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
Hilton
2
PARTICIPANTS
DRUG SAFETY AND RISK MANAGEMENT ADVISORY
COMMITTEE:
Peter A. Gross M.D., Chairman
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.
3
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.
4
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
5
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
6
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
7
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
8
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
9
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
10
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.
11
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
12
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
13
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
14
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