1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

DRUG SAFETY AND RISK MANAGEMENT

ADVISORY COMMITTEE

IN JOINT SESSION WITH THE

DERMATOLOGIC AND OPHTHALMIC DRUGS

ADVISORY COMMITTEE

Thursday, February 26, 2004

8:00 a.m.

Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland 20877

PARTICIPANTS

DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE:

Peter A. Gross M.D., Chairman

Shalini Jain, PA-C, M.B.A., Executive Secretary

Michael R. Cohen, R.Ph., M.S., D.Sc.

Stephanie Y. Crawford, Ph.D., M.P.H.

Ruth S. Day, Ph.D.

Jacqueline S. Gardner, Ph.D., M.P.H.

Arthur A. Levin, M.P.H.

Robyn S. Shapiro, J.D.

Brian L. Strom, M.D., M.P.H.

DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY

COMMITTEE:

Roselyn E. Epps, M.D.

Robert Katz, M.D.

Paula Knudson, Consumer Representative

Sharon S. Raimer, M.D.

Eileen W. Ringel, M.D.

Kathleen Y. Sawada, M.D.

Jimmy D. Schmidt, M.D.

Elizabeth S. Whitmore, M.D.

Michael G. Wilkerson, M.D.

CONSULTANTS (Voting):

Wilma F. Bergfeld, M.D.

Michael E. Bigby, M.D.

Margaret Honein, Ph.D., M.P.H.

Arthur H. Kibbe, Ph.D.

Sarah Sellers, Pharm.D.

Amarilys Vega, M.D., Ph.D.

Jurgen Venitz, M.D., Ph.D.

GUEST SPEAKER (Non-Voting):

Richard K. Miller, Ph.D.

PARTICIPANTS (Continued)

FDA STAFF:

Jonca Bull, M.D.

Steven Galson, M.D., M.P.H.

John Jenkins, M.D.

Sandra Kweder, M.D.

Paul Seligman, M.D., M.P.H.

Anne Trontell, M.D., M.P.H.

Jonathan Wilkin, M.D.

C O N T E N T S

PAGE

Call to Order and Introductions, Peter Gross, M.D.5

Conflict of Interest Statement,

Shalini Jain, PA-C, M.B.A., Executive Secretary 7

Effectiveness of the Isotretinoin Risk Management

Program for the Prevention of Fetal Exposure to

Accutane and its Generic Equivalents and

Consideration of whether Changes

to this Isotretinoin Risk Management Program would

be Appropriate:

Charge to the Committees, Steven Galson, M.D.,

M.P.H., Acting Director, CDER 12

Background and Regulatory History,

Jill Lindstrom, M.D., Division of Dermatologic

and Dental Drug Products, FDA 15

Questions to the Speaker from Committee 49

Open Public Hearing:

Robert A. Silverman, M.D. 68

Sidney Wolfe, M.D.,

Public Citizen Research Group 74

Curt D. Furberg, M.D., Ph.D. (Letter Read by

Dr. Sherri Shubin, M.D., MPH 83

Hoffmann-La Roche, Inc. Presentations:

Introduction, Joanna Waugh, Group Director,

Regulatory Affairs 90

Benefit/Risk, Martin H. Huber, Vice President,

Global Head Drug Safety Risk Management 94

Regulatory Overview, Joanna Waugh 96

C O N T E N T S (continued)

PAGE

Overview of the S.M.A.R.T. Program,

Susan Ackermann Shiff, Ph.D., Global Head Risk

Management, Drug Safety Risk Management 101

Evaluation of S.M.A.R.T. Program,

Martin H. Huber, M.D., Vice President,

Global Head Drug Safety Risk Management 116

Generic Firms' Presentations:

Isotretinoin Risk Management Program, Background

Information, Frank R. Sisto, Vice President,

Corporate Regulatory Affairs,

Mylan Laboratory, Inc. 140

Isotretinoin Survey, Allen A. Mitchell, M.D.

Slone Epidemiology Center, Boston University 152

Isotretinoin Enhanced Risk Management Program,

Program Elements for which Advisory Committee

Input is Requested, Robert W. Pollock, Vice

President, Lachman Consultant Services, Inc. 169

Questions to Roche and Generic Firms from Committee

174

Isotretinoin Pregnancy Exposure: Spontaneous

Reports 1 Year Pre- and 1 Year Post-Risk

Management Program,

Marilyn Pitts, Pharm.D.,

Office of Drug Safety, FDA 218

Isotretinoin Pregnancy Prevention Program

Evaluation,

Allen Brinker, M.D., M.S.,

Office of Drug Safety, FDA 237

Kaiser Presentation, Richard A. Wagner, Pharm.D.,

Kaiser Permanente Drug Use Management 265

Questions to Kaiser from the Committee 289

C O N T E N T S (Continued)

PAGE

Organization of Teratology Information Services,

Interim Report, North American Isotretinoin

Information and Survey Line, Richard Miller,

Ph.D., University of Rochester 296

Questions to OTIS from the Committee 313

Risk Management Options for Pregnancy Prevention,

Kathleen Uhl, M.D., Pregnancy Labeling Team, FDA 321

Selecting Risk Management Tools: Considerations and

Experience, Anne Trontell, M.D., M.P.H. Deputy

Director, Office of Drug Safety, FDA 338

Questions to Speakers from the Committee 366

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

2 Call to Order and Introductions

3 DR. GROSS: Good morning. I am Dr. Peter

4 Gross. I am Chair of the Drug Safety and Risk

5 Management Advisory Committee. I would like to

6 thank you all for coming this morning, and the

7 first order of business is for us to go around the

8 room and introduce everybody at the table. So, I

9 am Dr. Peter Gross. I am Chair of the Department

10 of Internal Medicine at Hackensack University

11 Medical Center and New Jersey Medical School.

12 MS. JAIN: Shalini Jain, Executive

13 Secretary, FDA, Center for Drug Evaluation and

14 Research.

15 DR. WILKERSON: Michael Wilkerson, MD.,

16 private practice, Tulsa, Oklahoma.

17 DR. RINGEL: Eileen Ringel, I am in

18 private practice in Waterville, Maine.

19 DR. DAY: Ruth Day, I direct the Medical

20 Cognition Laboratory at Duke University and I am on

21 the Drug Safety and Risk Management Committee.

22 DR. KIBBE: Art Kibbe, Chairman of the

1 Pharmaceutical Sciences Department, Wilkes

2 University School of Pharmacy and Chairman of the

3 Pharmaceutical Sciences Advisory Committee to the

4 FDA.

5 DR. GARDNER: Jackie Gardner, Professor of

6 Pharmacy, University of Washington, and Drug Safety

7 and Risk Management Advisory Committee.

8 DR. KATZ: Robert Katz, I am in private

9 practice in Rockville, Maryland, and Clinical

10 Assistant Professor of Dermatology at Georgetown

11 University.

12 DR. SELLERS: Sarah Sellers, Pharm.D. I am

13 a Masters in Public Health Candidate at Bloomberg

14 School of Public Health.

15 DR. TRONTELL: Anne Trontell, Deputy

16 Director of the Office of Drug Safety in the FDA

17 Center for Drugs.

18 DR. SELIGMAN: Paul Seligman, Director of

19 the Office of Pharmacoepidemiology and Statistical

20 Science, also in the Center for Drugs at the FDA.

21 DR. WILKIN: Jonathan Wilkin, Director of

22 the Division of Dermatologic and Dental Drug

1 Products in CDER, FDA.

2 DR. BULL: Good morning. Jonca Bull,

3 Director, Office of Drug Evaluation V in the Office

4 of New Drugs, Center for Drug Evaluation and

5 Research.

6 DR. KWEDER: Sandra Kweder, Deputy

7 Director of Office of New Drugs in CDER.

8 DR. GALSON: Steve Galson, I am the Acting

9 Director of the Center for Drug Evaluation and

10 Research.

11 MR. LEVIN: Art Levin, I am the consumer

12 representative on the Drug Safety Committee.

13 DR. SAWADA: Kathleen Sawada,

14 dermatologist, private practice in Lakewood,

15 Colorado.

16 DR. VENITZ: Jurgen Venitz, Associate

17 Professor, Virginia Commonwealth University and

18 Chair of the Clinical Pharmacology Subcommittee.

19 DR. STROM: Brian Strom, I am Chair of the

20 Department of Biostatistics and Epidemiology at the

21 University of Pennsylvania School of Medicine, and

22 I am a member of the Drug Safety and Risk

1 Management Committee.

2 DR. BERGFELD: I am Wilma Bergfeld,

3 dermatologist and dermatopathologist, head of

4 Clinical Research Department of Dermatology at the

5 Cleveland Clinic.

6 DR. RAIMER: Sharon Raimer, Chairman of

7 Dermatology at the University of Texas in

8 Galveston.

9 MS. KNUDSON: Paula Knudson, I am the IRB

10 administrator for the University of Texas at

11 Houston, and I am with the Dermatology Advisory

12 Committee.

13 DR. BIGBY: I am Michael Bigby. I am a

14 dermatologist at Beth Israel Deaconess Medical

15 Center and Harvard Medical School.

16 DR. HONEIN: I am Peggy Honein. I am an

17 epidemiologist with the Birth Defects Center at the

18 Centers for Disease Control and Prevention.

19 DR. COHEN: Mike Cohen, I am a pharmacist

20 with the Institute for Safe Medication Practices,

21 and I am with the Drug Safety and Risk Management

22 Advisory Committee.

1 DR. WHITMORE: Beth Whitmore, I am in

2 private practice in Wheaton, Illinois.

3 DR. SHAPIRO: Robyn Shapiro, I am

4 Professor and Director of the Center for the Study

5 of Bioethics at the Medical College of Wisconsin,

6 and I am on the Drug Safety and Risk Management

7 Advisory Committee.

8 DR. EPPS: Roselyn Epps, Chief of the

9 Division of Dermatology in Children's National

10 Medical Center, and also a member of the

11 Dermatologic and Ophthalmic Drugs Advisory

12 Committee.

13 DR. SCHMIDT: I am Jimmy Schmidt, in

14 clinical practice from Houston, Texas and I am on

15 the clinical faculty of University of Texas and

16 Baylor Medical School.

17 DR. CRAWFORD: Good morning. Stephanie

18 Crawford, Associate Professor, University of

19 Illinois at Chicago College of Pharmacy, and I am a

20 member of the Drug Safety and Risk Management

21 Advisory Committee.

22 DR. GROSS: Thank you all, and now I would

1 like to ask Shalini Jain to read the conflict of

2 interest statement.

3 Conflict of Interest Statement

4 MS. JAIN: The following statement

5 addresses the issue of conflict of interest with

6 respect to this meeting, and is made a part of the

7 record to preclude even the appearance of such at

8 this meeting.

9 The topics to be discussed at today's

10 meeting are matters of broad applicability. Unlike

11 issues before a committee in which a particular

12 sponsor's product is discussed, issues of broad

13 applicability involve many sponsors and their

14 products. All FDA participants have been screened

15 for their financial interests as they may apply to

16 the products and companies that could be affected

17 by the committee's discussions.

18 Based on this review, it has been

19 determined that there is no potential for an actual

20 or apparent conflict of interest at this meeting,

21 with the following exception: In accordance with

22 18 U.S.C. 208(b)(3), Dr. Ruth Day has been granted

1 a waiver that permits her to participate fully.

2 A copy of the waiver statement maybe

3 obtained by submitting a request to the Food and

4 Drug Administration's Office of Management

5 Programs, Division of Freedom of Information,

6 HF1-35 5600 Fishers Lane, Rockville, Maryland

7 20857.

8 Because issues of broad applicability

9 involve many sponsors and their products, it is not

10 prudent to recite all potential conflicts of

11 interest as they may apply to each member,

12 consultant and guest speaker. In addition, there

13 will be no industry representatives at today's

14 meeting. As you may be aware, the Food and Drug

15 Administration has appointed industry

16 representatives that currently serve on each of

17 these committees but Annette Stemhagen, Dr.PH., the

18 industry representative to the Drug Safety and Risk

19 Management Committee, and Peter Kresel, M.B.A., the

20 industry representative to the Dermatologic and

21 Ophthalmic Drugs Advisory Committee, work with

22 sponsors that are directly impacted by the matters

1 before the committee. FDA has contacted three

2 industry representatives from other Center for Drug

3 Evaluation and Research committees that have

4 experience with risk management issues and with FDA