, you

23 already failed the first step. In that post hoc

24 situation, yes, we accept some kind of post hoc

25 evaluation. But, you start with one covariate

175

1 adjustment. It was believed by the sponsor that

2 the abstinence goal was a very prognostic one. If

3 you have a model, just include treatment center and

4 that covariate of complete abstinence goal, you

5 don\'t find the statistical evidence.

6 If you then say, all right, let me look at

7 treatment center and the slip is okay, because that

8 is also differential in the opposite direction,

9 still you did not see the statistical evidence.

10 Even if you adjust for just one covariate,

11 treatment exposure, it is not there either.

12 So this post hoc nature was trying to

13 explain what is going on. You would expect that if

14 the effect is really there, then, using a fewer

15 number of covariates should still give you some

16 kind of treatment-effect size. But it wasn\'t in

17 this case.

18 So the post hoc nature, in this particular

19 situation, is very troubling.

20 DR. OREN: Dr. Schatzberg?

21 DR. SCHATZBERG: I appreciate the answer.

22 It was really more kind of a structural\--as Dr.

23 McCormick raised. But let me ask one other

24 structural one, if I might, because of something

25 that Robert raised before, and that is, while this

176

1 is somewhat of a different division, I guess, of

2 the FDA from the psychopharm group, is there

3 concern in the agency that recommending approval

4 based on the European portfolio and without U.S.

5 data would not jive or go with other efforts on the

6 part of this committee.

7 I am not a member of the committee so I

8 just raise that as a precedent, or is that just

9 because they are different illnesses and different

10 agencies and different criteria?

11 DR. McCORMICK: To answer your question,

12 there really are no concerns on the part of the

13 agency about making a regulatory decision based on

14 purely European data. As long as they are rigorous

15 and credible and the studies have been done using

16 good clinical practices and they are in sites where

17 we can do inspections.

18 In this case, there are. There have been

19 precedents where European data has been relied

20 upon. That is not an issue.

21 DR. OREN: Dr. Leon?

22 DR. LEON: Are there standards that the

23 agency uses for maximum dropout rate in clinical

24 trials? I mean, these dropout rates typically were

25 never less than 35 percent but, typically, 50 or 60

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1 percent dropout.

2 DR. WINCHELL: These are not unusual

3 dropout rates for addiction-treatment trials. If

4 we had standards for unacceptable dropout rates, I

5 don\'t think we would be able to do

6 addiction-treatment trials that lasted more than

7 two weeks.

8 DR. OREN: Dr. Winchell, I wonder if you

9 could just say a little more, just specifically

10 focussing on the European studies and not focussing

11 right now on the broader question of approval but

12 just specifically on the efficacy of acamprosate in

13 the European studies? How would you summarize your

14 analysis?

15 DR. WINCHELL: Well, let me say that,

16 based on the data that I had available to analyze,

17 the very short three-month Pelc study certainly

18 showed an effect of acamprosate on complete

19 abstinence. The Paille study was more marginal on

20 that and the PRAMA study showed and effect if you

21 imputed failure to all the dropouts and not

22 necessarily if you didn\'t.

23 So, on complete abstinence, it looks

24 promising but it is not a blockbuster. In my own

25 made-up, what else can I do besides cumulative

178

1 abstinence duration analysis, there is a difference

2 between the dose proposed for marketing and placebo

3 in favor of acamprosate in all the studies. As I

4 mentioned, that is again driven primarily by the

5 completely abstinent subjects who, in this

6 analysis, have failure imputed after dropout.

7 So I can certainly get a good result.

8 But, obviously, I have some reservations about how

9 much I should believe my own analysis. I don\'t

10 mean to sound disrespectful about these studies.

11 All I know is that the American study reported 100

12 volumes and some of the European study reports are

13 one volume.

14 So I just have so much more detail

15 available for my scrutiny for the American study.

16 That is what we are accustomed to, actually, is

17 something on the order of the 100 volumes per

18 study. I should say that the case-report forms

19 were submitted electronically as were the

20 case-report tabulations so those weren\'t even

21 included in there.

22 That is the type of thing we are

23 accustomed to having available for our examination

24 and we didn\'t have that for the European data. So

25 that is why we are here.

179

1 DR. OREN: Dr. Cook

2 DR. COOK: I think you have covered this,

3 but just to clarify for me. If you took the

4 predefined outcome variable and the predefined

5 analysis by the sponsor, number one, were those

6 defined? Is there any doubt about whether they

7 were defined? In other words, do you have a

8 document that clearly specifies it. And, for those

9 three trials, what happened with those primary

10 hypotheses and their primary analyses?

11 DR. WANG: Are you specifically talking

12 about just the European studies?

13 DR. COOK: Yes; just the European studies.

14 DR. WANG: As Dr. Winchell mentioned, the

15 European-study information given to us was limited.

16 So that is why, in my presentation, I only based it

17 on percent complete abstinence and not others. So

18 I cannot make too much out of what I have\--I mean,

19 in addition to what I have

20 DR. COOK: Okay. But, by limited, do you

21 mean that, in each trial, you couldn\'t see in their

22 documents that they had written a document before

23 the study started about what the predefined

24 analysis would be and what the predefined outcomes

25 were and did you have the data to see whether those

180

1 trials were positive given that standard.

2 DR. WANG: I think, from our internal

3 discussion while we were doing this priority

4 review, we had a discussion as to how much can we

5 believe in the European data in terms of the number

6 of days that the patients were abstinent.

7 As Dr. Winchell presented, there were\--if

8 you are talking about Pelc II, it is biweekly

9 visits. But, for others, is a one to three months

10 kind of difference. So if you are doing

11 imputation, there is big chunk of time that you can

12 impute by days. Therefore, it was believed that

13 the quality of the data with those were

14 questionable and that was the reason of the focus.

15 DR. WINCHELL: I have something else I can

16 say to address your question. At least one of the

17 studies\--I am thinking it is Pelc II\--it said that

18 the primary outcome variable, the main criterion of

19 judgment, would be abstinence. But what it didn\'t

20 have in the protocol was any operationalization of

21 how that would be evaluated.

22 As you have seen, if your main criterion

23 of judgment is abstinence, you could look at time

24 to first drink, time to first heavy drink, time to

25 relapse, cumulative abstinence duration or any

181

1 number of other measures of abstinence. So then,

2 appended to the protocol, we then had a statistical

3 report. In the statistical report, it was set

4 forth what analyses were done. At least one of

5 them was a blinded analysis. I can say that much.

6 So one could assume that the statistician

7 decided what to do first. It is unclear. But it

8 is not like what we are accustomed to seeing in an

9 American NDA in 2002.

10 DR. WANG: I would like to add to that is

11 the difficulty in analyzing the Paille study. In

12 fact, the patient\'s dropout reasons were

13 reclassified even though those data were used to

14 have a European approval. By using the new defined

15 reasons of dropout and looking at the three

16 treatment-arm comparisons, you can get a different

17 result.

18 DR. OREN: Dr. Mehta?

19 DR. MEHTA: One way to look at it would be

20 that there are very few areas of medicine where you

21 do fourteen placebo-controlled studies and you turn

22 out to be a winner fourteen times. What the

23 sponsor has done is, in European, twelve or

24 thirteen times, rolled the dice against placebo and

25 it came out as a winner.

182

1 By the law of averages, I would have

2 expected the next trial will be negative and what

3 they did is essentially ably demonstrated the law

4 of averages works.

5 DR. OREN: Dr. McCormick?

6 DR. McCORMICK: I would just like to point

7 out that we were only given full study reports of

8 three of the European studies. We know that they

9 haven\'t all succeeded and I don\'t believe that they

10 all had complete abstinence as an outcome.

11 DR. OREN: I think we will take Dr.

12 Rudorfer with the last question and then we will

13 take our lunch break.

14 DR. RUDORFER: I am sorry to have to

15 compete with lunch. Just a couple of questions.

16 We have all been talking about the fact that

17 European studies are a decade old. I am wondering

18 if we have learned anything in the interim. For

19 instance, are the postmarketing data available that

20 might be informative just in terms of do people

21 actually refill their prescriptions over a year\'s

22 duration, issues like that?

23 DR. WINCHELL: Obviously, Lipha has much

24 more information than we do, but I just know

25 recently looking at some of their materials, that

183

1 it said market research shows that typical duration

2 of use was, like, three to six months. So it

3 doesn\'t sound like people are typically using it

4 for a year or more. But, certainly, I will let\--I

5 see heads shaking but I did read that in the NDA

6 yesterday.

7 DR. CHABAC: I just want to remind you

8 that alcohol-dependent patients are very badly

9 compliant patients. To keep them treated for six

10 months with the treatment, I think it is a very

11 good sign that this drug could be beneficial to

12 them.

13 I told you that we have 1.5 million

14 patient years experience with the product. That

15 means that there are a lot of patients treated with

16 acamprosate. We have the experience with the NEED

17 Program where we treated nearly 2000 patients in

18 Europe. Dr. Mann can tell me if I am wrong, but I

19 think there is a benefit using that drug. It is

20 not a magic product but I just want to remind you

21 that the two drugs available on the market to treat

22 these kinds of patients have neither a very huge

23 rate of efficacy and that if we can bring something

24 safe to treat, to help, those patients, this is

25 something.

184

1 DR. MANN: I think to understand these

2 figures, the recommendation in Germany, at least,

3 is to give it for six months. All the doctors know

4 it would be given for six months and not for a year

5 or more which is now something that is recommended.

6 So if you have figures that show that it

7 is taken five or six months, this shows compliance

8 of the doctors, if you want.

9 DR. OREN: Dr. McCormick?

10 DR. McCORMICK: Just a word of caution

11 that I would like to insert and that is while it

12 may be important to understand how a drug plays out

13 in the postmarketing period, we would not accept a

14 postmarketing uncontrolled experience as evidence

15 of a product\'s efficacy as part of our making of a

16 regulatory decision.

17 DR. OREN: Before we break for lunch, I am

18 reminded to remind each member of the committee

19 that, because this is a public hearing, over the

20 one-hour lunch break, we are not supposed to talk

21 about any of this particular material because it is

22 out of the public forum. There will be plenty of

23 time later this afternoon to continue and we will

24 be back in one hour.

25 Thank you.

185

1 \[Whereupon, at 12:15 p.m., the proceedings

2 were recessed to be resumed at 1:15 p.m.\]

186

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

2 \[1:30 p.m.\]

3 Open Public Hearing

4 DR. OREN: We are now ready to begin the

5 Open Public Hearing on today\'s agenda. The first

6 speaker is Dr. Victor Hesselbrock, Vice President

7 of the Research Society on Alcohol.

8 Dr. Hesselbrock?

9 DR. HESSELBROCK: Good afternoon. I am

10 Victor Hesselbrock, Vice President of the Research

11 Society of Alcoholism. I am also a Professor in

12 the Department of Psychiatry, University of

13 Connecticut School of Medicine and I am Director of

14 the Alcohol Research Center at the University of

15 Connecticut.

16 At this time, I have no financial interest

17 in Lipha Pharmaceuticals or any pharmaceutical

18 company but, as Director of the Alcohol Center, I

19 will indicate to you that two individuals, Dr.

20 Stephanie O\'Malley and Dr. Henry Kransler, have

21 conducted studies of both naltrexone and

22 acamprosate and have received some remuneration

23 from the pharmaceutical companies. But they are

24 indirectly related to me. I am the Executive

25 Director and I am not associated with those

187

1 studies.

2 The Research Society on Alcoholism

3 appreciates the opportunity to present its views

4 about the importance of finding effective

5 pharmacological treatments for individuals

6 suffering from the psychological, social and

7 biomedical consequences of abusive drinking.

8 The RSA is a professional scientific

9 society of over 1400 members who are committed to

10 understanding and intervening in the negative

11 consequences of alcohol abuse through basic

12 research, clinical protocols, psychosocial research

13 and epidemiological studies. About one-third of

14 RSA members are also clinicians actively involved

15 in the treatment of individuals with

16 alcohol-related problems.

17 As we heard this morning, the cost of

18 alcohol abuse and dependence on American society

19 and individual lives is staggering. The cost to

20 the nation is estimated at approximately \$185

21 billing annually. Not only are the fiscal costs

22 real and powerful, but alcohol misuse is costly in

23 many ways.

24 Estimates of alcohol-use disorders ranging

25 from abuse through dependence from the National

188

1 Longitudinal Alcohol Epidemiological Survey

2 indicates that about 7.5 percent or 14 million

3 Americans are affected. Further, a Robert Wood

4 Johnson Foundation report indicates that more than

5 700,000 people receive alcoholism treatment on any

6 given day. Approximately only 15 percent receive

7 inpatient treatment and these patients often have

8 the most severe form of alcohol problems.

9 The remaining patients receive outpatient

10 treatment from a variety of different treatment

11 providers including psychiatrists, primary-care

12 providers, psychologists, social workers and

13 self-help groups such as Alcoholics Anonymous.

14 Based on Project MATCH data, approximately 40 to 50

15 percent of those in outpatient treatment are able

16 to abstain in the first week of therapy but many

17 relapse shortly thereafter.

18 Although the combination of behavioral

19 therapies and currently available medications such

20 as disulfiram and naltrexone help 40 to 70 percent

21 of persons with alcoholism either reduce their

22 alcohol consumption or maintain abstinence up to

23 six months following treatment.

24 The relapse within one year of treatment

25 still ranges from 30 to 50 percent. The primary

189

1 reason for relapse to abusive drinking is

2 noncompliance with both the pharmacologic as well

3 as the behavioral treatment.

4 Importantly, and I think this is something

5 that has not been mentioned this morning to date is

6 a significant number of adolescents and young

7 adults are frequent consumers of large amounts of

8 beverage ethanol with disastrous consequences.

9 These are individuals that also would benefit from

10 new therapies.

11 A recently released report on college

12 drinking sponsored by the National Institute of

13 Alcohol Abuse and Alcoholism reveals that 1400

14 college students between the ages of 18 to 24 die

15 each year from unintended alcohol-related injuries.

16 An additional half a million students per year

17 between the ages of 18 to 24 are unintentionally

18 injured under the influence of alcohol. The

19 majority of these individual have not developed

20 physical dependence as discussed in some of the

21 studies this morning and typically do not seek

22 treatment. But, still, these are individuals that

23 would benefit from new therapies.

24 Alcohol abuse and alcohol dependence are

25 cites as major causes of medical morbidity, mental

190

1 retardation, accidental death and injury, homicide,

2 suicide, lost productivity and disruption of

3 family. Further, frequent and prolonged heavy

4 drinking contributes to illness in each of the top

5 three causes of death, heart disease, cancer and

6 stroke.

7 Chronic alcohol abuse is linked to nearly

8 half of all cirrhosis deaths, the tenth-leading

9 cause of death in the U.S. For some special

10 populations of American society such as Native

11 Americans and African Americans, the costs

12 associated with alcohol misuse are

13 disproportionately higher and may be directly

14 linked to some of the major health problems in this

15 group such as hypertension and diabetes.

16 The Indian Health Service estimates that

17 age-adjusted alcoholism mortality for American

18 Indians is 63 percent higher than the rate for all

19 other ethnic groups in the U.S. Overall, alcohol

20 mortality rates are particularly higher among

21 African-American men even though alcohol use tends

22 to be moderate for African Americans compared to

23 Caucasians and Hispanics.

24 Given the range and diversity of the

25 severity of alcohol problems across the general

191

1 population of the U.S., the number of available

2 medical treatments is extremely limited. As we

3 heard this morning, there were only two types of

4 medications and, in fact, only two medications that

5 are FDA approved, and that includes disulfiram

6 which is an aversive agent available since the

7 early 1950s and, more recently, naltrexone which is

8 the first medication approved by the FDA for

9 alcoholism treatment in nearly 50 years.

10 Compliance with both these medications is a problem

11 but, when combined with behavioral therapy, both

12 have been shown to be useful in reducing drinking

13 in selected but not all patient groups.

14 However, medication is not without its

15 limits in relation to safety of use. Neither

16 disulfiram nor naltrexone, for example, are

17 recommended for individuals with significant liver

18 injury or liver disease such as cirrhosis or

19 hepatitis C. Given that alcohol is a known

20 hepatotoxic agent, many individuals who desperately

21 need to quit drinking in order to improve their

22 health are not candidates for these medications.

23 Alternative treatments that are not

24 hepatotoxic and that can be safely used by

25 medically compromised patients are critically

192

1 needed. A larger number of medical treatments are

2 required given that no one pharmacological

3 treatment is strongly effective and probably helps

4 only a subgroup of patients.

5 Currently, members of the RSA and other

6 scientists are conducting both basic and clinical

7 trials on a number of promising compounds to

8 identify effective pharmaceutical agents to treat

9 individuals with alcohol dependence or those who

10 chronically abuse alcohol. The RSA asks that you

11 give careful consideration to the current proposal

12 for approval of acamprosate as the currently

13 available clinical armamentarium is quite sparse

14 and is really insufficient to address the very

15 needs of the treatment providers across the

16 spectrum of alcohol-related problems that they are

17 asked to treat.

18 Thank you for the opportunity to present

19 our views.

20 DR. OREN: Thank you.

21 Has Dr. Johnathan Chick arrived? No?

22 Then we will go on. The next Open Public Hearing

23 presenter is Dr. Steven Mirin, Medical Director of

24 the American Psychiatric Association.

25 DR. MIRIN: Thank you, Mr. Chairman,

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1 members of the advisory committee. I am Steve

2 Mirin, Medical Director of the American Psychiatric

3 Association, a medical specialty society

4 representing more than 38,000 psychiatric

5 physicians nationwide.

6 I commend the FDA and this committee for

7 undertaking a review of the efficacy of acamprosate

8 for the treatment of alcohol dependence. I have no

9 association with any pharmaceutical company that

10 develops or distributes this drug.

11 I come before you not as an expert on the

12 pharmacology of acamprosate but as the

13 representative of 38,000 care-givers concerned

14 about the public-health need for more effective

15 treatment for alcoholism. Alcohol, as you know,

16 remains the commonly abused drug by youth and

17 adults alike in this country. About 14 million

18 Americans meet medical criteria for the diagnosis

19 of alcohol abuse or dependence and 40 percent of

20 Americans have direct family experience with the

21 illness.

22 The financial burden of alcohol abuse and

23 dependence is estimated at \$185 billion a year, 52

24 percent greater than the estimated cost of all

25 illegal drug use and 21 percent greater than the

194

1 estimated cost of smoking-related problems. More

2 than 70 percent of this amount is attributable to

3 lost productivity and lost earnings, but the

4 medical costs are also staggering. Up to 40

5 percent of patients in urban hospital beds are

6 there for the treatment of conditions caused by or

7 exacerbated by alcohol including diseases of the

8 brain and liver, certain forms of cancer, accidents

9 and violence.

10 These data underscore the need for more

11 effective clinical interventions in people

12 suffering from alcoholism. In this context,

13 approval of the use of acamprosate, a drug shown in

14 numerous international studies to be effective in

15 the maintenance of abstinence and relapse

16 prevention in patients with a history of alcohol

17 dependence would be, in our view, in the interests

18 of this large patient population and an important

19 new tool for the practitioners I represent and for

20 other healthcare providers across the country

21 As you know, acamprosate is currently

22 approved for use in 39 countries and about 1.5

23 million persons with alcohol dependence have been

24 treated worldwide. The drug appears to be well

25 tolerated with no serious adverse side effects and

195

1 no evidence of abuse potential or rebound effects

2 when discontinued. It can be used safely in

3 patients with liver disease and it does not impair

4 performance on motor tasks like driving. It has a

5 very high margin of safety.

6 Multiple controlled clinical trials have

7 demonstrated the efficacy of acamprosate in

8 reducing craving for alcohol and helping maintain

9 abstinence in previously dependent patients. This

10 is not a trivial finding. It can reduce the time

11 to first drink. There is a higher rate of complete

12 abstinence, a greater percentage of abstinent days

13 while on medication and these effects are sustained

14 over post-treatment follow-up periods for as long

15 as one year in some studies.

16 There are fewer hospitalizations for

17 detoxification and diminished need for

18 rehabilitation in institutional settings and a

19 diminished rate of relapse to heavy drinking or

20 even sporadic drinking. As one of the

21 investigators in the early studies of naltrexone, I

22 can well appreciate the need to avoid slips in

23 alcoholics. Slips are not trivial events. They

24 are the forerunner of relapse.

25 Not surprisingly, a study conducted in 600

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1 outpatients with alcohol dependence in this country

2 indicated that patients who were not motivated to

3 be abstinent are not as likely to benefit from

4 acamprosate whereas those who were significantly

5 more likely to meet their treatment goals when

6 compared to folks given placebo. This suggests

7 that, as in other addictive disorders,

8 psychotherapy is just one aspect of a successful

9 treatment program.

10 In summary, we believe that on the basis

11 of the findings to date, acamprosate has

12 demonstrated efficacy in the treatment of alcohol

13 dependence and has provided a cost-effective

14 treatment for these patients. Given the high

15 prevalence of alcoholism in this out and the

16 medical, economic and emotional costs of these

17 disorders, approval of acamprosate can have

18 important benefits for millions of our citizens and

19 for our society as a whole.

20 Thank you for the opportunity of

21 presenting this testimony.

22 DR. OREN: Thank you, Dr. Mirin.

23 Our next public speaker is Dr. Edward

24 Eder, Medical Director of the Comprehensive

25 Addiction Treatment Program, Fairfax, Virginia.

197

1 DR. EDER: Good afternoon, Mr. Chairman

2 and panel members of the advisory committee. I

3 appreciate the opportunity to speak on this

4 subject.

5 My name is Edward Eder. I am an internist

6 with twenty years practice predominantly in the

7 field of addiction medicine. I am a consultant to

8 Fairfax County\'s Alcohol and Drug Services, a

9 member of the American Society of Addiction

10 Medicine and Medical Director of the Comprehensive

11 Addiction Treatment Services.

12 As an internist and Medical Director of

13 the Comprehensive Addiction Treatment Services

14 affiliated with INOVA Fairfax Hospital, I have been

15 aware of the high risk of relapse in patients with

16 alcohol dependence despite involvement in

17 well-designed outpatient treatment or in sober

18 structured environments. With the advent of

19 greater understanding of the neurochemistry of the

20 addicted brain, I share the hope that

21 pharmacological agents would become available to

22 assist patients in maintaining abstinence.

23 Our current list of medications to reduce

24 relapse is very limited and acamprosate would be an

25 important addition to therapeutic options. There

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1 are three specific categories of patients who would

2 most benefit from acamprosate in terms of our

3 clinical practice. One, patients on opioids who

4 are not candidates for naltrexone and would benefit

5 from an agent that would assist alcohol abstinence.

6 In methadone-maintenance programs, up to 50 percent

7 of patients have alcohol-dependence or alcohol-use

8 disorders for, instance.

9 Also, patients with hepatotoxicity

10 excluding Child Class C category who may not

11 qualify for disulfiram or naltrexone as well as

12 patients who might benefit from the neuroprotective

13 effect of acamprosate such as individuals with

14 alcohol-withdrawal seizures.

15 The addition of acamprosate to the

16 available medicines for treatment of alcohol

17 dependence would allow for future combinations that

18 may afford greater efficacy. Given the novel

19 pathways which acamprosate appears to act upon, the

20 potential for additive or, perhaps, synergistic

21 effects is promising.

22 I believe that there is a strong clinical

23 justification for a medication such as acamprosate

24 and believe multicenter trials in Europe appear to

25 confirm both efficacy and safety. I urge the panel

199

1 to consider the approval of the medication for the

2 treatment of addiction.

3 Thank you very much.

4 DR. OREN: Thank you, Dr. Eder.

5 Since this is an Open Public Hearing, I

6 wanted to ask if there is any member of the general

7 public here who wishes to make a statement in

8 regard to the topic at hand.

9 Please. Do you want to introduce

10 yourself?

11 DR. PUBLICKER: My name is Mark Publicker.

12 I was actually on the comment list. I am the Chief

13 of Addiction Medicine for Kaiser Permanente in the

14 MidAtlantic Region. I am also President of the

15 Virginia Society of Addiction Medicine.

16 I am speaking on behalf of the Chiefs of

17 Addiction of Addiction Medicine for Kaiser

18 Permanente nationally. We provide care to over 10

19 million Kaiser Permanente members coast-to-coast.

20 I am also speaking on behalf of Virginia\'s

21 addiction-medicine specialists. I am also speaking

22 on behalf of my alcoholic patients many of whom are

23 desperate for an effective medical treatment for

24 this disabling behavioral disorder.

25 Following the lead of earlier speakers, I

200

1 should hasten to add I have no financial interest

2 in Lipha and, quite frankly, I don\'t have any

3 investments that will help me pay for my daughter\'s

4 college education next year. So I am clean.

5 Since its FDA-approved indication for the

6 treatment of alcoholism, I and my local partners

7 have prescribed naltrexone to thousands of

8 alcoholic patients. I am proud to say I appear to

9 hold the record. We have found it to be very

10 effective in combination with behavioral therapies

11 and decreasing craving and relapse allowing our

12 patients to focus their energies on psychosocial

13 treatments rather than on white-knuckling their

14 recovery.

15 We have found that patients are grateful

16 for such psychotherapy much in the same way that

17 chronic heartburn sufferers are grateful the first

18 time they are prescribed proton-pump inhibitors. I

19 have received many phone calls of the same quality.

20 I would like to also add that I have a number of

21 patients who schedule follow-up visits with me

22 every six months for the last few years checking on

23 the status of acamprosate because they are getting

24 incomplete relief when they are on their

25 naltrexone.

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1 Nonetheless, many patients cannot take

2 naltrexone. Some develop intolerable

3 gastrointestinal side effects that prevent its use.

4 Methadone-maintained patients and chronic-pain

5 patients on long-term opioid therapy with

6 co-occurring alcoholism cannot take naltrexone.

7 Finally, despite dosages of 100 to 200 milligrams

8 daily, some patients continue to experience both

9 craving and relapse.

10 I have carefully reviewed the European and

11 North American literature on acamprosate. There is

12 extensive documentation of its superiority to

13 placebo in promoting enhanced abstinence and early

14 recovery. Acamprosate has an excellent safety

15 profile and there is some suggestion it may have a

16 neuroprotective effect. Studies have shown

17 acamprosate and naltrexone, taken together, have an

18 additive effect in promoting abstinence.

19 I urge the panel to consider the millions

20 of lives that will benefit from the addition of

21 such an effective new treatment for such a

22 devastating disease and approve acamprosate.

23 Thank you.

24 DR. OREN: Thank you.

25 Any other general comment from the public?

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1 Charge to the Committee

2 DR. OREN: I will now call upon Dr.

3 Cynthia McCormick to deliver the charge to the

4 committee.

5 DR. McCORMICK: Thank you, Dr. Oren. This

6 morning, you have heard from Lipha and from the FDA

7 on the four clinical trials in question. I would

8 like to remind you that this advisory committee

9 meeting today will not be one in which a final

10 approval recommendation is being requested.

11 Recall that there are other aspects of the

12 drug-approval decision which are not being brought

13 for discussion today. The drug safety, as I

14 mentioned earlier, is still under evaluation and is

15 expected to be completed by the end of this month.

16 Both clinical inspections and inspections of the

17 manufacturing sites have also not been done yet.

18 In fact, one of our inspectors is here today and

19 will be leaving for France this afternoon to begin

20 his inspection of some of the European sites.

21 So these will both have to be weighed into

22 the decision for approval and in the timing of

23 approval, potentially.

24 We are asking you to assist the FDA in

25 assessing the weight of the evidence provided in

203

1 support of the efficacy of this product. A number

2 of exploratory analyses have been performed in an

3 effort to understand or explain the discrepant U.S.

4 results both by the FDA and by Lipha. You should

5 regard these analyses not as definitive but as

6 hypothesis-generating.

7 The FDA, in the end, does not accept the

8 results as positive nor feel that they should be

9 weighed in the decision for approval nor does the

10 FDA have an explanation for the failure of the

11 trial. So where does that leave us? It leaves

12 with questions about whether the populations are so

13 different that the European results may not apply,

14 about whether the differences in methodology alone

15 account for the successes of the European studies

16 and, therefore, whether the effect was real.

17 The effectiveness standards for approval

18 of a new molecular entity include at least two

19 adequate and well-controlled studies that

20 demonstrate a significant effect on the outcomes

21 that have been determined to demonstrate a

22 clinically meaningful result regardless of the

23 trial\'s origins, European or U.S., of course with

24 the caveat, as I mentioned earlier today, that the

25 sites are those that can be inspected. So the fact

204

1 that the bulk of the experience, the efficacy

2 experience, is European is not a problem for the

3 FDA.

4 The standards require a certain level of

5 quality such as the existence of a prospective plan

6 to assure data quality, availability of source

7 documents that can be used to verify the quality of

8 the data and the accuracy of the data and conduct

9 of the study following the standards of good

10 clinical practice. As is the agency\'s practice,

11 there will be inspections, as I mentioned, to

12 evaluate the veracity of the data.

13 As alluded to earlier, there is the

14 question of the credibility of the approach of

15 using highly imputed data in the European studies.

16 This should be carefully considered when assessing

17 the value of these studies. We will ask you to

18 reflect on all that you have heard, consider the

19 totality of evidence giving consideration and

20 weight to such factors of quality of data, strength

21 of the effect size and, most importantly, whether

22 the results that are positive are credible.

23 At the end of the day, the FDA must have

24 confidence that its decision will be based on

25 information that cannot be questioned.

205

1 So, in returning to the meeting, we ask

2 you to deliberate on the following questions, and I

3 will read them to you. Given the conflicting

4 results between the European studies and the

5 American study, is there sufficient evidence of the

6 efficacy of acamprosate in the treatment of

7 alcoholism to warrant approval? In this, consider

8 not only the quantity but also the quality of the

9 evidence provided in support of the effectiveness

10 claim.

11 How can the discrepant results be

12 reconciled or do they need to be? Finally, do the

13 data support any conclusions regarding subgroups of

14 patients more likely to benefit from acamprosate?

15 Please discuss that.

16 Thank you very much.

17 Continuation of Discussion

18 DR. OREN: Before the committee begins its

19 open discussion, I have a few questions that I

20 wanted to ask of the sponsor to help eliminate some

21 of our discussions. Could you, perhaps, clarify

22 what was your NDA strategy for this drug?

23 DR. GOODMAN: As I mentioned earlier this

24 morning, our NDA strategy was always planning to

25 use the European dossier as a substantial part of

206

1 our database. We always intended to use at least

2 two of the European studies as fulfilling the

3 requirements that Dr. McCormick has just mentioned,

4 adequate and well-controlled, and, in addition, we

5 felt it incumbent upon us to also preform a study

6 in the United States to confirm both the efficacy

7 as well as get further information on safety in a

8 broader population.

9 When the U.S. study results for the ITT

10 population did not show a difference between

11 treatment and placebo, our strategy was redefined

12 in terms of the amount of European data that we

13 were going to use in that we decided to add an

14 additional study to what we considered to be our

15 pivotal study.

16 The remaining studies that were submitted

17 as \"supportive\" studies, it did not mean that, in

18 our opinion, any of these studies could not also

19 have been pivotal from the point of view of their

20 design being adequate and well-controlled, having

21 case-report forms, electronic databases, and so on,

22 but it was more a question\--in some instances, the

23 study centers were not available anymore or the

24 practitioners who were there weren\'t available.

25 So the three studies that we

207

1 identified\--and we identified those from the very

2 beginning, the PRAMA and Paille study, and we added

3 the Belgian-French study, the Pelc II study. These

4 were always going to be\--or at least the first two

5 were always going to be part of our pivotal

6 database.

7 We did not submit, in the NDA, the U.S.

8 study as a pivotal study and we really think it is

9 misconstruing to say that we thought this was a

10 pivotal study. We didn\'t. We feel as interested

11 as the committee and the FDA in understanding why

12 the results weren\'t the same as the European

13 studies for the ITT population, but we think we

14 have done a good job in terms of trying to get an

15 interpretation on a subgroup that could really

16 benefit from the drug.

17 DR. OREN: Given that the European studies

18 are a key to our discussion of efficacy, could you

19 also clarify further or tell us more about the data

20 structure in those studies and the capacity of

21 those specific studies to provide valid endpoints

22 for us.

23 DR. GOODMAN: If I could, I would like to

24 ask Dr. Cook to address that point with Dr. Mason\'s

25 help, perhaps.

208

1 DR. G. COOK: The European studies had

2 assessments at specific time intervals. My

3 understanding is that those assessments would be

4 considered sufficient to identify departures from

5 abstinence, that, if a patient had a departure from

6 abstinence, it would be likely to be a major

7 departure and, through the various reporting

8 mechanisms, one would have been able to have

9 captured such a departure.

10 Now, that simply means that when you focus

11 on an abstinence-oriented endpoint, things are

12 fairly straightforward, whether it is complete

13 abstinence throughout the time period in the study

14 or time to first departure from abstinence or even

15 the number of assessments in which abstinence was

16 reported.

17 Certainly, the FDA has correctly

18 identified some difficulty in a calculation of

19 number of days with abstinence because that

20 involves some assumption about the time interval

21 between the assessments. I think the spirit of the

22 sponsor\'s categorization of all days subsequent to

23 an assessment of nonabstinence as drinking days was

24 simply based on the principle that if a patient had

25 a departure from abstinence, they would be

209

1 considered a drinker until the data structure

2 proved that they were no longer a drinker.

3 Again, that was probably based on the

4 philosophy that a departure from abstinence is not

5 something that just occurs for a few hours or a day

6 or two but that it actually is a total return to

7 the alcoholism for which they originally were being

8 cared for.

9 Whether that assumption is right or wrong,

10 I can\'t really comment on. I was just trying to

11 give some clarification as to why the sponsor,

12 potentially when they developed this strategy\--why

13 they basically called all days after a nonabstinent

14 day a drinking day following essentially a

15 last-observation-carried-forward principle.

16 Perhaps my colleagues here can comment on it

17 further. But, regardless of how you choose to deal

18 with that intervening interval, I believe that

19 abstinence was accurately characterized by the data

20 structure because, again, I think my colleagues can

21 reinforce the point that if a patient had a

22 nonabstinent episode, that data structure was

23 probably adequate to capture it.

24 So I would like Dr. Mann and Dr. Mason,

25 perhaps, to comment on these points further.

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1 DR. MASON: In terms of the importance of

2 a slip or a drinking episode, as I had mentioned

3 earlier, one of the diagnostic criteria for alcohol

4 dependence is going on to\--when the person with

5 this disorder, one of the ways they are

6 characterized is by their going on to drink much

7 more than they originally intended.

8 They may go to the wedding reception

9 planning on having just one drink and wake up a

10 case of beer later. That is one of the hallmarks

11 of the disease. All of the intervals that were

12 used as assessment intervals in the European trials

13 were of sufficient duration as demonstrated by

14 Sobell and others working as methodologists in the

15 area of alcohol dependence. They were of

16 sufficient duration to capture these important

17 episodes of abstinence and nonabstinence and long

18 enough to capture episodes of infrequent drinkers.

19 If you have a very quick rating period, it

20 is possible that you would miss a drinker because

21 the drinking just hadn\'t occurred in a narrow

22 interval. You do need an interval of sufficient

23 time to capture the infrequent drinkers who have

24 more of the binge-type pattern.

25 A final point that I would like to make

211

1 about the duration of the intervals that the

2 European data collection used and the method in

3 which the drinking data were collected in Europe is

4 how closely it follows U.S. clinical practice. I

5 believe that, given how the methods and the

6 intervals follow clinical practice, and the

7 benefits shown with acamprosate in this type of

8 setting and under this level of inquiry will

9 likewise benefit U.S. patients with alcohol

10 dependence that was diagnosed under exactly the

11 same set of criteria as those patients with alcohol

12 dependence in Europe.

13 DR. MANN: I certainly agree with what has

14 been said about a slip and how a slip is a short

15 return to drinking in general mounts up to what is

16 a full-blown relapse in 80 to 90 to 95 percent.

17 So, in taking into account a slip and counting it

18 as a relapse until the next visit, I think that was

19 the most conservative and the most valid way of

20 looking at these data.

21 I would also like to mention one more

22 point. The German study, the PRAMA study, was

23 published in the Archives of General Psychiatry in

24 1996 and that would say something about the

25 validity of the self reports using gamma GT,

212

1 figures that we have not heard yet today.

2 There we state that between 81 and 100

3 percent of the patients who self-reported relapses

4 had higher gamma GT levels in both groups, so there

5 was no difference between both groups, and also

6 that the gamma GT values above the normal reference

7 range also corresponded with the number of patients

8 who had had relapses, again in both groups.

9 So I think there is some solid evidence

10 that these self reports are validated by external

11 sources.

12 DR. OREN: We will now turn the discussion

13 over to the committee for us to discuss amongst

14 ourselves. Dr. Titus reminds me that we can also

15 feel free to ask the FDA, ask the sponsor,

16 questions that are of relevance to our discussion

17 to further us along.

18 Obviously, the three questions we have

19 been charged with are all interrelated with each

20 other but, perhaps, we can start with one and try

21 and focus on one and move towards the other. The

22 first one is how can we reconcile discrepant

23 results between the older European studies and the

24 more recently concluded American study?

25 Dr. Hamer?

213

1 DR. HAMER: First of all, I want to say

2 that I am less than impressed by the argument that

3 the assessment methodology in the European trials

4 followed closely the clinical practice in the

5 United States. That seems to me to be an analogous

6 argument for not using the Hamilton Depression

7 Scale in our depression studies because, after all,

8 in clinical practice, we don\'t use the Hamilton

9 Depression Scale to assess our patients.

10 DR. OREN: Dr. Fuller?

11 DR. FULLER: My comment is somewhat

12 related and it was already made earlier by two

13 individuals. One was Dr. Hamer. That is the issue

14 that if you do several clinical trials, you will

15 get discrepant results. One, perhaps, is just by

16 chance. Another could be different methodologies.

17 But we have already mentioned the

18 depression studies where this is not an uncommon

19 occurrence, at least as reported in Science last

20 year. Even with effective therapies, you will get

21 some studies where the medication is no better than

22 the placebo.

23 But the comment I wanted to make was more

24 of a historical nature and that has to do with

25 aspirin for preventing myocardial infarction in

214

1 people who have myocardial infarction. This is

2 considered very important by cardiologists and

3 groups such as Medicare who pays for healthcare.

4 Yet, there was a similar situation where there were

5 two positive studies and then there was a large

6 negative study that involved 2000 individuals.

7 Then there was a fourth study.

8 On the basis of three positive studies,

9 one negative study, people undertook metaanalysis

10 and it has become faith that people who have had a

11 myocardial infarction ought to have aspirin and

12 even those who don\'t should have it. I just wanted

13 to bring that historical vignette in.

14 What I was leading up to was this

15 sometimes happens, these discrepant results.

16 Others here may have insight into why they happen,

17 but we may not be able to reconcile the discrepant

18 results. But they do occur.

19 DR. OREN: Dr. Winokur?

20 DR. WINOKUR: To begin to address the

21 issue of the discrepant results, we certainly heard

22 a lot of discussion this morning about some

23 important differences in the populations included.

24 One important point that was mentioned and

25 acknowledged by the FDA is the request to broaden

215

1 the scope of patients including polysubstance use

2 for safety assessment, and that clearly may have

3 changed the composition of the population

4 considerably.

5 But picking up on a comment that Dr.

6 O\'Brien made, I also wanted to raise the question

7 as to whether there may be a change in the

8 treatment of alcohol dependence and whether this

9 changed the nature of patients available for

10 studies that occurred earlier in the European

11 studies which were, as we have mentioned, over a

12 decade ago with the more recent studies.

13 Again, the other major difference that we

14 are really grappling with is the issue which was

15 unexpected of the substantial number of patients in

16 the U.S. study who were not abstinent at the time

17 of start of treatment. I know we heard from the

18 FDA that they are willing to accept studies from

19 Europe as a basis for approval but I wonder if

20 there is a reason to discuss whether situations may

21 have changed not necessarily with the illness but

22 the environment in which people are not carrying

23 this illness and are being treated such that the

24 population being studied more recently really

25 represents a different cross-section.

216

1 DR. OREN: Do you want to say more? I

2 think that is an intriguing thought.

3 DR. WINOKUR: I was really hoping to get

4 some input from people that really work in the

5 field with this population which I certainly don\'t.

6 DR. OREN: Dr. O\'Brien?

7 DR. O\'BRIEN: Just to continue on the

8 theme of Dr. Winokur, actually is it what Dr.

9 Winchell said. There are clear differences that,

10 in the populations, in terms of\--first of all, the

11 environment, the availability of detoxification is

12 a major difference. The number of people who

13 started off not being detoxified. That is a big

14 difference in all the addicting drugs that we

15 study.

16 The coincidence of other kinds of

17 substance abuse at the same time makes for a more

18 heterogenous population. We haven\'t said much

19 about comorbid other diagnoses but we know that

20 there is a very high comorbidity of anxiety

21 disorders and affective disorders in alcoholics.

22 That has tended to vary both in different countries

23 and in different sites.

24 For example, some questions were raised

25 earlier about what is the percentage of alcoholics

217

1 who have substance abuse or who have one thing or

2 another. It really depends on whether you are

3 talking about a community program, a V.A. program,

4 an HMO, a private program. Every environment that

5 you go to is different.

6 So you have all of these environmental

7 factors. Of course, the time. For example, if you

8 did these studies in Germany or France today, you

9 might find a lot more comorbid substance abuse

10 because I believe that there are a lot more street

11 drugs available over there now.

12 But, in addition to all of these factors,

13 you have the biological differences in alcoholism.

14 We all know that there are different ways of

15 categorizing alcohol and the current ones are Type

16 1, Type 2, A and B. But none of these really

17 capture what are probably endophenotypes that,

18 among people who may use the same amount of grams

19 of alcohol per week but they are biologically very

20 different.

21 For example, if we give them alcohol in

22 the laboratory, one difference that is

23 extraordinary is the fact that some people get a

24 huge increase in plasma beta endorphin and other

25 people don\'t. They also get a different response.

218

1 It is either activation from alcohol or sedation

2 from alcohol.

3 When we give them the other drug that has

4 been mentioned here, naltrexone, some people, it is

5 just life-saving in the sense that they say that,

6 gee, it has really turned my life around and they

7 get a tremendous benefit from it and, if we stop

8 it, they relapse to alcoholism. So there is no

9 doubt in the mind of the patient and the person

10 treating the patient that the drug is active.

11 But, on the other hand, there are other

12 patients for whom you give the drug and there is no

13 benefit whatsoever even though, according to the

14 usual classification of alcoholism, they might be

15 identical. So we haven\'t come to the point in

16 alcoholism where we can make a diagnosis like, for

17 example, with anemia. We can take two people with

18 an hematocrit of 30 percent but we know that, by

19 doing hemoglobin electrophoresis, they may have

20 totally different kinds of anemia and you would

21 treat them totally differently even though their

22 symptoms are very similar.

23 We maybe someday\--I hope, someday\--will be

24 able to do that with alcoholism but to have

25 complete lack of divergence across clinical trials

219

1 would be totally unreasonable today since we are

2 lumping together people who are very heterogeneous

3 not only according to the environment things that

4 Dr. Winokur brought up but also according to the

5 biology of the illness.

6 DR. OREN: Dr. Rudorfer?

7 DR. RUDORFER: Just to follow up Dr.

8 O\'Brien\'s comments, in addition to some of these

9 cross-sectional issues, I just want to remind us

10 about the longitudinal aspect of this disorder.

11 Several of us have made references to mood

12 disorders, a similar kind of chronic relapsing

13 recurrent disease.

14 It seems to me that, just to kind of

15 restate something we have been saying from a

16 different perspective, there are certainly

17 different phases of the illness of alcoholism and I

18 fear that sometimes those have gotten lumped

19 together here today just in terms of talking about

20 treatment of alcoholism.

21 The issue with the percent of patients

22 abstinent at baseline I think is important in terms

23 of considering the phase of the illness so that the

24 European data really point to efficacy in the

25 prevention of relapse in patients who are already

220

1 abstinent, and not just already abstinent but

2 abstinent following an inpatient detoxification.

3 That is a particular stage of this illness and many

4 people may go through that multiple times during

5 their lifetime or not at all but to intervene at

6 that particular point, I think, is simply not the

7 same as intervening at another point.

8 So, to a certain extent, I see a certain

9 amount of apples and oranges in the European and

10 the U.S. trials.

11 DR. OREN: Dr. Hamer?

12 DR. HAMER: I think it is unfortunate that

13 the U.S. trial was almost an effectiveness study

14 rather than an efficacy study because what was

15 probably needed was an additional efficacy study in

16 the U.S. In terms of the decision we are being

17 asked to make, I think that, regardless of the way

18 that the sponsor presented the data and regardless

19 of the way we listen to it, it is clear from the

20 FDA\'s charge and from the things that have been

21 said elsewhere that, except for the issue of trying

22 to reconcile what happened in the U.S. study versus

23 the European studies, that the decision to approve

24 and probably, thus, most of our deliberations to

25 that part of addressing efficacy ought to be based

221

1 on the European studies, and the U.S. study ought

2 to be viewed as simply an additional failed study

3 and we should attach no more and no less weight to

4 that then we would in similar situations.

5 Having said that, the data the sponsor

6 presented showing efficacy of a sort in the U.S.

7 study depended upon what might appear to be a

8 carefully crafted set of covariates figured into

9 the analysis post hoc. Evidence that those

10 covariates are useful and meaningful and, in fact,

11 mean something in the course of the U.S. study

12 would be useful to us.

13 One way to address that might be to take

14 those same covariates or ones as similar as you can

15 obtain in your database and apply them in the

16 European data and see if they improve the effect

17 size. I wonder if you have done anything like

18 that.

19 DR. LEHERT: My name is Philip Lehert from

20 the University of Brussels and the World Health

21 Organization. I have examined, as a third party,

22 the whole database coming from acamprosate from the

23 European and the American data. I have done

24 exactly what you said.

25 I have examined 4,500 patients on the

222

1 basis of initial motivation, whether they drink or

2 not, and ten or fifteen different covariates. I

3 found exactly the same covariates in European as in

4 the United States. In using the same covariates on

5 the 4,500 patients in my model, I just used the

6 interaction between the United States, yes or no,

7 and the treatment.

8 I found a significant effect of these five

9 covariates and no significant effect of the

10 interaction. This is just telling you that what I

11 have done is justification of these five covariates

12 all around the world.

13 DR. HAMER: Although, depending on which

14 model we are talking about, there were either six

15 or seven covariates used in the U.S. trials.

16 DR. OREN: Could you identify those

17 covariates?

18 DR. LEHERT: Yes. The first I have,

19 unfortunately, not slides of that but I would just

20 like to say that this would belong to part of the

21 dossier. The first was whether or not the patient

22 was motivated. I would like to stress that

23 motivation was part of the European data but just I

24 had to take this data on the CRFs, themselves.

25 The second was the most important variable

223

1 I found for all the five. This was whether or not

2 the patient was drinking at baseline. I would like

3 to stress that the FDA has done the same analysis

4 of the American study but just on the seven first

5 days.

6 I did it on the basis of time-line

7 follow-back for Day 0, just Day 0. In other words,

8 I am able to look at all the patients that were

9 drinking at baseline and I found this very

10 surprising and very interesting medically speaking

11 results that the interaction of acamprosate and

12 abstinence at baseline was more important than the

13 acamprosate main effect only. This means that

14 before being treated by acamprosate, a patient must

15 be good willing to heal and not drink at baseline.

16 My first impression in the United States

17 data is that when I just look at those patients who

18 are not drinking at baseline, I found different

19 results in line with the European results.

20 I have a very last thing to say which is

21 the four other main effects were medication

22 compliance, and I would like to stress that it is

23 not compliance during the trial but the compliance

24 measure at the beginning of the trial and it is

25 just at the first three days we had this question.

224

1 My question was to know whether or not, in

2 using the compliance in the beginning, would should

3 have some image of the motivation because you know,

4 in the European data, I had no motivation of the

5 patient. In other words, I had to find another way

6 of measuring the motivation of the patient and I

7 found that in two things.

8 The first was that whether or not they

9 were drinking at baseline and second if they were

10 good willing to be compliant for the three first

11 days. That is what I found. And I finish in

12 saying that a moderate baseline I will call

13 dependency severity I suppose that everyone can

14 understand that the severity of the illness can be

15 of some importance in the predictive model. At the

16 end, just living with a partner and a child was the

17 thought.

18 I am happy to tell you that on my 4,500

19 patients, I was able to collect more than 35

20 percent of the whole variance which makes that my

21 model is somewhat explanatory, something that never

22 happens even in the World Health Organization in my

23 predictive models. I was very happy to have that.

24 And, at the end, what I was able to see is that

25 there was no interaction when I put that out

225

1 between the U.S. and the non-U.S. data.

2 In other words, there was no interaction

3 between the country, the trials and the product,

4 itself. In other words, my selection of my four

5 different endpoints was probably favorable for

6 explaining exactly. This is what we call a

7 metaanalysis based on individual patient data.

8 Thank you.

9 DR. OREN: Dr. McCormick.

10 DR. McCORMICK: I would just like to

11 caution the committee that these are not analyses

12 that we have had the opportunity to review and to

13 comment on. In fact, we haven\'t seen most of the

14 sixteen trials in detail that you have used in this

15 reanalysis. So I would caution the committee not

16 to rely too heavily on something that we have not

17 had the opportunity to review carefully.

18 DR. OREN: As committee members, we are

19 also at the same level of ignorance as far as

20 awareness.

21 Dr. Hughes?

22 DR. HUGHES: Just a quick yes/no question.

23 When you did your analysis, did you look at just

24 abstinence as a covariate and get an

25 interaction\--not the full four, just abstinence,

226

1 because clinically no one is going to say, well, if

2 you got a, b, c and d, I will give you the drug.

3 The most we can get is, perhaps, one thing. So,

4 with just abstinence did you find an interaction?

5 DR. LEHERT: I just used the fact on the

6 TLFP that I had abstinence in drinks every day and

7 I just looked at Day 0 and the very beginning of

8 Day 1. Then I repeat. I apologize to come back to

9 the study, if you allow me that, that this variable

10 was by far the most important predictor of success.

11 I think it was so important that I put that.

12 DR. HUGHES: But I am just asking if you

13 just had the model with just abstinence as the only

14 other thing in the model, did you show an

15 interaction of abstinence with treatment

16 assignment?

17 DR. LEHERT: Yes; I did

18 DR. HUGHES: Thank you.

19 DR. WINCHELL: Just to clarify, this was

20 the European database combined with the American

21 database that you analyzed this way?

22 DR. LEHERT: I analyzed in a metaanalysis

23 file all the data together including the American

24 study. That\'s right.

25 DR. WINCHELL: So the only subjects who

227

1 were not abstinent at baseline in your 4,500

2 patients were from the American study and then a

3 few in the U.K. study; correct?

4 DR. LEHERT: Yes; that\'s correct.

5 LIPHA: Just as a point of clarification,

6 that was submitted as a part of the integrated

7 summary of efficacy.

8 DR. WANG: Can I just add? This is Sue

9 Jane Wang from the FDA. In the analysis for the

10 U.S. study when just the abstinence goal was

11 included in addition to treatment in the center

12 that was included the model, I get the p-value of

13 0.431 of the medium dose compared to placebo. But

14 this is just for the U.S. study.

15 In other words, if you adjust for that

16 prognostic covariate, I do not see a treatment for

17 the medium dose.

18 DR. OREN: Dr. Rudorfer?

19 DR. RUDORFER: A question for the sponsor.

20 We have been discussing today studies that lasted

21 from six to twelve months. I am wondering if you

22 had any secondary measures in terms of function of

23 quality of life that would help us understand the

24 efficacy data better?

25 DR. GOODMAN: We did not include anything

228

1 regarding quality of life in the NDA. I know that

2 Dr. Lehert has done such an analysis of the

3 European data but it has not been submitted with

4 the NDA.

5 DR. OREN: Dr. Hamer?

6 DR. HAMER: I just wanted to confirm; in

7 the metaanalysis of individual patients that you

8 did, you used all the U.S. and European subjects.

9 So what you don\'t have is confirmation in the

10 European data alone that the same predictor\--that

11 is, abstinence\--is predictive in the European data

12 alone as it was or was not in the American data and

13 that also, since basically you had all abstinent

14 patients in the European data, that variable really

15 is largely confounded with the European versus

16 American studies; right\--since half the U.S.

17 patients were not abstinent and none of the

18 European patients were\--excuse me; half of the

19 American patients were not abstinent and none of

20 the European patients were not abstinent.

21 DR. LEHERT: The U.K. patients are

22 included into this data file metaanalysis and I

23 think, and I presume, that everybody\'s view of

24 statistics will assume that it would be doubtful to

25 make at least an analysis on only U.K. What I did

229

1 was that every time I assessed my model, I used a

2 defined protocol for analyzing the interaction of

3 the first order and then every time this

4 interaction was found, I included it in the model.

5 What I found was that only the interaction

6 between abstinence and the treatment was present in

7 my data. But I have done that exactly as you said.

8 DR. OREN: Dr. Hughes?

9 DR. HUGHES: Dr. Hamer, I am thinking very

10 differently than you here. The FDA said that when

11 they had abstinence, they didn\'t find anything. So

12 if he is finding in the full dataset, it must be a

13 whopping effect in the U.K. to swamp out the lack

14 of interaction in the U.S. Am I thinking right

15 here?

16 DR. HAMER: Or suppose there was no

17 abstinence effect in the U.S. study, that half the

18 patients in the U.S. were abstinent and also in the

19 U.S. study, abstinence didn\'t make a difference and

20 also in the U.S. study, we didn\'t show much of an

21 acamprosate effect. In the European studies, let\'s

22 suppose exclusive of the British study because that

23 is a small portion of the patients they have there,

24 everyone was abstinent and there was an effect,

25 therefore the difference you find in sort an

230

1 acamprosate effect versus a nonacamprosate effect

2 is fairly confounded with the U.S. versus European

3 studies and also fairly confounded with abstinent

4 nor nonabstinent. So that is not surprising.

5 I don\'t think I sort of asked my question

6 adequately. What I would have liked to have seen,

7 since they presented three European studies as part

8 of the NDA, would have been an independent

9 confirmation in the data from those three studies

10 alone, not including the U.S. data and not

11 including any of the other European data, that the

12 same set of covariates showed prediction in those

13 data as well, in the same way as they did in the

14 U.S. data.

15 DR. G. COOK: I think I understand what

16 your question is. I think that those analyses have

17 not been done. I think they mainly have not been

18 done because the direct analyses of the European

19 studies, regardless of covariate adjustment, do,

20 indeed, show significant results. The analyses

21 that the sponsor has done with the U.S. study are

22 largely explanatory. They are not being done to

23 prove anything because they couldn\'t prove anything

24 even if they found something that looked

25 attractive.

231

1 They are simply an attempt to see whether

2 or not they can identify trends that seem to be

3 consistent with the findings in the U.S. study. A

4 rather key part to the analyses they did along

5 those lines is to hone in on the motivated group

6 and the motivated group that you have to work with

7 for that purpose is the group that is motivated to

8 be abstinent in the strictest sense.

9 You also have to do the analysis that, in

10 the denominator, uses all days, if people dropped

11 out for an alcoholism-related reason and use days

12 up to time of discontinuation if they dropped out

13 for some other reason and that other reason was

14 considered credible.

15 But these analyses are more to identify

16 trends. They are not necessarily analyses that are

17 intended to produce attractive p-values. You don\'t

18 get attractive p-values that are durable in the

19 U.S. study. You can find suggestions in the U.S.

20 study that some of you may find reassuring but you

21 need to make your decision on the basis of your

22 confidence in the efficacy shown in the European

23 studies with whatever reassurance you are finding

24 from the U.S. study, recognizing that finding that

25 reassurance may be hard.

232

1 DR. OREN: Dr. Schatzberg?

2 DR. SCHATZBERG: This bears on that. This

3 is for the sponsor. If you look at the dropout

4 rates on the U.S. study, the dropout rates on

5 active drug are pretty high, particularly on the

6 2000 milligram per day dose. They run about 60

7 percent. I am just wondering how you reconcile

8 that kind of dropout with Dr. Mann\'s comment about

9 the PRAMA study, the German study, in which staying

10 in was seen as a good thing.

11 What kind of assurance can you have that

12 this doesn\'t mean that this isn\'t really a kind of

13 a really very fallible, very flawed study where

14 nobody stays in and 60 percent of the patients

15 dropping out. You can\'t have it both ways in the

16 argument. If you are the sponsor, you can\'t say,

17 yeah, people stayed in, it\'s great and then, in a

18 very large-scale trial, you have a very, very poor

19 completion rate.

20 So I don\'t know how you reconcile the two

21 arguments in the same presentation.

22 DR. GOODMAN: I don\'t plan to answer that

23 directly but I think that we were trying to

24 demonstrate, and again, just from an interpretation

25 as to how to explain our results in the ITT

233

1 population, I believe what Dr. Mason was trying to

2 do when she reviewed the demographics was to show

3 you that, collectively, we considered this 2-gram

4 group to be somewhat disadvantaged in a variety of

5 demographic measures, or baseline measures, relate

6 to drinking.

7 Barbara, I don\'t know if you want to say

8 anything more.

9 DR. MASON: It wasn\'t just their

10 disadvantage in relation to drinking. It was the

11 fact that they also had fewer psychosocial supports

12 like full-time employment, living with someone.

13 These are all aspects of rootedness and structure

14 that contribute to stability and staying in

15 treatment. Also, in general, in terms of the high

16 rate of dropouts, that is something that has been

17 demonstrated very nicely by the group at the

18 University of Connecticut where they looked at

19 dropout rates across clinical trials involving the

20 addictions, primarily illicit drug use, relative to

21 dropout rates involving clinical trials for other

22 psychiatric disorders.

23 The difference in the rate of dropouts

24 were very marked, particularly as one gets into

25 illicit substance use. So I believe that that

234

1 probably also colored the dropout rates of the U.S.

2 study that was so characterized by illicit drug

3 use.

4 DR. OREN: Dr. Leon?

5 DR. LEON: Let me follow up on what Dr.

6 Mason just said. The slide that she showed, each

7 of those differences at baseline looks very

8 trivial, 2 or 3 percent. Certainly, none of them

9 were statistically significant so I don\'t think we

10 should overstate the importance of that. They are

11 on the slides on Page 8 of your handout for anyone

12 that wants to see.

13 I want to say a couple of other things.

14 The intent-to-treat principle was referred to in

15 the analysis. The sponsor referred to that for the

16 pivotal trials. It is my understanding, though,

17 the that intent to treat was applied in an

18 unconventional way where the last observation was

19 carried forward, imputed for all data after

20 subjects dropped out of the trial.

21 In other words, the treatment and

22 assessment were very tightly linked. As soon as

23 someone stopped receiving treatment, they stopped

24 being assessed. Is that correct? Before I get the

25 answer, I look at the intent-to-treat principle to

235

1 be more tightly interpreted, to mean that, whether

2 or not somebody is receiving treatment, the

3 assessments are continued for the duration of the

4 trial.

5 DR. G. COOK: So that would mean you would

6 only be confident in a trial that had zero

7 dropouts.

8 DR. LEON: No. I just wouldn\'t call it an

9 intent-to-treat analysis. I wouldn\'t call what

10 they refer to as an intent to treat invoking the

11 intent-to-treat principle. They are imputing data

12 with the last observation carried forward.

13 DR. G. COOK: So you are saying that you

14 can only do intent to treat when there are zero

15 dropouts.

16 DR. LEON: No; that is not what I am

17 saying. That is what you are saying.

18 DR. G. COOK: But if what they did as an

19 analysis of all randomized patients is not an

20 intent-to-treat analysis, then it can only fail to

21 be not intent to treat because it imputed a failure

22 status to a dropout.

23 What it basically did was it had a certain

24 number of patients complete and, in the European

25 trials, you would have had a status of the patient

236

1 at the time of completion. The patients who

2 dropped out were basically managed as treatment

3 failures.

4 Now, the FDA did analysis in which they

5 managed those dropouts in other ways. There was

6 also an attempt to look at time to first departure

7 from abstinence as well. That was the

8 time-to-event analysis. That tried to deal with

9 the data. But, to avoid a semantic difficulty,

10 whatever the sponsor called intent to treat, I

11 believe was simply referring to all randomized

12 patients or all randomized patients with a few

13 exceptions who may not have taken at least on dose

14 of treatment. But that was only a small number, I

15 think, in Dr. Mann\'s presentation.

16 DR. LEON: Just so I understand this, this

17 was all randomized subjects were included and

18 assessed until they dropped out but none, or very

19 few, were assessed after they stopped taking their

20 treatment; is that correct?

21 DR. G. COOK: That\'s correct. There is

22 not a retrieved dropout.

23 DR. LEON: Although an alternative

24 strategy, assessment strategy, would be to continue

25 to assess the patients after they stop taking their

237

1 drug.

2 DR. G. COOK: Yes. And that is very much

3 recommended in today\'s environment although, again,

4 my understanding from Dr. Mann and others is that a

5 patient who drops out when they are being treated

6 for alcoholism is a patient who is very, very

7 likely to relapse, that these patients are very

8 fragile and, to some extent, dropping out is almost

9 tantamount to treatment failure.

10 Perhaps Dr. Mann would want to comment on

11 that further, or Dr. Mason.

12 DR. MASON: Andy, a point I would just

13 like to make in dealing with this population is

14 that once they are gone, they are really gone. It

15 is very hard to track them after they have lost

16 control of drinking. That is why this type of

17 intervention is so critically important just to

18 keep them involved in treatment.

19 Then, if there is a relapse, as long as

20 they are involved, as long as they remain engaged

21 for whatever reason, you can get them through the

22 relapse. I believe that the label for acamprosate

23 says to continue administering during a relapse.

24 But in a clinical trial involving

25 outpatients with alcohol dependence, once they are

238

1 gone\--it is not like where you can very practically

2 say, you are going to continue research assessments

3 even though they have left the treatment arm of

4 involvement. It just tends to go when you have

5 someone really lose control in that way.

6 DR. OREN: Dr. Cook

7 DR. COOK: This is for the FDA. Did you

8 find evidence that they had documented how they

9 were going to handle failures in the

10 analysis\--predefined, of course?

11 DR. WANG: For the European trials

12 DR. COOK: Maybe I can make a comment in

13 terms of how I am thinking about the questions.

14 The U.S. trial was failed.

15 DR. WANG: Also, the algorithm was

16 prespecified

17 DR. COOK: Pardon me? So now my question

18 is about the European trials because what I am

19 really trying to focus on is do we have evidence

20 for more than one adequately conducted controlled

21 trial for efficacy? The U.S. trial is not going to

22 be it. The sponsor acknowledges that. But I hear

23 questions about the three European trials.

24 I keep coming back to the point of

25 predefined analysis endpoints, et cetera, and how

239

1 failures are handled.

2 DR. WANG: My understanding is, for the

3 European trials, the definitions of dropouts, who

4 they are going to evaluate, as I showed in all the

5 slides, I distinguished between dropout as is and

6 as relapsed.

7 DR. COOK: So my question is what did the

8 sponsor predefine as the way they were going to

9 handle dropouts?

10 DR. WANG: I guess maybe we can go trial

11 by trial. The Pelc II trial was a three-month

12 study. Because we weren\'t very sure about those

13 imputations for the CAD data, cumulative abstinence

14 duration, the way to analyze these data, we can

15 only say the way they do the imputation on the

16 dropout patients, in some trials, they used the

17 worst-case analysis, worst-case here, I mean they

18 would impute all the dropout patients as patients

19 who relapsed.

20 But they don\'t do this consistently across

21 the three trials.

22 DR. COOK: Let me clarify because I think

23 we are getting into a little bit of an metaanalysis

24 of all the studies instead of coming back to the

25 principle that Dr. Leon pointed out that, to me, is

240

1 what we have to adhere to. If the three are

2 slightly different but within reason, I want to

3 know what was the analysis they prespecified.

4 Did they write that down? Is that a

5 document that we can verify and did their primary

6 specified analysis show a difference? We have

7 gotten confused. One page would be more helpful

8 than hundreds.

9 DR. WANG: For the three European trials,

10 we really don\'t know. That is why we are

11 struggling with presenting two ways of dropout as

12 is versus as relapsed. We have trouble with the

13 definition of what is the primary efficacy outcome.

14 It was not really stated.

15 DR. OREN: I would like to, at this point,

16 use this as a segue in our discussion to move away

17 from the first question, which was how can the

18 discrepant results be reconciled and to summarize

19 that.

20 We have heard at least that there may have

21 been different outcome endpoints between the

22 American study and the European studies. There are

23 certainly different levels of rigor. Randomness

24 may play a role and just this happened to be an

25 unlucky American study, different times, ten years

241

1 ago versus two years ago, different populations,

2 European versus American, different populations as

3 far as comorbid substance abuse, whether people

4 were drinking at the time of entering the study.

5 We have just heard about a metaanalysis

6 that suggests that maybe they can be easily

7 reconciled. I sort of feel like it is the old

8 Perry Mason show where a surprise witness comes in

9 at the end except in this case I am no judge. But

10 we don\'t have the full evidence to be able to

11 consider it at this point.

12 But this is, I think, at least the

13 background. At this point, this might be a good

14 time to move to the central question of, given the

15 results that we have seen today, and it seems

16 predominantly the European studies that we are

17 interested in, is there sufficient evidence of the

18 efficacy of acamprosate in the treatment of

19 alcoholism to warrant approval.

20 Again, we will take a vote whether to

21 recommend on the efficacy question, to make a

22 recommendation to FDA on how to act in that regard.

23 In that vote, I will go person-by-person through

24 the entire committee asking everybody to register

25 their vote, yes, no or abstain.

242

1 But, before that, we have open time for

2 discussion and I would certainly invite everyone,

3 in the course of this discussion, to make your

4 viewpoint known if you like.

5 Dr. Fuller?

6 DR. FULLER: I think my question bridges

7 both Question 1 and Question 2 in that we were just

8 discussing whether there were predetermined

9 endpoints in the European studies. I can be

10 corrected if I am wrong, but when I read this

11 document, I thought two of the three European

12 studies did have predetermined endpoints. I

13 believe\--I think, analysis, but the predetermined

14 endpoints, as I read them was in the Pelc study was

15 sustained abstinence and in I will call it the

16 German study was time to first drink. I think that

17 is what they had decided initially to use as

18 endpoints.

19 Then I believe that there was also an

20 endpoint for all three studies added on slightly

21 later, the cumulative abstinence days. I think I

22 am speaking correctly.

23 DR. LEON: I am working from this

24 document. I will show you the page numbers.

25 DR. WINCHELL: Which document?

243

1 DR. LEON: The FDA background document.

2 If you turn to page 32 of the medical record from

3 Dr. Winchell\'s report, the evaluation of endpoints,

4 Section 5314, the prespecified main criterion of

5 judgment listed in the protocol was, \"the

6 consumption of alcohol, no a prior strategy for

7 transforming the data collected into an overall

8 assessment of alcohol consumption was identified.\"

9 Also, on that page, as long as we are on

10 that page, there is no explicit data-analysis plan.

11 That is the next big paragraph down.

12 If we turn to the Paille study, Page 13 of

13 the statistics in the FDA document, the last

14 paragraph on Page 13, the first sentence, says that

15 no statistical-analysis plan was included here and

16 the protocol-dependent variable is also on that

17 page, the primary efficacy endpoint is here. The

18 number of abstinent days is right above that

19 paragraph, but this is not the one that was used in

20 the analyses that were presented.

21 As long as we are on this trial, I do want

22 to quote from the sponsor\'s report that there was

23 not a significant difference between 1332

24 milligrams and placebo. I think that has been lost

25 in the discussion today. In the Paille study, the

244

1 sponsor\'s report said there was not a significant

2 difference between placebo and the 1300 milligrams.

3 If you want to see where I got that, that

4 is in FDA report, Page 18, of the statistics

5 report.

6 DR. OREN: Although, since the protocol is

7 for approval for 2000, is that still a problem?

8 DR. LEON: Oh; if we are going to ignore

9 all studies that didn\'t test 2000, we would knock

10 out some other European data, wouldn\'t we? We

11 would knock out a third of the data from Pelc and

12 what else?

13 The other dependent variable, though, as

14 long as we are going through these, in PRAMA, was

15 time to relapse. That was defined on Page 61 of

16 the medical record from the FDA. That was time to

17 relapse and that was the day on which alcohol

18 consumption started again.

19 So that is my point of clarification on

20 the dependent variable.

21 DR. G. COOK: I think you are identifying

22 some of the same kinds of considerations that the

23 FDA reviewers identified in the course of their

24 review which is that studies that were launched in

25 the late 1980s and the early 1990s did not have

245

1 detailed statistical statements in their protocols

2 and they may not have had detailed statistical

3 analysis plans that were formally written prior to

4 unblinding.

5 Because of that, it becomes important for

6 analyses of the data structures that those studies

7 produced to be relatively consistent and robust.

8 So that is why it was somewhat important for the

9 FDA, in their reanalyses under any number of

10 conventions, to find similar significant results to

11 what the sponsor found in their analyses. It is

12 much more critical that the majority of analyses

13 agree with one another in terms of p-values below

14 0.05 when you do not have detailed plans that are

15 identified up front.

16 That is why the robustness from both the

17 FDA analyses as well as the sponsor looking at

18 several things all pointing in the same direction

19 was something that had some discussion.

20 DR. OREN: Dr. McCormick?

21 DR. McCORMICK: I tend to agree with Dr.

22 Cook in his assessment of the quality of

23 prospective strategies in some of the older

24 studies. I think, in our frustration when we

25 reviewed these studies, of not having carefully

246

1 laid out primary endpoints and statistical analyses

2 plans and so forth, led us to take probably the

3 most rigorous approach we possibly could take.

4 So we basically looked at these trials

5 with the perspective of what is the highest bar we

6 could set for these studies and it was complete

7 abstinence. We felt that the studies made it on

8 that criteria.

9 Our discomfort, as I mentioned this

10 morning, is\--I think we have almost moved past this

11 problem of not having the prospective strategies

12 before us and that is really dealing with the issue

13 of this imputed data. Do we believe it or not? Is

14 it really credible? Three months of really no

15 ascertainment, can we know what really happened or

16 not?

17 If I were to summarize the crux of our

18 discomfort, it has to be that.

19 DR. MANN: That is something I understand.

20 I think, in looking back at these in our early

21 days, we have the same kind of discomfort. But,

22 fortunately, we have also other data, the ones that

23 were shown by your statistician, which is

24 abstinence rate per visit. Only one day, and you

25 take all the information that you can get and you

247

1 say someone is abstinent or is not abstinent.

2 You are not computing back or forth or

3 anything. You just say, today is abstinent or nor

4 abstinent. If we do that, then we also have a very

5 clear-cut difference in favor of acamprosate versus

6 placebo. So we do not only rely on these things

7 that make us have some kind of discomfort.

8 We could show it to you. It is in

9 different studies, even. Abstinence per visit is

10 clearly significant in favor of acamprosate as has

11 been shown.

12 DR. G. COOK: Could you comment on how

13 many departures from abstinence might have been

14 missed because of the visit schedule? Do you have

15 a reasonable degree of confidence that the study

16 captured the vast majority of departures of

17 abstinence?

18 DR. MANN: That is, of course, something

19 which I cannot give you exact figures on. This is

20 more what you would call a gut feeling or clinical

21 experience. I think, and you have to be aware of

22 the fact that these patients were not just

23 outpatients which you see maybe three or four or

24 five times. But you have seen them for a week or

25 for two weeks or for three weeks as inpatients and

248

1 you know all about it, and they have already told

2 you how it was and how bad it was and they have

3 already confessed, more or less, that they had all

4 these terrible experiences.

5 Also, their relatives come in. We have

6 talked to their relatives so we know. They don\'t

7 have anything to hide anymore. If we see them

8 again after six weeks or after twelve weeks, we

9 know that these feelings of guilt and of shame of

10 admitting that you have a relapse, that is

11 something that we have already talked about in the

12 past.

13 If we miss it, then the spouse called us,

14 \"How come you don\'t pick up that he is drinking for

15 the last two weeks?\" That is what is happening, or

16 we have this kind of information in 30 to 40

17 percent of our patients throughout the year.

18 So I think we are fairly confident that we

19 picked up most of the relapses during the year and

20 I am very sure that we did not have a difference in

21 picking up those relapses or not between

22 acamprosate or placebo. The same margin of error

23 certainly is true for both groups.

24 DR. OREN: Dr. Hughes

25 DR. HUGHES: I just want to comment on the

249

1 last part that you said which is when we get

2 imprecision, which is the word FDA keeps talking

3 about is precision, you don\'t worry about it as

4 long too much as long as it is not systematic

5 because what it does is it introduces noise. So

6 what the imprecision does it makes it such that

7 those prior studies had to have a bigger effect in

8 order to detect it.

9 So I almost use the imprecision as an

10 argument that those European trials had a bigger

11 effect and we only found this much of an effect.

12 So, actually, the imprecision doesn\'t bother me

13 very much.

14 DR. KECK: This is sort of jumping on the

15 same bandwagon, but I think this is the beauty of

16 randomization. It is what randomization should

17 control for especially in a study or studies of a

18 drug that is, from what I can tell\--I have never

19 seen anybody in such a trial\--virtually

20 indistinguishable from placebo.

21 So the likelihood of unblinding or some

22 kind of systematic, as Dr. Hughes said, bias

23 contributing to the results despite the imprecision

24 of methods I think is pretty small.

25 I guess what I am hung up on a little bit,

250

1 and I would actually appreciate some input from

2 people like Dr. O\'Brien and other people who

3 actually done trials in alcoholic patients is Dr.

4 Mason set out a nice table in her slide kit on Page

5 4 comparing the different methods involved in the

6 U.S., which I think is so different than the

7 European studies it is not worth obsessing about

8 anymore, but in the three European studies, how

9 good are these methods because my gut reaction is,

10 in totality, they are not bad.

11 But I want to be comfortable with the .

12 DR. FULLER: You may disagree with me. I

13 don\'t think they are that bad. Let me try and

14 justify that. It is not uncommon in alcoholism

15 treatment trials, depending on the length of the

16 trial, to interview the person every two or three

17 months. Granted, ideally, you would like to

18 interview them every day, but that is not feasible.

19 Some day, we will have a little wristwatch

20 you can wear that will measure alcohol and we won\'t

21 be having these discussions. But, until that day

22 arrives, you follow the patient, you track them,

23 you interview them. It is always, then, a

24 retrospective report.

25 Now, the advantage to the time-line

251

1 follow-back is that, hopefully, it improves the

2 accuracy of that or in that patients are given

3 prompts, holidays as indicators of certain days.

4 They are shown these pictures of quantity. So you

5 may get a better frequency, quantity report but,

6 basically, they are both capturing the data, in a

7 sense, retrospectively. The time interval is two

8 to three months.

9 So I think what was done in the European

10 studies was fine. It could have been improved a

11 little bit by current standards.

12 The other comment I will make has to do

13 with randomization. Even if there was somewhat

14 more imprecision in the data collection in the

15 European studies, this should have been randomly

16 distributed across the treatment groups. So I

17 think the data collection is okay.

18 DR. OREN: Dr. O\'Brien?

19 DR. O\'BRIEN: I really agree with what Dr.

20 Fuller just said. I should tell you all that I

21 have never had any kind of relationship with Lipha,

22 not a consultant or anything like that, but I do go

23 to Europe a lot and I have read all these trials

24 when they first came out and I have heard them

25 presented, both in English and in French. I have

252

1 discussed them when they were fresh.

2 I always was aware of the differences in

3 methodology between the European\--as a matter of

4 fact, I have slides of their trials that I have

5 used to compare the kinds of studies we have done

6 here and there. I have used these for years,

7 actually, not just recently, because it has always

8 been very obvious.

9 Then a couple of years ago, I was involved

10 with a group that included Dr. Mann to plan some

11 joint American and European studies of alcoholism

12 using the other medication that has been talked

13 about here, naltrexone, a depo form of it. So I

14 think we had people representing many of the

15 European countries where these studies were done.

16 We arrived at combined protocols. But, in

17 the past, they really were different. But, at the

18 same time, I was always impressed and I still am,

19 that there is an effective drug there and that,

20 while I always had problems with the design of the

21 studies, the way they originally were done, I still

22 felt that there was some efficacy there. That is

23 also borne out by my talking with clinicians in

24 Europe who, in fact, believe, for what it is worth,

25 that the drugs are effective.

253

1 DR. OREN: Dr. Schatzberg?

2 DR. SCHATZBERG: I have a question for the

3 FDA staff. In terms of the PRAMA study, which had

4 longer intervals going out, were you folks

5 satisfied that, in the first 120 days where you had

6 more frequent interviews of the patients, that the

7 drugs separated in terms of either time to first

8 drink, as was presented earlier by Dr. Mann, or in

9 terms of total abstinence because I think if there

10 is an effect still at the 120 days, which is a

11 reasonable length of time for these folks, that

12 would connote substantial benefit for the large

13 group of patients and would still be within that

14 time of frequent assessment so you wouldn\'t have to

15 worry about whether you are, in fact, having some

16 sort of systematic effect in terms of recall.

17 DR. WINCHELL: I didn\'t look at 120 days.

18 I know that Dr. Wang replicated the

19 time-to-first-relapse analysis.

20 DR. SCHATZBERG: You did?

21 DR. WANG: As she showed you on her slide,

22 there is a delay of the time to first relapse that

23 comes out statistically significant.

24 DR. SCHATZBERG: Even if you just go to

25 120 days?

254

1 DR. WINCHELL: Oh; I don\'t.

2 DR. WANG: I didn\'t specifically look at

3 120 days, either, but what I would like to point

4 out for the PRAMA study is time to first relapse is

5 the prespecified primary efficacy endpoint. This

6 is the only study that prespecified and had a

7 result coming out consistent with other endpoints.

8 What I am really struggling with was there

9 was a question asked from the committee whether the

10 company used the same model to do the European

11 studies. Because I did so many different analyses

12 in trying to understand what is going on, if what

13 we are seeing here from the U.S. trial is true,

14 which means that the acamprosate median dose has a

15 shorter treatment exposure, more dropouts, by that

16 kind of modeling adjustment, it to make the worst

17 outcome to be better.

18 If this logic applies, then the European

19 trials, using the same kind of definition, it

20 should be in favor of placebo, logically.

21 DR. OREN: Sometimes, the wisest people

22 are silent. I know, Dr. Porrino, you haven\'t said

23 much today. I wonder if you might share some of

24 your thoughts on this efficacy question.

25 DR. PORRINO: Part of my silence really

255

1 comes from the fact that I am a basic scientist who

2 is now starting to dabble in looking at human

3 patients and, in particular, alcoholics. I don\'t

4 conduct clinical trials, so I consider this a

5 remarkable learning experience for me and I

6 appreciate the opportunity to be a part of this

7 because I have learned a tremendous amount.

8 But one of the things that keeps coming

9 up\--there are two things that I could comment on.

10 One of them is the discussion of motivation,

11 motivation as an important variable, and the

12 difference between motivation to completely stop,

13 to remain completely abstinent, and those that are

14 willing to slip a little.

15 In our experience, and this is not just

16 experience with alcoholics where I have much less

17 experience, but with marijuana users where I have a

18 tremendous amount of experience. We have looked at

19 subjects at that point and we have asked them sort

20 of that very question, although not exactly phrased

21 that way, and then we have done some brain

22 imagining.

23 I will say that there is a large

24 difference between the brains of those individuals

25 who are willing to slip occasionally and those that

256

1 are really trying. So motivation is a very

2 important variable and I don\'t think it should be

3 underestimated nor do I think that combining the

4 two is necessarily appropriate.

5 So I appreciate that it sounds the same

6 and very often is the same, but, actually, in our

7 hands, it looked quite different. Their brains

8 looked quite different so I was quite interested in

9 putting those two together versus separating them

10 which I think is a more appropriate thing to do.

11 The other thing that I can comment on is

12 the fact that, in the patients that I have seen and

13 the alcoholics that I have seen, there is a

14 tremendous desire to have aids and any possible

15 chances to try and remain abstinent. They want to

16 get better, at least many of the ones that I see.

17 And there are no ways to help them.

18 So acamprosate, although it may not be the

19 perfect drug, may certainly work for some where

20 other drugs don\'t work. I think we need to

21 consider that very importantly.

22 DR. OREN: Dr. Malone?

23 DR. MALONE: I don\'t really work with

24 drugs and alcohol either, but, in looking at the

25 result of the American study, I think the problem

257

1 that it didn\'t find any result, I guess, makes us

2 look more closely at the European studies. So it

3 seems that they were using older methodologies and

4 they didn\'t have preplanning which is troubling.

5 Then I think you start thinking about the

6 way we deliver medical care now and you wonder

7 whether the results from those older studies will

8 be applicable in the way we deliver care in the

9 United States right now for efficacy.

10 DR. OREN: Beyond that, as a child

11 psychiatrist, there is no data presented with

12 regard to alcoholism in youth. Do you have any

13 thoughts on that?

14 DR. MALONE: We study conduct disorder. I

15 guess maybe these children might go on to drink.

16 They might drink now and we don\'t really know. We

17 have the same problems with following out

18 populations. Half of them never come back to the

19 studies.

20 But I think one of the things that we did

21 learn is that it seems to me that some of the

22 treatments work better in one setting than another.

23 So, for instance, you might have a treatment that

24 works pretty well in an inpatient controlled

25 setting, but when you take it to the outpatient

258

1 setting, it doesn\'t seem to work as well.

2 So this is really the problem I have with

3 the older European data is that it really is about

4 a treatment for a different setting. The only data

5 we have in the current American setting is negative

6 data. Overall, I think that does cast some doubt

7 on the efficacy of using that dataset to say

8 whether the drug will work the way it is used in

9 the United States, the way it would be used, people

10 not getting detoxed, and maybe being on drugs,

11 polydrugs, when they start the treatment.

12 DR. OREN: Dr. Winokur?

13 DR. WINOKUR: I had wanted to come back to

14 the issues that I had raised before but directed to

15 the FDA representatives, Dr. McCormick or Dr.

16 Winchell, and Dr. Malone came back to that

17 beautifully. So I just wanted to follow up on

18 that.

19 One possibility might have been that we

20 have had data from the U.S. study that supported

21 efficacy and then we could put that together with

22 the European studies that were done a bit ago, but

23 also have some data supporting efficacy and look at

24 them together. As it has happened, we generally

25 agreed that we are going to have to primarily look

259

1 at the European studies and think through how

2 convincing we find the efficacy data to guide our

3 thoughts.

4 We have heard from Dr. McCormick that

5 there is precedent or openness to consider data

6 from the European trials to form an opinion for

7 approval, but, I guess the concern that I had

8 thought about, and Dr. Malone expressed, is if

9 there are differences between the clinical

10 circumstances in the European studies in this case

11 done a while ago and what we have heard to be the

12 case currently in the U.S., and we are talking

13 about a U.S. approval, does that represent a

14 problem from the agency\'s point of view in terms of

15 that being the exclusive basis in terms of efficacy

16 data?

17 What I am explicitly thinking about is the

18 use of the inpatient detox as a lead-in to having

19 abstinent patients to begin the trial which was

20 done in Europe we have heard is rarely possible in

21 the U.S. We have seen that when a study was

22 launched in the U.S. with the intention of having

23 abstinent patients, there was a very high degree of

24 lack of success in achieving that.

25 So I would like to hear some response from

260

1 the FDA.

2 DR. McCORMICK: I don\'t believe that that

3 would be a problem. There are ways to abstinence

4 that are nonpharmacologic. So I guess that is

5 another question that we have to you. I guess that

6 is really the essence of the third question, are

7 there subsets that we could identify that might be

8 more responsive and is abstinent prior to

9 initiation of treatment necessary.

10 But the approval of this product, based on

11 European data, given a different set of medical

12 conditions, would not preclude our approval of this

13 product.

14 DR. OREN: Dr. Schatzberg?

15 DR. SCHATZBERG: It would seem to me that

16 the only positive data you have are in abstinent,

17 fully abstinent, detoxified patients so that there

18 are no data that we have seen that it works,

19 particularly in the U.S. trial\--that if you are not

20 detoxified, it will have any effect. So I would

21 think that that one group would have to be there

22 because I think it would be misleading to imply

23 that to the public that you could just sort of hand

24 it out in your office to an actively drinking

25 subject and you are going to have any efficacy that

261

1 is true.

2 Just a couple of comments because I am

3 going back to the West Coast. I think the FDA has

4 done a service, in a way, to the sponsor in going

5 that extra mile to look at the European database to

6 see if there is something that can be common across

7 the studies in terms of looking at abstinence and

8 brought some clarity.

9 From a consultant\'s end, we can\'t comment

10 on the quality of the data because we don\'t have

11 the books. We really don\'t know what they look

12 like, but fact that there is some assurance that

13 two or three of the trials, with the drugs

14 separated on a very highly conservative measure,

15 that does have public-health significance and

16 really ought to count in spite of the fact that you

17 have a failed or a negative U.S. trial where you

18 can\'t say anything except that it didn\'t work and

19 there was a high placebo-response rate and a high

20 dropout rate, which are two kisses of death, I

21 think, for clinical trials.

22 But I think you and your staff ought to be

23 given some kudos for really trying to bring clarity

24 on this problem although I am not sure that any of

25 us, either as consultants or people on the

262

1 committee, can tell you what the data looks like.

2 You have got those data right there.

3 DR. McCORMICK: Thank you.

4 DR. OREN: Dr. Ortiz, I know you have been

5 on the left so I haven\'t always looked straight at

6 you. Is there anything you might want to

7 contribute?

8 DR. ORTIZ: No. I actually had just

9 written down some thoughts. Since we had left

10 Question No. 1, although it seems like we seem to

11 be moving in a direction that the differences can\'t

12 really be reconciled very well, and we were on

13 Question No. 2, I had come to the same conclusion

14 that Dr. Schatzberg had addressed, that we clearly,

15 I think, seem to have evidence that it is an

16 effective medication for abstinent alcoholic

17 patients.

18 DR. OREN: Dr. Hamer?

19 DR. HAMER: For me, I think the U.S. study

20 is sort of off the table. I think that the

21 decisions need to be based on the European studies.

22 Also, with respect to American study, I want to

23 drag in some really trite, elementary statistics

24 and just remind everyone that failure to reject the

25 null hypothesis doesn\'t prove the null hypothesis

263

1 is true.

2 So, merely because, in that U.S. study, we

3 failed to show that acamprosate beat placebo

4 doesn\'t prove that it doesn\'t beat placebo. All

5 the noise in the world will just make it look

6 worse. That doesn\'t carry as much weight. I am

7 reassured that the reanalyses that the FDA carried

8 out with some fairly hard endpoints in a

9 conservative way, in a relatively precisely defined

10 group, as Dr. Schatzberg mentioned, seems to

11 indicate that this at least beats placebo in those

12 trials, and, therefore, as an additional weapon in

13 the armamentarium that is fairly sparse right now,

14 might have some use in medical practice.

15 DR. OREN: Dr. Fuller?

16 DR. FULLER: I second those comments. I

17 am persuaded\--I think, from the European data, that

18 acamprosate has some efficacy and it is really

19 based somewhat on the literature. Some of these

20 studies were published before. Of course, the

21 problem with the literature, I recognize you don\'t

22 have the full report, also, by the material that

23 was presented here, and Dr. Winchell\'s summary of

24 those reports.

25 So I would second the last two comments,

264

1 that the European data do indicate efficacy.

2 DR. OREN: Dr. Mehta. Then we are going

3 to one-by-one through everyone to ask you to

4 register your opinion.

5 DR. MEHTA: Just a comment to what Dr.

6 Malone said. Dr. Goodman showed a slide which

7 showed that the core illness for alcohol dependence

8 is similar in the U.S. and in Europe. This was

9 shown based on a letter written to FDA by NIAAA.

10 DR. OREN: Dr. Malone; you have a

11 question?

12 DR. MALONE: No; the study populations

13 were very different, though, because the European

14 one did not really include people who had abusive

15 drugs and it didn\'t include people who were

16 drinking. So even if just alcoholism is the same,

17 the study populations were very different.

18 DR. OREN: We have a little more time for

19 commentary, it turns out. Dr. Hughes

20 DR. HUGHES: You know, the thing that is

21 hanging me up, and let me try to put it as an

22 analogy. It seems to me the analogy is it is like

23 Lipha is a guy who\--let\'s say a baseball player and

24 he has hit a home run thirteen times in a row, and

25 he comes to somebody else and he says, \"I can hit a

265

1 home run.\" And the other person says, \"Well, I

2 don\'t know about that.\"

3 And the guy says, \"Well, I tell you what.

4 I will prove it to you. I will do it right now.\"

5 And he tries to do it right now and he doesn\'t hit

6 the home run. We know he has hit it thirteen times

7 in a row but he put himself at risk by saying, he

8 can prove it to you to you that next time.

9 So what I am hung up on is, as a result of

10 this trial, I am less confident that this drug

11 works than I was at the get-go. So I am a little

12 bit worried about the precedent. In other words,

13 what would have Lipha had to have done in this

14 trial to disprove it. I am not sure what they

15 would have had to have done for us to say, \"You

16 can\'t have approval.\"

17 Then, as a result, I worry about the

18 precedent there; that is, that it seems to me that

19 if you make an agreement, that you agree that you

20 have to show your drug works in a subset before you

21 are going to get approval and then you don\'t get

22 it, that is what we used to call going back in your

23 word.

24 So that is where I am hung up.

25 DR. OREN: Or, to use your baseball

266

1 analogy, perhaps when a ball player was younger in

2 the different town, he could hit home runs. But it

3 a few years later and he is in a different city and

4 time has passed a little.

5 Dr. O\'Brien, did you want to say

6 something?

7 DR. O\'BRIEN: Before the baseball, we were

8 talking about detoxified patients. I just wanted

9 to point out that, while it is the mode right now

10 to not admit people for detox or even pay that much

11 for outpatient care, if, indeed, there were

12 evidence about the state of a patient\--in other

13 words, if this is emphasized that the people should

14 be drug free before they start on the medication,

15 then this probably would be cost-effective\--in

16 other words, to invest something in a

17 detoxification, to start them off clean\--because

18 what you would pay at the outset, even if you had

19 to admit them for a few days would be more than

20 offset, if you were an HMO, by the savings over the

21 next few years.

22 We already heard that Kaiser Permanente is

23 using another drug which is reasonably expensive

24 and they must be doing it because it is

25 cost-effective. I think there are data showing

267

1 that it is cost-effective.

2 So I think that we needn\'t worry about the

3 fact that, in the American trial, there weren\'t a

4 lot of people who were abstinent at the beginning

5 because there could have been if, in fact, that had

6 been a requirement.

7 DR. HAMER: I just want to continue the

8 baseball analogy a little bit. I think what has

9 happened here might be that the baseball player hit

10 thirteen home runs and then made the wager with his

11 friend. Then, after they agreed, the friend said,

12 \"Oh; by the way, for this at bat, we are using a

13 smaller baseball, you are getting a lighter bat and

14 the pitcher is a foot and a half taller and has

15 been lifting weights for the last five years.\"

16 DR. OREN: Dr. Malone?

17 DR. MALONE: Back to what Dr. Hughes said,

18 the problem was that the American trial was

19 negative. Was the American trial necessary? They

20 could not have come forward with just the European

21 trial? I don\'t quite understand.

22 DR. OREN: Do you want to repeat the

23 question?

24 DR. MALONE: Back to what Dr. Hughes was

25 saying. You have these positive trials and now

268

1 you, somehow, come here to the FDA and you do

2 another trial and it is negative. I would think

3 that would put you in a worse position unless that

4 trial was somehow not necessary.

5 DR. McCORMICK: I guess, to go back to the

6 baseball analogy, we don\'t expect all home runs.

7 As I mentioned this morning, we frequently do see

8 development programs in which there are trials

9 which may trend in the right direction but are not

10 statistically significant on the primary endpoints

11 and, occasionally, we see some that really show no

12 effect at all.

13 We try to understand why that is the case.

14 We try to assure ourselves, as we are in this case,

15 that the studies that we are relying upon, or the

16 studies that are positive, aren\'t fallacious.

17 First of all, let me just set the record

18 straight. There aren\'t thirteen home runs. Let\'s

19 just say the three pivotal studies that we have

20 reviewed may be characterized as home runs. I see

21 a difference of opinion which we would like to hear

22 from, but the fact that there is a negative study

23 doesn\'t trouble us. It is not a preclusion to

24 approval.

25 DR. OREN: Dr. Malone?

269

1 DR. MALONE: Was the purpose of the

2 American study for efficacy or really just safety

3 in the different sample that you get in the United

4 States?

5 DR. WINCHELL: The purpose of the American

6 study, as we understood it when we first met with

7 the company, was because they wanted to make a

8 change from marketing the 333-milligram tablet to

9 the 500-milligram tablet. So, since there were no

10 studies on the 500-milligram tablet, what we agreed

11 to do was accept a marketing application that

12 consisted of a single study using the 500-milligram

13 tablet with a nominally very similar total daily

14 dose of 2 grams, although we didn\'t expect that

15 complete bioequivalence, as we define it, would be

16 established.

17 We said, okay; if you can do one winning

18 study with the 500-milligram tablet, the other

19 stuff you have got here on the 333 milligrams, two

20 tablets TID, will serve as your supportive evidence

21 of efficacy, your confirmatory evidence. That is

22 how this whole story began.

23 DR. McCORMICK: If I can just add another

24 word. We did conceive of this as an efficacy study

25 and a safety study and it was designed to obtain

270

1 efficacy information and proof of efficacy.

2 DR. OREN: Dr. Cook

3 DR. COOK: I want to refer to the thirteen

4 home runs again. First of all, there are three

5 studies submitted besides the U.S. study, so there

6 can only be three home runs. Number two, some that

7 are not submitted were not positive, at least one.

8 Number three, I count three studies. Based on the

9 analyses, number one, you could consider none of

10 them at bats on the basis of no

11 prospective-analysis plan.

12 So, to go beyond that is to bend over

13 backwards, I think. I don\'t care if it was 1988,

14 if we were in the clinical-research center at any

15 major university, if you didn\'t have a prospective

16 data-analysis plan, the study wouldn\'t go through.

17 This study would not have been approved for funding

18 at most institutions.

19 Then, if we look at the analysis, two

20 studies seem to be positive, the Pelc II and the

21 Paille. Dr. Wang I think was fairly convincing

22 that, unless you look at it just the right way, the

23 Paille was not. Again, you have to be conservative

24 if you didn\'t prespecify the analysis.

25 Now we have two studies. That is enough

271

1 in the analogy that two hits out of four is a

2 pretty good batting average or the idea that more

3 than two well-conducted studies have been positive

4 Now, I have already said I have a problem

5 with well-conducted. But, seeing that this hasn\'t

6 been monitored, anything in the monitoring that

7 doesn\'t show that randomization was perfect, that

8 everything was on the up-and-up, in me, may be

9 based on what we have that is tentative and not

10 fully monitored. But, it is very slippery.

11 Anything that is weaker than it already is in those

12 studies is a problem.

13 I worry about the differential dropout

14 rate with placebo in those studies. That is why I

15 am concerned about randomization.

16 DR. OREN: I am going to try and move on a

17 little bit. Before we go on a person-by-person

18 vote, I just wanted to ask the members of the

19 committee if any of you wanted to make any general

20 statement before we each register our opinions.

21 What I will do is I will go

22 person-by-person asking you to say yes, no, or

23 abstain. If you wish, you can argue at that point

24 or share some of your rationale for your vote if

25 you would like. But, before we register those,

272

1 does anybody want to make any additional point from

2 the committee or from the guests?

3 What I would like to do is, for the

4 nonvoting members of the committee, I just want you

5 to say if you were voting, please share with us how

6 you might vote and why you might do that, although

7 you are obviously not voting.

8 Dr. Mehta?

9 DR. MEHTA: I just wanted to make a

10 comment that I don\'t know why we are hung up about

11 the prospective plan for analysis. These studies

12 were done 1998 in Europe. That was the state of

13 the art. Probably these are designed a couple of

14 years earlier. If I go back and look at my own

15 studies in this country and major pharmaceutical

16 companies submitting across all the divisions,

17 these are not very different than what they have

18 done.

19 Maybe in clinical research centers, it

20 would be different. Maybe at different places, it

21 might be different, but certainly not in drug

22 trials, particularly submissions. I have never had

23 any comments from FDA statisticians which says

24 that, look, this protocol or analysis is not

25 acceptable. No. That is absolutely not true.

273

1 DR. OREN: So if you were going to be

2 voting, how would you vote, the question being, is

3 there sufficient evidence of the efficacy of

4 acamprosate in the treatment of alcoholism to

5 warrant approval.

6 DR. MEHTA: Just one additional comment.

7 In another division, the Cardiorenal Division,

8 there was a major ace inhibitor approved for heart

9 failure. The only major and important study was in

10 the United States. It was totally negative. Bob

11 Temple said they had tried, just like what you have

12 done, about twenty different ways of looking at the

13 data to find out if there was some redeeming

14 feature in that study. There was none.

15 Nevertheless, based on the two or three

16 European studies, the drug was approved and it is

17 on the market. Subsequently, several years later,

18 there was an American positive study.

19 All right. Coming back to this drug, I

20 would approve it because there are three studies

21 which have been shown that the drug is clearly

22 different than placebo. The U.S. study, I would

23 just ignore it. It is three to one, batting

24 average.

25 DR. OREN: Thank you.

274

1 Dr. Hughes, if you were voting, what would

2 you tell us?

3 DR. HUGHES: Vote for approval.

4 DR. OREN: Any additional comment? No?

5 Dr. Porrino?

6 DR. PORRINO: I vote for approval.

7 DR. OREN: Dr. O\'Brien? You are obviously

8 influential in the field of alcoholism and whatever

9 you think will clearly have a great impact. So,

10 although you are not voting, tell us how you would.

11 DR. O\'BRIEN: Well, first of all, I would

12 like to say that I was extremely impressed with the

13 material that the FDA gave us to prepare for this.

14 I was already familiar with most of these papers.

15 I had reviewed some of them for publication. This

16 was the best exposition I had seen. Drs. Winchell

17 and Wang gave just beautiful presentations this

18 morning.

19 I think they were correctly very rigorous.

20 So certainly I will have to say that, if I had been

21 asked this question before I got these materials

22 and heard them, I would have been much more

23 positive about the drug. But I still feel, and it

24 is hard for me to separate the three studies from

25 what I know about the other group of studies, I

275

1 would consider two of the other studies not to be

2 positive and all the rest of them, for various

3 reasons, I don\'t have to go into here\--but, in

4 other words, the vast majority were positive.

5 To me, it is remarkable that they were

6 positive because of the imprecision involved, I am

7 critical of some of the design, and also because of

8 all of the problems with studying this. When we

9 have situations where, with antidepressants, there

10 is evidence that 50 percent of the trials fail to

11 show an advantage for a so-called active drug over

12 placebo. We had a debate on this at ACNP a couple

13 of years ago.

14 So, anyway, the fact that you could get

15 this much positive with alcoholism must mean that

16 there is efficacy there. So, based on the evidence

17 that we have, if I had a vote, I would have voted

18 positive.

19 DR. OREN: Thank you.

20 Dr. Fuller, you do have a vote, so please

21 tell us.

22 DR. FULLER: I am going to make this five

23 or six hits in a row. I find, I think as I

24 expressed earlier, the European data are reasonably

25 credible. I think the method of collection of data

276

1 was reasonably standard. I believe in many of the

2 studies they did breath alcohols at the time of the

3 interview and these are little tricks that are done

4 to try and improve the quality of data.

5 The differential dropout rate in the

6 European studies actually I think is in favor of

7 the medication. My thinking is along these lines.

8 I think the placebo patients felt that they weren\'t

9 getting something out of the treatment so they were

10 more likely to drop out of treatment.

11 Now, one can always think of caveats.

12 Certainly, if there were problems

13 post-randomization that are not apparent from the

14 material that was given, that would influence me.

15 But, taking it as a whole, the material that was

16 given with its pros and cons, with the summaries

17 prepared by Drs. Winchell and Wang, and based sort

18 of on my clinical and other research experience,

19 weighing all these, I think the European data

20 indicates there is some efficacy for acamprosate

21 and it should be approved.

22 DR. OREN: Dr. Cook

23 DR. COOK: I have one general comment that

24 I can\'t leave without stating. I don\'t want to

25 minimize the importance of motivation in treatment

277

1 but I don\'t want patients who participated in

2 trials as described as less than motivated because

3 my view is, whether people are abstinent or not,

4 they are motivated to stop this.

5 I particularly want to point out whether

6 people\'s goal was different. The issue is how they

7 answered the question. The question was, I seek

8 total abstinence versus I seek total abstinence but

9 realize I may slip. I realize I may not be

10 perfect. That actually may be a step in the right

11 direction to somebody who is recognizing they don\'t

12 have complete control over themselves.

13 Had the question been, my goal is complete

14 abstinence, or my goal is complete abstinence with

15 a few slips, that is a different question. So, I

16 have struggled with this, obviously a lot, and I

17 guess I said before, I do see two positive studies,

18 Pelc and PRAMA, no matter how it is looked at and

19 the only question is verification.

20 So I guess I say yes with that caveat.

21 DR. OREN: Dr. Ortiz?

22 DR. ORTIZ: I am very appreciative of the

23 FDA staff for bringing this confusing picture to us

24 from around the country and to the public to

25 consider what to recommend for the American public

278

1 given some of this confounding data and confusing

2 data.

3 I was very confused at home going over the

4 data. But I also realize, again having the

5 gentleman from Kaiser that represents, basically,

6 the working alcoholic in the United States that is

7 insured and their willingness to use new

8 medications for this group, in thinking about my

9 population from New Mexico which is a rural

10 population with lots of Hispanics and Native

11 Americans, I guess, again, again going back to the

12 American study, I am concerned that it doesn\'t

13 represent what the American alcoholic is like.

14 It seems that the issue is really what is

15 shown by the European studies and I also concur

16 that they do appear to show efficacy.

17 DR. OREN: Let\'s go down to the other side

18 of the table. Dr. Leon?

19 DR. LEON: I have expressed my concerns

20 about the methodology, the prospective\--I mean,

21 getting to the home-run analogy, I feel like the

22 fence was moved after the ball landed, as you have

23 heard me say that many times today.

24 So I vote against it. I think there is a

25 need for another study with more rigorous,

279

1 prospectively defined\--that is, defined before the

2 first subject is enrolled\--more rigorous

3 methodology using the assessment procedures of the

4 U.S. study.

5 DR. OREN: Dr. Keck?

6 DR. KECK: I am not going to use the

7 baseball analogy. I am actually going to limit my

8 remarks because they have already been well

9 expressed by Drs. Fuller and O\'Brien. I will vote

10 in the affirmative.

11 DR. OREN: Dr. Hamer?

12 DR. HAMER: I hate to disagree slightly

13 with my colleague Dr. Leon, but in terms of the

14 prespecified endpoint, I am reminded of an incident

15 four or five or six years ago in cardiorenal in

16 which a clinical trial was stopped early because so

17 many fewer patients were dying with placebo than

18 with drug and then the sponsor had a great deal of

19 trouble getting it approved because death was not a

20 prespecified endpoint.

21 We need to be rigorous, but I think we

22 need to put a great deal of thought into it. I

23 especially complemented the FDA reviewers earlier

24 in person and I want to complement them publicly on

25 the absolutely thorough coherent job they did with

280

1 this material. My vote would be in favor of

2 efficacy.

3 DR. OREN: Dr. Winokur?

4 DR. WINOKUR: I also vote in favor of

5 efficacy based on the European studies. I echo all

6 the comments about the extremely high quality of

7 their review and presentation by the FDA reviewers.

8 I guess my other comment is, even though

9 I, and many of us, have stated the opinion that the

10 data available do meet our standards for

11 demonstration of efficacy, it is also clear, and

12 especially in the discussion of the U.S. trial,

13 that there is an awful lot more to be learned. I

14 would hope that the sponsor and the investigators

15 in the field would continue to work forward to

16 understand more about the complex variables that

17 are related to effective use of this agent.

18 DR. OREN: Dr. Malone?

19 DR. MALONE: I think everything taken

20 together, I would say that it seems to be

21 efficacious in the sample who undergo detox and are

22 abstinent at the time of starting the drug. But I

23 think, for other samples, you don\'t have any data

24 for efficacy. So, for that one sample. And the

25 American sample might really end up being different

281

1 because maybe the alcohols in the United States

2 tend to use what seemed, from the data, a lot of

3 drugs and they are not going to be abstinent when

4 they start taking the medicine.

5 DR. OREN: Actually, we will come to

6 samples as a part of our last question.

7 Dr. Rudorfer?

8 DR. RUDORFER: I would like echo what Dr.

9 Malone just said. I am troubled by the American

10 study in that it seems to have been the best

11 conducted one and I think Dr. McCormick used the

12 term this morning about the targets of the drug,

13 were it to be approved and the U.S. study actually

14 consisted of the real targets.

15 Having said that, I am persuaded that at

16 least two of the European studies did show efficacy

17 under narrowly defined conditions. Patients who

18 were medically detoxified, and even if it is hard

19 to do inpatient nowadays in the U.S., it can be

20 done on an outpatient basis and people who were

21 abstinent on entry to the study, I believe did

22 benefit from the drug. So, overall, I would vote

23 in the affirmative.

24 DR. OREN: For my vote, just so Dr. Leon

25 won\'t be alone, I will join you in voting in the

282

1 negative although that is the minority vote. I

2 think that it is not unreasonable to hold a drug to

3 current standards even if the data are from the

4 past. About fifteen years ago, I bought a

5 townhouse from a chronic alcoholic who was one of

6 the designers of the Challenger space shuttle that

7 crashed. If we were trying to evaluate a new

8 proposal for a space-shuttle design and we were

9 being submitted with the original standards because

10 they were good enough in that time, I am sure that

11 we would not accept that because we have learned

12 something since then.

13 I think it behooves us to try and take the

14 latest knowledge and use it and make the best

15 possible use of it. So, although the narrow

16 circumstances of the European studies, I hear them,

17 I am not fully persuaded by them.

18 Having said that, if the FDA

19 were\--clearly, there is a strong sense of a

20 majority opinion to encourage the FDA to approve

21 the drug, my encouragement, and this was be the

22 segue into the last question for us to talk about

23 which is do the data support any conclusions

24 regarding subgroups, I didn\'t hear the sponsors

25 describe the drug as being a home-run hitter.

283

1 It wasn\'t described as a panacea. It

2 wasn\'t a lithium, a penicillin, a fluoxetine. So I

3 think it would be very important that, if the drug

4 were to be approved, that the indications for it be

5 very clearly identified and we should talk about

6 what those indications might be.

7 I would encourage, certainly, the FDA to

8 not be reticent about describing those indications

9 and not hesitate about the marketing of the drug,

10 that its limited value be not overstated in the

11 marketing.

12 So maybe this would be a good time to turn

13 then to the last question which is do the data

14 support any conclusions regarding subgroups and

15 this might give the FDA some guidance in\--

16 MS. TITUS: I just want to do a formal

17 vote into the record so there are no phone calls

18 back to me later on what the formal vote was. It

19 was eight yesses, two nos and, of the eight yesses,

20 there were several conditions attached to that

21 which you will see in the transcript when it comes

22 through.

23 DR. OREN: Okay. On the last question,

24 does anybody want to offer some comments or

25 suggested answers

284

1 Dr. Hughes?

2 DR. HUGHES: I think it would be very

3 important that the FDA replicate the analyses on

4 the 4500. I thought the way the FDA went through

5 the different hypotheses of subgroups, is it

6 severity, is it behavior therapy, is it motivation,

7 is it abstinence, et cetera, that if we did that

8 same sort of analysis with this larger sample size,

9 that would be a very good way to decide on any

10 subgroups.

11 DR. WINCHELL: We would need that efficacy

12 data. We do have the integrated safety data but I

13 don\'t believe we have got the efficacy data.

14 DR. McCORMICK: We do have the efficacy

15 data on the three European studies that we have

16 been discussing, so that would be feasible.

17 DR. HUGHES: I guess, since I am not a

18 member of anything, I would really encourage Lipha

19 to provide the data of the 4500 patients so that

20 you can replicate that or perhaps some third

21 disinterested party could replicate that, I think

22 would be very important because I think that is

23 your best data source for deciding whether or not

24 to restrict the use to a subgroup.

25 DR. OREN: Dr. Leon?

285

1 DR. LEON: A point of clarification. I

2 know in one of these documents, it not only

3 mentioned that the indication was for the

4 maintenance of abstinence but also for they

5 recommended one year of treatment. Is that part of

6 this vote, or part of this discussion? It is?

7 Okay. I just want to point out, in my looking at

8 the data which I did, I notice that actually none

9 of the trials treated anyone for a full year. One

10 of them came close, 48 weeks.

11 That was the PRAMA trial. In that, only

12 79 subjects out of the subjects who were enrolled,

13 on active medication completed the trial. So I

14 don\'t think there is a lot of data there supporting

15 one year of treatment.

16 There is actually no data there supporting

17 one year of treatment and there are 79 subjects

18 that went 48 weeks.

19 DR. HUGHES: If I could comment on that.

20 It is often with medications, physicians use longer

21 durations than are labeled, so, especially with

22 drug-dependent patients in which oftentimes many

23 clinicians feel like a longer duration is

24 warranted, I would hope there would be some

25 flexibility around that duration because I know, in

286

1 my field, I have done a lot.

2 There was, early on, a statement that you

3 should not use agonist therapy beyond a certain

4 point, should not do this. I think that has been

5 somewhat harmful to field. I would rather see use

6 beyond some point at the discretion of the

7 prescribing physician.

8 DR. OREN: Dr. Rudorfer?

9 DR. RUDORFER: Just another comment and

10 then maybe a question to the FDA related to that.

11 We are specifically not addressing safety issues at

12 this meeting but, in real life, if the drug were

13 approved, of course, physicians would need to

14 consider the benefit-to-risk ratio which I would

15 assume that issues like duration of treatment

16 should be considered at that time.

17 So, for instance, if there are adverse

18 effects that only appear after six or eight or ten

19 months, then that may well influence the length of

20 treatment.

21 DR. McCORMICK: You are absolutely right.

22 We are looking at that and will have that

23 information within the next few weeks.

24 DR. OREN: Two of the predictors, or

25 positive predictors, of good response from the drug

287

1 were someone being detoxified before starting the

2 use of it and being committed to abstinence. Does

3 the committee accept these particular subgroups and

4 should this be something that the FDA should,

5 perhaps, encourage in its labeling or in terms of

6 marketing or indications?

7 Dr. O\'Brien?

8 DR. O\'BRIEN: The one about abstinence is

9 something which is physiological. You can think of

10 a lot of other situations in which a recommendation

11 about the use of a drug is dependent upon a

12 particular state that someone is in. So I think it

13 is pretty clear-cut and you can even verify it with

14 the appropriate tests.

15 The one about the motivation is much more

16 difficult because, with all due respect to the

17 questionnaires that were used, no one would really

18 expect that an alcoholic or any other person who

19 has been diagnosed with a substance-use disorder

20 has any consistent level of motivation.

21 We actually have motivational scales that

22 we use that would get at it more specifically, but

23 ambivalence is one of the hallmarks of this

24 disorder so that a person may tell you one minute

25 that, I am totally motivated to be abstinent for

288

1 the rest of my life and walks out of your office

2 and starts drinking again.

3 This happens all the time. It is not that

4 they were lying in one case. It is just that they

5 are impulsive and things change. So I am not so

6 sure that we would gain very much by that, but I am

7 in favor of recommending that people not use the

8 drug until they achieve abstinence and then it is a

9 drug for maintaining abstinence rather than helping

10 to induce abstinence.

11 DR. OREN: Dr. Malone?

12 DR. MALONE: It seemed also from that data

13 that they would have to be abstinent from other

14 substances, so it wouldn\'t just be alcohol. You

15 shouldn\'t be abusing other substances, it seemed to

16 me, at least, comparing the American and European

17 data, that was one of the key differences, was

18 using other substances.

19 DR. OREN: Dr. Winokur?

20 DR. WINOKUR: Just to reinforce that, I

21 think it is important to point out that the only

22 data that we had a chance to look at where we did

23 see efficacy was under circumstances where

24 abstinence was the case at the time of instituting

25 treatment, and the study that didn\'t go that way,

289

1 there was a more complicated situation.

2 So, until we have other data to broaden

3 our understanding, that really has to be the

4 starting point.

5 DR. OREN: Dr. O\'Brien?

6 DR. O\'BRIEN: I think it has been

7 mentioned but it might be worth highlighting that I

8 believe that one of the studies that most people

9 would\--that was negative in Europe was the U.K.

10 study where there was a lot of nonabstinence when

11 they started on the medication. So, in a sense,

12 that certainly supports the conclusion that might

13 draw from the American study and it suggests sort

14 of two-for-two, when they were not abstinent, the

15 results were not better than placebo.

16 DR. OREN: Any additional comments from

17 the committee? Do the FDA staff want us to address

18 any other particular aspects?

19 DR. McCORMICK: No. I would like to thank

20 you. This discussion this afternoon has been

21 extremely helpful for us. You have answered,

22 really, all the questions that we have had. Thank

23 you.

24 DR. OREN: I would like to thank the

25 public who has been here for us, the sponsor for

290

1 presenting their data and, of course, all of

2 members of the committee for your time. I will

3 call this meeting to adjournment. Thank you.

4 \[Whereupon, 4:00 p.m., the meeting was

5 adjourned.\]

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