Department of health and human services food and drug administration

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Thursday, February 26, 2004

8:00 a.m.

Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland 20877

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.


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.
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.
Richard K. Miller, Ph.D.


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.

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)
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

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


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)
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
5 advisory committee processes. However, none were
6 available to participate in this meeting. Dr.
7 Stemhagen and Mr. Kresel are present in the
8 audience and attending as interested observers.
9 Further, we would like to note that Dr.
10 Louis Morris, a member of the Drug Safety and Risk
11 Management Committee, has been recused from
12 participating in today's meeting. Dr. Morris is
13 also present in the audience and attending as an
14 interested observer.
15 We would like to remind the FDA
16 participants not to discuss the issues at hand
17 outside the advisory committee meeting. In the
18 event that the discussions involve any other
19 products or firms not already on the agenda for
20 which FDA participants have a financial interest,
21 the participant's involvement and exclusion will be
22 noted for the record. With respect to all other

1 meeting participants, we ask in the interest of

2 fairness that they address any current or previous
3 financial involvement with any firm whose product
4 they wish to comment upon. Thank you.
5 DR. GROSS: Thank you. The topic for
6 discussion for the next two days is the
7 effectiveness of the isotretinoin risk management
8 program for the prevention of fetal exposure to
9 Accutane and its generic equivalents, and to
10 consider whether changes to this risk management
11 program would be appropriate. Dr. Steven Galson
12 will give our committees the charge. He is Acting
13 Director of the Center for Drug Evaluation and
14 Research.

15 Charge to the Committees

16 DR. GALSON: Thank you very much, Dr.
17 Gross. I want to thank all of the committee
18 members for being here. Your commitment to public
19 service, indicated by the time commitment that you
20 have agreed to make to this subject, is extremely
21 important for the Food and Drug Administration and,
22 indeed, very important for all the patients taking

1 this drug and our decision-making process.

2 Today and tomorrow you are going to hear
3 details about the regulatory history of
4 isotretinoin. You are going to review data that
5 has been collected over the last few years about
6 the Pregnancy Prevention Program, and you are going
7 to help us by giving us advice about where this
8 program should go in the future. These
9 perspectives are extremely important to us. We can
10 spend a lot of time talking to each other and
11 tossing ideas around about what is the best course
12 of action but when we have outside observers who
13 have taken a fresh look at these programs it is
14 enormously helpful to us as we move down the path
15 to make decisions.
16 Isotretinoin has been on the market for
17 about 22 years and it may take the record for the
18 single drug with the most advisory committee
19 meetings. I don't know if that is true but it is
20 certainly very close. When Roche established the
21 current S.M.A.R.T. program in consultation with the
22 FDA in 2001, the agency established several goals

1 for the program. They were that no person should

2 begin isotretinoin therapy if pregnant and that no
3 pregnancy should occur while a woman is taking
4 isotretinoin.
5 I want to just note that although those
6 were the goals, the agency is very cognizant of the

7 fact that setting a zero goal as a metric for

8 something that really depends on human behavior for
9 success and is probably not possible to attain. It
10 is good to set that goal but when these issues are
11 totally out of the control of manufacturers,
12 physicians or the agency it is really impossible to
13 actually meet that, and we have been criticized for
14 saying our goal is zero. I want to make it clear
15 that we recognize that it is probably not
16 attainable but we still think it is important to
17 set these important goals because it helps us set
18 the stage for figuring out what steps we want to
19 take and we think that is very important.
20 Setting these goals and establishing
21 metrics to get there is very consistent with one of
22 the evolving foundations of CDER's risk management

1 program which is that risk management programs must

2 be periodically evaluated for effectiveness.
3 Efficiency in risk management is very important
4 and, without measuring the effectiveness of the
5 program and knowing whether we are getting adequate
6 preventive power for the resources devoted we
7 really don't know where to go in the future with
8 this program, and it doesn't help us in terms of
9 establishing and setting up new programs for
10 additional drugs.
11 Manufacturers of isotretinoin have been
12 challenged by the agency to work together to
13 minimize adverse events related to this drug, and
14 we are really extremely heartened by the degree of
15 collaboration that has taken place to date and by
16 the way the manufacturers are working together to
17 look towards the future. We really expect this
18 collaboration to continue and we think that the
19 goal of minimized the teratogenic risk of this drug

20 is something that we all share with all the

21 manufacturers and we, again, want to congratulate
22 and are very heartened by the degree to which these

1 groups have been working together. We look forward

2 to hearing about how the S.M.A.R.T. program has
3 worked and how the companies have been working in
4 detail together.
5 I want to just talk about the committee
6 now. We ask you to really remain focused on the
7 purpose of this meeting, the risk management
8 program for the prevention of fetal exposure. We
9 are aware that there are other important safety
10 issues related to this drug but we really are going
11 to focus on prevention of fetal exposure in this
12 meeting. We would like you to consider the data
13 presented. We want you to consider the past risk
14 management programs and their achievements, and we
15 are really looking forward to your recommendations
16 as to whether the program, as it now exists, should
17 continue; whether it is as effective as it could
18 be; and how we should enhance it or establish new
19 or different tools. So, with that I will close and
20 pass it back to the Chair. Thank you very much.
21 We are looking forward to a great meeting.
22 DR. GROSS: Thank you, Dr. Galson. You

1 are keeping us on time, setting a high target. The

2 next speaker is Jill Lindstrom, a medical officer
3 for the Division of Dermatologic and Dental Drug
4 Products at the FDA, who will talk about the
5 background and regulatory history of this
6 medication.
7 Background and Regulatory History
8 DR. LINDSTROM: Good morning.
9 [Slide]
10 My objectives this morning are to set for
11 you a clinical context for the use of isotretinoin;
12 to outline the history of risk management efforts

13 for this drug; to describe the current risk

14 management plan in some detail; and to provide the
15 committee with some rough guidelines for their
16 assessment of the data that will be presented.
17 [Slide]
18 Isotretinoin is an oral retinoid that is
19 indicated for the treatment of severe recalcitrant
20 nodulocystic acne. It is the only drug moiety
21 approved for this indication, although there are
22 other oral related products in development. The

1 innovator was approved in 1982 and three generic

2 products have recently entered the market.
3 [Slide]
4 This patient has nodular acne, a
5 devastating disease that can result in significant
6 scarring and permanent disfigurement. You can see
7 that he has many lesions, to include large
8 fluctuant nodules on his forehead, his cheeks, his
9 chin and his nose.
10 [Slide]
11 This patient also has nodular acne and,
12 again, you can see the many lesions on his face,
13 the large fluctuant nodules extending down onto his
14 trunk.
15 [Slide]
16 This is the same patient, a view of his
17 back.
18 [Slide]
19 Again, a view of that patient's face prior
20 to isotretinoin therapy--
21 [Slide]
22 --and following conclusion of a course of

1 isotretinoin therapy--he is dramatically improved.

2 [Slide]
3 And a third clinical example of a patient
4 with severe nodular acne. Again, you can see the
5 nodules, sinus track formation and scarring. This
6 is the patient prior to a course of isotretinoin
7 therapy--
8 [Slide]
9 --and at completion of his course of
10 therapy.
11 [Slide]
12 Because of its unique effectiveness,
13 current practice standards have expanded the use of

14 isotretinoin to the setting of non-nodular but

15 still scarring acne.
16 [Slide]
17 This patient does not have nodules, does
18 not have classic nodular acne. She has severe
19 papulopustular acne and her disease is scarring.
20 You can also imagine that, in addition to the
21 cutaneous morbidity, she has significant
22 psychosocial morbidity from her disease. This is

1 her presentation prior to treatment with

2 isotretinoin--
3 [Slide]
4 --and her result at conclusion of therapy.
5 [Slide]
6 And a second patient, again without
7 nodular acne but with severe scarring papular acne.
8 This is a front view--
9 [Slide]
10 --and a side view prior to treatment with
11 isotretinoin--
12 [Slide]
13 --and the patient's result at conclusion
14 of therapy, again dramatically improved.
15 [Slide]
16 Now, isotretinoin is unique among the
17 therapies in the acne armamentarium in that it
18 addresses all four of the known pathogenetic
19 mechanisms of acne. It decreases sebum production
20 and shrinks the size of the sebaceous glands. It
21 normalizes follicular hyperkeratinization and
22 reduces follicular plugging. It decreases P. acnes

1 colonization, although not through a direct

2 antibacterial mechanism but probably through making
3 the micro climate of the follicle inhospitable to
4 the organism. Finally, it is mildly
5 anti-inflammatory.
6 [Slide]
7 These events can be seen in this
8 histological specimen, this biopsy of a comedo
9 prior to isotretinoin therapy. You can see the
10 dilated follicle filled with keratinous debris, the
11 large sebaceous glands. Not well appreciated in
12 the black and white photograph is the
13 perifollicular inflammation and the numerous

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