DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
DRUG SAFETY AND RISK MANAGEMENT
IN JOINT SESSION WITH THE
DERMATOLOGIC AND OPHTHALMIC DRUGS
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
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.
GUEST SPEAKER (Non-Voting):
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.
C O N T E N T S
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
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
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
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
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
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.
DR. KIBBE: Art Kibbe, Chairman of
1 Pharmaceutical Sciences Department, Wilkes
2 University School of Pharmacy and Chairman of the
3 Pharmaceutical Sciences Advisory Committee to the
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
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
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
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
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,
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
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
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
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
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
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.
DR. GROSS: Thank you all, and now
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
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
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
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
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
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,
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
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
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
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
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.
DR. GROSS: Thank you, Dr.
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
7 Background and Regulatory History
8 DR. LINDSTROM: Good morning.
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.
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
other oral related products in development. The
1 innovator was approved in 1982 and three generic
2 products have recently entered the market.
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.
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
16 This is the same patient, a view of his
19 Again, a view of that patient's face prior
20 to isotretinoin therapy--
--and following conclusion of a course of
1 isotretinoin therapy--he is dramatically improved.
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
9 --and at completion of his course of
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.
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
psychosocial morbidity from her disease.
1 her presentation prior to treatment with
4 --and her result at conclusion of therapy.
6 And a second patient, again without
7 nodular acne but with severe scarring papular acne.
8 This is a front view--
10 --and a side view prior to treatment with
13 --and the patient's result at conclusion
14 of therapy, again dramatically improved.
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
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
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
14 bacteria in the follicle.
16 In a biopsy of a follicle following
17 isotretinoin therapy the sebaceous glands--again, I
18 regret that I don't have a pointer but the
19 sebaceous glands are much smaller in size; the
20 follicular lumen is narrow. There is no follicular
21 plugging and there is an absence of perifollicular
2 Isotretinoin is also unique in that a
3 course of therapy is temporally circumscribed.
4 Other anti-acne agents have no long-term impact and
5 are effective only while they are being used. A
6 course of isotretinoin, however, can result in
7 complete and prolonged disease remission. Thus,
8 patients with severe scarring acne like the
9 clinical examples that I just showed you prior to
10 the approval of isotretinoin would have faced
11 years, perhaps even decades, of therapy with oral
12 antibiotics in combination with topical agents.
13 Now such patients, after a course of isotretinoin
14 therapy, will see their disease become quiescent
15 and the progression of their disfigurement halted,
16 and they are spared the risk, the expense and the
17 inconvenience of years of oral and topical
20 However, isotretinoin does present its own
21 risks. It is a known human teratogen. In utero
exposure to isotretinoin can result in an increased
1 risk of spontaneous abortion and premature births,
2 as well as structural abnormalities. Approximately
3 28 percent of exposed fetuses will have sufficient
4 stigmata at the time of birth to be diagnosed with
5 retinoid embryopathy. Additionally, many babies
6 who are exposed to isotretinoin in utero will
7 appear normal at birth and will go on later in life
8 to manifest neurodevelopmental deficits.
10 What has been done to manage this risk?
11 At the time of approval in 1982 it was understood
12 from animal data that isotretinoin was likely a
13 teratogen, and in labeling the drug was classified
14 pregnancy category X. Prescribers and patients
15 were advised in the contraindications, warnings and
16 precautions sections of labeling not to become
17 pregnant while using the drug.
19 The first report of a human malformation
20 following in utero exposure to isotretinoin was
21 published in 1983. In response, red warning
stickers were distributed to pharmacies to be
1 affixed to each isotretinoin prescription that was
2 dispensed. Additional reports of exposed
3 pregnancies were received raising the concern both
4 in the agency and the manufacturer. Multiple "dear
5 doctor" letters were issued to inform the medical
6 community of this risk and the label was revised as
7 information became available.
9 In 1988 the sponsor proposed a
10 multi-tiered program to augment the risk management
11 plan which they entitled the Pregnancy Prevention
12 Program. An advisory committee was convened to
13 review this proposal. There were, as I said,
14 multiple components. First, the label was altered
15 to include warnings printed directly on the
16 package, and the "avoid pregnancy" icon was
17 introduced, the familiar red circle with the slash
18 and the pregnant figure. And, the packaging was
19 changed to blister packaging.
21 The package insert was updated to include
boxed warning informing physicians and patients
1 of a need for a negative pregnancy test seven days
2 before treatment initiation; the importance of
3 using two reliable forms of contraception; waiting
4 to begin therapy until the second or third day of
5 the next menses; and limiting the supply dispensed
6 to 30 days; and the importance of repeating
7 pregnancy testing and contraceptive counseling on a
8 monthly basis.
10 An informed consent form for females was
11 introduced in that program. A kit for prescribers
12 was provided to explain the details of the program,
13 and the first iteration of the voluntary patient
14 survey was introduced at that time. Additionally,
15 there was a tracking survey to assess prescriber
16 use of the program. That advisory committee
17 recommended approval of the Pregnancy Prevention
18 Program and the program was implemented in 1989.
20 What was the impact of the program? It is
21 somewhat difficult to say. From the time of
approval of isotretinoin in 1982 pregnancies have
1 been reported to the agency. At the time of the
2 introduction of the Pregnancy Prevention Program we
3 gained a new tool to gather information about
4 pregnancy reports, the patient survey. Those
5 pregnancy reports are represented by the light blue
6 bars from 1989 on.
7 Both of these reporting mechanisms,
8 spontaneous reports as well as reports through the
9 survey, are voluntary reporting mechanisms and so
10 it is difficult to ascertain an accurate pregnancy
11 rate. I want to remind you that this is a
12 historical view prior to the implementation of the
13 current risk management program, but what we can
14 say is that the public health burden from exposed
15 pregnancies continued to be large.
17 Additionally, during this time or during
18 the '90s Accutane use was increasing significantly.
19 Because of these reasons, the large public health
20 burden from exposed pregnancies as well as the
21 increasing use, an advisory committee was convened
again to consider augmentation of the risk
1 management plan.
3 This advisory committee was convened in
4 September of 2000 and they determined that there
5 was, indeed, a compelling need for augmentation of
6 the risk management plan. The agency agreed and
7 this was communicated to the sponsor in a letter
8 dated October 6, 2000. This letter has been
9 included in the briefing package for the committee.
11 In this letter risk management is
12 addressed from two perspectives, both pregnancy
13 prevention and potential neuropsychiatric adverse
14 events. Pregnancy prevention is the focus of this
15 advisory committee. However, since the letter was
16 included in your packet and does address
17 neuropsychiatric risk management I want to briefly
18 update the committee on the status of risk
19 management efforts with regards to potential
20 neuropsychiatric risk.
Three points of action were
1 the committee and communicated in that letter.
2 First, that the informed consent be amended to
3 inform patients of the potential for
4 neuropsychiatric adverse events, and this has been
5 done. Second, it was advised that an educational
6 program for prescribers be implemented, and this
7 has also been done. Third, it was recommended that
8 a comprehensive research program be undertaken to
9 include clinical trials.
10 The sponsor submitted clinical protocols
11 to investigate neuropsychiatric risk to the agency.
12 When the agency reviewed them and gave the area
13 some additional considered thought it was
14 recognized that more basic science groundwork
15 needed to be done before moving on to clinical
16 trials, and this basic science groundwork is now
17 being undertaken in collaboration with the National
18 Institute for Mental Health. As that data is
19 accrued we will move on at the appropriate time to
20 clinical trials.
21 That is all I am going to say today about
risk management of neuropsychiatric risk. I want
1 to remind both the committee and the public that it
2 is not the subject of this advisory committee.
4 Moving on to pregnancy prevention, also
5 addressed in that letter, two goals, as Dr. Galson
6 already mentioned, were articulated. The first,
7 that no one should begin isotretinoin therapy if
8 they are pregnant and the second, that effective
9 pregnancy prevention would occur throughout the
10 course of isotretinoin therapy. Implied in these
11 two goals is that we would have the ability to
12 assess whether or not they have been achieved.
14 To achieve these two goals, five points of
15 action were advised: augmentation of patient
16 education; registration of all patients;
17 registration of prescribers; implementation of a
18 pregnancy registry; and linkage of prescription
19 dispensing to adequate pregnancy testing.
21 The agency and the sponsor, having heard
committee's recommendations, entered into
1 extensive discussions and negotiations in an
2 attempt to design a plan that would incorporate the
3 five points of action to achieve the two goals that
4 had been articulated.
5 However, obstacles were encountered,
6 particularly regarding patient privacy issues and
7 compliance with the newly passed Health Insurance
8 Portability and Accountability Act. Eventually,
9 however, a plan was crafted and was approved in
10 October, 2001. The innovator was the only product
11 on the market at that time and they named their
12 risk management plan S.M.A.R.T., a System to Manage
13 Accutane-Related Teratogenicity. I will refer to
14 their plan and the subsequent generic risk
15 management plans as the current risk management
16 plan so when I use the term the current risk
17 management plan, you can think of that as
18 interchangeable with S.M.A.R.T., S.P.I.R.I.T,
19 I.M.P.A.R.T., etc.
20 I want to now move and describe how the
21 plan that was crafted sought to incorporate those
five points of action and then I will describe for
1 you the mechanics of the plan in some detail.
3 The first point of action articulated by
4 the committee was a heightened educational program
5 for each patient that included verifiable
6 documented written informed consent. This is
7 fairly straightforward and is a component of the
8 current risk management plan.
10 The second point was complete registration
11 of all patients, both male and female. This was
12 intended to provide the denominator for
13 ascertainment of the pregnancy rate. However,
14 registries raise issues regarding patient privacy.
15 The sponsor proposed an alternative proposal to
16 estimate the denominator using pharmacy databases
17 and survey data. This, of course, would avoid
18 those patient privacy issues but the accuracy of
19 the alternative proposal was dependent on
20 increasing the survey response rate. The sponsor
21 felt that this would be achievable.
1 The third point of action was complete
2 registration and certification of all prescribers.
3 The sponsor objected that they did not have the
4 authority to certify prescribers and so a plan of
5 voluntary registration was devised in which
6 prescribers self-attest that they possess the
7 relevant competencies needed to safely prescribe
8 isotretinoin. Additionally, prescribers singed a
9 commitment to use the current risk management plan.
10 The sponsor does provide prescribers with
11 information about the plan, but the responsibility
12 for obtaining the necessary education to achieve
13 the relevant competencies rests with the
14 prescriber. I will detail these competencies in a
15 few moments.
17 The fourth point of action was a
18 comprehensive plan to track fetal exposures to
19 isotretinoin to include a formal pregnancy
20 registry. This was intended to provide the
21 numerator for ascertainment of the pregnancy rate.
Again, because it involved a registry, it raised
1 concerns regarding patient privacy and issues
2 regarding compliance with the newly passed HIPPA.
3 Again, to avoid these obstacles and to
4 speed the implementation of augmented risk
5 management measures, the sponsor proposed
6 extrapolation of the numerator from survey response
7 data. Accurate extrapolation from survey response
8 data would require an increased survey response,
9 which the sponsor identified as an increased
10 response rate of greater than 60 percent. Now,
11 they did feel that this would be achievable and, in
12 order to achieve the increased rate, they planned
13 targeted education of prescribers to increase
14 awareness of the survey and they increased
15 reimbursement for patient participation by 300
18 The final point of action advised by the
19 committee was the linking of dispensing of
20 isotretinoin to verification of adequate pregnancy
21 testing. This is accomplished in the current risk
management plan through the use of yellow
1 qualification stickers. The physician verifies the
2 negative pregnancy test and fills out the
3 qualification sticker. The patient takes the
4 prescription with the qualification sticker to the
5 pharmacist who then verifies that the patient has,
6 indeed, been qualified. However, in the current
7 plan the pharmacist does not independently review
8 the negative pregnancy test lab report. Pharmacist
9 participation in the current plan is voluntary but
10 encouraged through the way that the plan is
13 I want to take a moment now and describe
14 in some detail the mechanics of how the current
15 risk management plan works. It can be a bit
16 complex if you haven't used it yourself in a
17 clinical setting. The program begins with a
18 physician who decides that they would like to
19 prescribe isotretinoin and that they possess the
20 relevant competencies necessary to do so.
21 The physician will sign a one-time letter
understanding with the manufacturer, attesting
1 that they do possess the necessary knowledge and
2 experience in order to safely prescribe the drug,
3 specifically that they are knowledgeable about the
4 different forms of acne and its treatment; that
5 they are knowledgeable about isotretinoin and its
6 risks for teratogenicity; that they are
7 knowledgeable about the risks for and the
8 prevention of unplanned pregnancy; and finally,
9 that they are knowledgeable about the current risk
10 management plan and that they agree to use its
12 When the manufacturer receives this signed
13 letter of understanding, they then forward to the
14 prescriber the qualification stickers and separate
15 educational materials for both the prescriber as
16 well as for patients. Prescriber educational
17 materials consist of things like best practices
18 guides that inform the prescriber how to use the
19 components of the current risk management plan.
20 Educational materials for patients include things
21 like brochures and videos.
The physician then encounters a patient
1 for whom they believe treatment with isotretinoin
2 is indicated. From this point forward, as I am
3 describing the mechanics when I refer to a patient
4 I am speaking specifically of a female patient.
5 So, when the prescriber encounters a patient for
6 whom isotretinoin is indicated the first thing that
7 they will do, having made the preliminary decision
8 to prescribe the drug, is obtain a screening
9 pregnancy test. They would also provide
10 educational materials to the patient and the
11 informed consent forms, which I will talk about in
12 a minute.
13 Also at this time, contraception
14 counseling and contraception would be provided.
15 This can be accomplished in one of two ways, the
16 prescriber him or herself, if they possess the
17 necessary expertise, can provide the counseling
18 themselves or they can refer to a reproductive
19 health specialist such as a gynecologist for
20 provision of the contraception counseling and the
21 contraception. The female patient, unless they
select complete abstinence, must be on two forms of
1 contraception, at least one of which must be a
2 primary form, for 30 days prior to the initiation
3 of isotretinoin therapy.
4 The patient reads the educational
5 material, obtains the contraception counseling and
6 the contraception and reads through the informed
7 consent documents, signs those and returns them to
8 the physician. There are actually two informed
9 consent documents. The first is an informed
10 consent/patient agreement which is given to both
11 male and female patients. This outlines the risks
12 for teratogenicity, as well as the potential risk
13 for psychiatric adverse events, and also elicits
14 agreement from the patient that they will abide by
15 the risk management principles of the current risk
16 management program, such as that they will not
17 share their isotretinoin with other people; they
18 will not give blood until at least 30 days after
19 the conclusion of their therapy; that they will
20 return to their physician on at least a monthly
21 basis. The second informed consent document is
specific for female patients and goes into much
1 greater detail about the risks of unplanned
2 pregnancy and the risk of teratogenicity with
3 isotretinoin therapy.
4 Both of those informed consent forms and
5 the informed consent/patient agreement need to be
6 signed and returned to the physician.
7 Additionally, before prescribing isotretinoin the
8 physician must obtain a second pregnancy test, this
9 time timed to the woman's cycle within the first
10 five days of the menses or, if the patient is
11 amenorrheic, at least 11 days after the last
12 episode of unprotected intercourse. After these
13 steps have been accomplished the physician then
14 fills out the prescription form, affixes the
15 qualification sticker and fills that out with the
16 date of qualification signifying that two negative
17 pregnancy tests have been obtained; that the
18 patient understands the risk management program;
19 that adequate contraception, either two forms or
20 absolute abstinence, have been initiated.
21 The patient then takes the prescription
with the qualifying sticker affixed and filled out
1 to the pharmacist. The pharmacist verifies that
2 the sticker has been affixed, has been properly
3 completed, and also that the receipt of this
4 sticker and the dispensing of the isotretinoin
5 occur within seven days of the date of the
6 physician's qualification of the patient. If all
7 of those criteria are met the pharmacist dispenses
8 the isotretinoin along with a medication guide
9 which is an information brochure for patients
10 which, by law, must be dispensed each time
11 isotretinoin is dispensed that describes in
12 layman's language the risks of the drug and the
13 steps that need to be taken to minimize those
15 The patient then initiates their course of
16 isotretinoin therapy and on a monthly basis will
17 return to the prescriber to be requalified.
18 Requalification consists of repeating the pregnancy
19 test and verifying that the test is negative;
20 re-counseling the patient regarding contraception;
21 and ensuring that the risk management program is
being abided by.
1 We receive data about the program from
2 several sources, first, spontaneous adverse events
3 reports come to the agency from physicians, the
4 manufacturer, from patients as well as from
5 pharmacists. Additionally, the patient is
6 encouraged to participate in the voluntary patient
7 survey and data is gathered through that mechanism.
8 Finally, pharmacies are surveyed and the
9 prescriptions are audited to check for compliance
10 with the sticker program.
12 The risk management plan, as I have
13 described, was approved for the innovator in
14 October of 2001. Since that time three generic
15 products have been approved and have entered the
16 market. Their risk management plans are identical
17 in the essential elements that I have just
18 described to the innovator plan. So, again, when I
19 speak of the current risk management plan, that
20 would be interchangeable for either the innovator
21 plan or the plan of the three generic products.
1 However, while the four risk management
2 plans are identical in their essential elements and
3 can be considered interchangeable, there are some
4 differences that have caused marketplace confusion.
5 Besides having different trade names for the four
6 drugs, each manufacturer has elected to name their
7 risk management program by a different name so for
8 Accutane with have S.M.A.R.T., the System to Manage
9 Accutane-Related Teratogenicity. For Amnesteem we
10 have S.P.I.R.I.T, the System to Prevent
11 Isotretinoin-Related Issues of Teratogenicity. For
12 Sotret it is I.M.P.A.R.T., Isotretinoin Medication
13 Program Alerting you to the Risks of
14 Teratogenicity. For Claravis it is A.L.E.R.T, the
15 Adverse Event Learning and Education Program
16 Regarding Teratogenicity. Additionally, different
17 survey contractors have been employed by the
18 innovator who uses Degge/SI and the generic firms
19 who all use the Slone Epidemiology Unit. Finally,
20 mid-course changes by the patient's pharmacy
21 provider in brand of isotretinoin dispensed can
result in patient confusion and perhaps multiple
1 enrollment in the voluntary survey.
3 When this current risk management plan was
4 approved the sponsor was instructed to submit a
5 comprehensive report on the metrics of the program
6 after one year of implementation. This advisory
7 committee has been convened to comment on those
8 data. The advisory committee in 2000 did not
9 address benchmarks nor define success. Indeed, to
10 do so is challenging. But at this time I want to
11 provide you with some rough guidelines that you can
12 use as you are thinking about three parameters in
13 particular, the survey response rate, the sticker
14 use and the number of fetal exposures.
16 The survey response rate, by the sponsor's
17 own assertion, would need to be greater than 60
18 percent. The success of the current risk
19 management program in terms of accurate estimation
20 of that numerator for the pregnancy rate is
21 dependent on this higher survey response rate. The
agency's approval of the current risk management
1 plan was based on the sponsor's assertion that they
2 would be able to achieve this threshold.
4 The qualification stickers serve as a
5 surrogate endpoint for the use of the current risk
6 management plan. When the agency approved the plan
7 it was understood that the stickers were an
8 imperfect surrogate and, in fact, as the data has
9 come in they may be more imperfect than we had
10 realized, and other speakers will describe to you
11 the linkage between the stickers and various
12 components of the program such as pregnancy
13 testing. However, at the time of approval the
14 sponsor was informed that because the sticker
15 served as a surrogate, and an imperfect surrogate
16 at that, the threshold for success would be very,
17 very high and, in fact, would approach 100 percent
18 in terms of sticker use.
20 Finally, and perhaps most importantly,
21 fetal exposures--it would be difficult to identify
acceptable number for fetal exposures.
1 considering what success would look like in terms
2 of fetal exposures the committee may want to think
3 of this in parallel with the two goals that were
4 articulated by the 2000 advisory committee, the
5 first goal being that no one initiate isotretinoin
6 therapy if pregnant. This goal, the responsibility
7 for which rests largely on the shoulders of
8 prescribers, may best be achievable.
9 The second goal, that no one become
10 pregnant while on isotretinoin therapy, is more
11 complex because it depends on patient behavior.
12 Again, in considering the threshold of success in
13 terms of fetal exposure you may want to think of
14 these two populations independently, and also in
15 considering what risk management tools would impact
16 these populations you may want to consider them
17 separately as different tools may be appropriate.
19 In summary, isotretinoin is a uniquely
20 effective drug for the treatment of severe,
21 scarring acne, a truly devastating disease. There
been a long history of risk management efforts
1 to prevent fetal exposures to this drug which were
2 built sequentially. The current risk management
3 program has introduced some new tools and the
4 advisory committee is being asked to comment on the
5 effectiveness of these new tools and the current
7 I and my colleagues look forward to
8 hearing your considered input on the data and how
9 we can optimize the public health by ensuring that
10 isotretinoin is available to the patients who
11 needed it in a context that minimizes and best
12 manages the risks. So, I thank you for your
13 attention this morning and I would be happy to take
14 your questions.
15 DR. GROSS: Thank you very much, Dr.
16 Lindstrom. Before the questions, I would like to
17 introduce an additional consultant who will be
18 participating in our joint advisory committee
19 session, Dr. Vega. Dr. Vega, would you please
20 introduce yourself?
21 DR. VEGA: Yes, good morning. I am a
Board-certified pediatrician with a Masters in
1 Public Health and a Fellowship in
2 Pharmacoepidemiology from the Food and Drug
3 Administration. I am also a former medical
4 epidemiologist from the Office of Drug Safety, with
5 extensive experience with the isotretinoin
6 pregnancy prevention issue. I presented at the
7 last advisory committee the data on the different
8 options to modify the Pregnancy Prevention Program.
9 I currently work for PSI International in their
10 adverse event reporting project.
11 Questions from the Committee
12 DR. GROSS: Thank you. Now Dr. Lindstrom
13 will entertain questions from the committees. Yes?
14 DR. CRAWFORD: Dr. Lindstrom, thank you
15 for the overview. In terms of considering possible
16 risk management tools to enhance pregnancy
17 prevention, one thing I am not sure of after
18 reading all the materials we were provided is
19 whether the reasons for failure have been
20 identified. So, has there ever been any thought
21 given to some type of failure mode analysis
determining for those patients who do become
1 pregnant, exactly what went wrong so efforts could
2 be targeted on preventing those failures in the
4 DR. LINDSTROM: That is an excellent
5 question. The speakers that follow will be
6 addressing the data and I believe also, as much as
7 we know, the reasons for failures. So, if you
8 don't mind, I think I will defer the answer to that
9 question to the presentations that will follow
11 DR. GROSS: Dr. Gardner?
12 DR. GARDNER: Dr. Lindstrom, could you
13 give us some idea of the epidemiology of the severe
14 acne for which these drugs are both specifically
15 indicated and also for which they are being used?
16 For example, can you tell us the incidence or even
17 the prevalence of the condition in the population
18 and the distribution by gender and by age, if you
20 DR. LINDSTROM: I will do my best to
21 answer that question. Acne is extremely common,
particularly in the adolescent age range. The
1 incidence has been reported to be 80 percent in the
2 12-20 year-old group and falling to about 3 percent
3 in the over 45 year-old age group. You can sort of
4 extrapolate the decrease during that time.
5 DR. GARDNER: Is that severe acne?
6 DR. LINDSTROM: No, that is all acne.
7 There is not an ICD-9 code for severe acne so it is
8 difficult--I don't actually know and I couldn't
9 find, in preparing for this committee meeting, an
10 incidence or a prevalence for severe acne. I can
11 tell you that recalcitrant nodular acne is not the
12 majority of acne. Severe scarring acne is a larger
13 proportion of acne patients. As a practicing
14 dermatologist, it was not uncommon. I saw scarring
15 acne on essentially a daily basis but I don't have
16 incidence or prevalence figures for you, other than
17 the prevalence of acne in the population at large.
18 DR. GROSS: Sarah Sellers?
19 DR. SELLERS: A quick question on the
20 qualification in the current program, the
21 qualification sticker that goes to the pharmacy has
qualification date on it?
1 DR. LINDSTROM: Yes.
2 DR. SELLERS: And, is that date the date
3 of the confirmed negative test?
4 DR. LINDSTROM: Yes, it is. For
5 initiation of therapy it would be the date of the
6 second confirmed negative pregnancy test and for
7 ongoing therapy it would be the date of the
8 repeated negative pregnancy test.
9 DR. SELLERS: It is not the date that a
10 sample was taken for a pregnancy test?
11 DR. LINDSTROM: No, I believe it is the
12 date--I am sorry, I didn't follow actually your
14 DR. SELLERS: The qualification date is
15 actually when the negative result is received--
16 DR. LINDSTROM: That is my understanding.
17 DR. SELLERS: --not the date a sample is
18 drawn for analysis to go to the lab?
19 DR. LINDSTROM: Correct.
20 DR. SELLERS: Thank you.
21 DR. GROSS: Yes, Robyn??
DR. SHAPIRO: I guess I am curious
1 the HIPPA problem that you have found with some of
2 the registry ideas. Why couldn't the patients
3 simply authorize release of particular information
4 in order for them to get the drug and, therefore,
5 make that information available?
6 DR. LINDSTROM: At the time of the prior
7 advisory committee and at the time that the agency
8 and the sponsor were working to craft the plan,
9 HIPPA had just been approved and towards the end of
10 that time period was being implemented. In working
11 with consul from the company as well as consul
12 within the agency, working out the details of HIPPA
13 compliance proved difficult and while it probably
14 would have been achievable, it was taking a lot of
15 time. So, the sponsor proposed and the agency
16 approved these alternative methods in order to have
17 a plan in a more timely fashion that could be
18 implemented that could augment the risk management
19 program. As understanding of compliance of HIPPA
20 has matured, I think it would be much easier to
21 navigate those waters at this time but at that time
Act had just been passed and was in the process
1 of being implemented and understanding was not yet
3 DR. GROSS: Dr. Bigby?
4 DR. BIGBY: I have two questions. The
5 first one is that you stated that some patients who
6 take Accutane never have acne again. Are you or
7 someone else going to actually tell the committee
8 what the actual numbers are in terms of the
9 long-term efficacy of Accutane?
10 DR. LINDSTROM: What I had hoped to state
11 was that patients may achieve complete and
12 long-term remission. I have read different figures.
13 Approximately 10-20 percent of patients who are
14 treated with Accutane never require treatment with
15 Accutane again. Another way to state that would be
16 that 10-20 percent of patients who undergo a course
17 of isotretinoin therapy do require a second course
18 of isotretinoin therapy. Of the 80-90 percent that
19 only require one course of isotretinoin therapy, a
20 portion of those are then able to be maintained
21 with no treatment at all. A portion would require
only topical therapy and some may require oral
1 antibiotic therapy.
2 DR. BIGBY: I just think that it is
3 important for the committee to know actually what
4 those proportions are and I just hope somebody
5 brings that data to the table.
6 DR. LINDSTROM: I don't have those
7 numbers. All I can tell you is that between 10-20
8 percent of isotretinoin patients do undergo a
9 second course of therapy.
10 DR. BIGBY: Well, those numbers do exist
11 and I just hope it is sort of made known to the
12 committee what those numbers are.
13 The other question I had was of the
14 pregnancies that occurred prior to S.M.A.R.T. and
15 during S.M.A.R.T., is there any data about who the
16 prescribers were?
17 DR. LINDSTROM: I am sorry, can you repeat
18 your question?
19 DR. BIGBY: You presented information
20 about pregnancies that occurred for the year prior
21 to S.M.A.R.T. and during a year of S.M.A.R.T. What
would like to know is who the prescribers of
1 Accutane were for those women who got pregnant.
2 DR. LINDSTROM: Yes, actually I did not
3 present any data about pregnancies during
4 S.M.A.R.T. My objectives at this point of the day
5 were to set the historical context so the slide
6 that I showed was that reported pregnancies to the
7 agency were from 1982 through 1999. Speakers later
8 today will update you with the current pregnancy
9 data, the more recent data during the
10 implementation of the current risk management
12 Now, there were two parts to your question
13 and I only answered half. Can you tell me again
14 the second part of that question?
15 DR. BIGBY: No, you answered it.
16 DR. LINDSTROM: Okay.
17 DR. GROSS: Dr. Michael Cohen?
18 DR. COHEN: Earlier you mentioned that
19 there may occasionally be some confusion between
20 the various risk management programs for
21 isotretinoin that exist and perhaps also the brand
names. Are you saying that that
1 contributes to some of the problem that we are
2 seeing with isotretinoin and the way that it is
3 handled? Also, who actually does the selection?
4 Is it the prescriber or the pharmacist? Is it a
5 substitution that is made? I didn't understand
7 DR. LINDSTROM: In stating the various
8 names and alluding to confusion, my point is just
9 to give the perspective of patients and
10 prescribers. It is a somewhat complex plan and
11 there are various names out there, and to just make
12 the committee aware that that is a potential source
13 of confusion, the multiple names for the risk
14 management plans. I did not mean to imply that
15 there should not be different trade names for the
16 products of the various manufacturers but, rather,
17 that the risk management plan having multiple names
18 does present some confusion for patients. The
19 second part of your question?
20 DR. COHEN: Well, I guess I am a little
21 bit confused about who actually selects the brand
that will be used. You mentioned
1 a patient can go from one brand to another--
2 DR. LINDSTROM: Right.
3 DR. COHEN: --does that contribute to any
4 confusion that we should be concerned about? I
5 understand the plans are pretty much the same.
6 DR. LINDSTROM: Right.
7 DR. COHEN: They have the same baseline
8 requirements but are there any errors that this
9 contributes to that, you know, might have an
10 adverse outcome that we should know about?
11 DR. LINDSTROM: Sure.
12 DR. COHEN: In other words, should there
13 be one plan?
14 DR. LINDSTROM: I think that is an
15 excellent question and one that the committee will
16 need to be considering as the day goes forward.
17 Other speakers will present to you the details of
18 the data that has been obtained from the current
19 risk management plan and will be in a better
20 position to address confusion from the agency's
21 perspective in terms of data collection from
1 As far as whether a patient receives one
2 particular manufacturer's isotretinoin or another,
3 a physician can specify that as they write the
4 prescription but I think in many instances it is
5 the pharmacy provider that makes that determination
6 of which patient receives which brand. So, it is a
7 little bit outside of the prescriber-patient
9 DR. GROSS: Dr. Kweder?
10 DR. KWEDER: Yes, I think I can clarify a
11 little bit. We do not have specific data on the
12 frequency of switching between brands. We have
13 heard for patients and providers that this is a
14 potential source of difficulty but we do not have
15 data saying how common it is for patients to be
16 required to switch mid-course. Just like any
17 medication, the source of imposing a change could
18 be anything from the patient wanting a cheaper
19 brand to the pharmacist pressing for that, or the
20 physician or even the health insurance plan that
21 will only pay a certain amount.
DR. GROSS: Dr. Trontell?
1 DR. TRONTELL: I was going to just
2 elaborate on Dr. Kweder's remarks. We don't yet
3 have any data to document that confusion has
4 occurred between these programs.
5 DR. GROSS: Thank you. Dr. Whitmore, did
6 you have a question?
7 DR. WHITMORE: The answer came up already,
8 thank you.
9 DR. GROSS: Dr. Day?
10 DR. DAY: Was any provision made for
11 providing the risk management plan for mail order
12 prescriptions? I assume that originally Accutane
13 was available through mail order.
14 DR. LINDSTROM: The prior risk management
15 plan did allow for mail order prescriptions. For
16 the current risk management plan, as I understand
17 it, a mail order prescription might be challenging
18 in that the drug needs to be dispensed within a
19 seven-day window of qualification. Not only that,
20 but there are other features of the plan that might
21 not happen. So, it is not allowed.
DR. GROSS: Dr. Honein?
1 DR. HONEIN: I just want to follow-up with
2 some questions on the multiple risk management
3 programs. I wondered if there was any data on how
4 often women get one set of information from a
5 prescriber and a different set of information from
6 the pharmacist at the time it is dispensed, and if
7 there are any reports of that contributing to
9 DR. LINDSTROM: The information that the
10 patient receives from the pharmacist would be the
11 medication guide which would be the same for all of
12 the manufacturers' products, the innovator as well
13 as the generic. The pharmacy has the option of
14 providing additional patient education information
15 that is not part of the current risk management
16 plan that would be in addition to that.
17 DR. HONEIN: Don't they get enrollment
18 forms both from the prescriber and the pharmacy,
19 and wouldn't those be different if they got
20 different sets of material?
21 DR. LINDSTROM: Thank you. That is a good
point. The enrollment forms are
included with each
1 prescription that is dispensed and the enrollment
2 form for the innovator uses one contractor and the
3 enrollment forms for the generics utilize a
4 different contractor so you are correct that that
5 would be another potential source of confusion for
6 a patient.
7 DR. GROSS: Dr. Knudson?
8 MS. KNUDSON: I am curious about the age
9 distribution of the women taking the drug. I would
10 like to know does the enrollment form or the survey
11 form or the qualifying sticker carry the age?
12 DR. LINDSTROM: The qualifying sticker
13 does not. Age may be obtained by the pharmacy as
14 part of an independent pharmacy data collection
15 with age, date of birth and so forth to ensure that
16 the correct prescription is dispensed to the
17 correct patient. Age is a component of the
18 voluntary patient survey.
19 DR. GROSS: Dr. Ringel?
20 DR. RINGEL: This is a quibbling point
21 from the "nothing in life is perfect" department.
mentioned that it should be possible to prevent
1 initiation of isotretinoin therapy before a
2 pregnancy, and there are ways you can actually
3 manage it if you consider that there is a certain
4 number of false-negative pregnancy tests,
5 particularly early in pregnancy, and also there can
6 be confusion with bleeding at implantation and
7 bleeding for other reasons with menses. If you put
8 those together, in fact, it would be possible to be
9 pregnant, despite all of our efforts, before
10 initiating Accutane.
11 DR. GROSS: Dr. Strom?
12 DR. STROM: In the era of increasing
13 computerized data entry, how would this risk
14 management plan work?
15 DR. LINDSTROM: I am sorry, can you
16 elaborate on your question?
17 DR. STROM: Sure. The current risk
18 management plan, as I understand it, relies on a
19 sticker program.
20 DR. LINDSTROM: Yes.
21 DR. STROM: There is increasing use of
computerized prescribing and a big push nationwide
1 to increase that.
2 DR. LINDSTROM: Yes.
3 DR. STROM: How could this be
4 operationalized? How could this plan possibly work
5 in that context?
6 DR. LINDSTROM: The current risk
7 management plan does not allow for computerized
9 DR. STROM: Just to clarify, given the
10 current environment in pharmacy, neither mail order
11 nor computerized prescriptions are compatible with
12 the current plan.
13 DR. LINDSTROM: Computerized prescriptions
14 are not compatible with the current plan and I
15 think mail order would be difficult with the
16 current plan. Again, I have set the historical
17 context and described the current plan.
18 DR. GROSS: Dr. Kibbe?
19 DR. KIBBE: I have just a question about
20 the two figures that you gave us and the data that
21 is contained therein. Have you taken the number of
reports of pregnancies for the years from '91 to
1 '99 and divided them by the number that you show
2 for the number of female patients during those same
3 years and gotten, even though it is an inaccurate
4 number, at least an estimate of number of
5 pregnancies per 1,000 patients over that time
7 DR. LINDSTROM: I believe that you are
8 bringing up the issue of pregnancy rate. While the
9 absolute number of pregnancies reported to the
10 agency was relatively constant, the number of women
11 receiving isotretinoin prescriptions was rising. I
12 don't want to belabor this point but there are two
13 issues related to deriving a rate from the data
14 that I showed. First, pregnancy reporting is
15 voluntary, both the spontaneous reports and those
16 received through the survey. They are voluntary.
17 Both are voluntary mechanisms. We know that
18 adverse event reporting declines over time and we
19 know that it does not capture all events so it is
20 an imprecise number.
21 Second, even if that numerator in terms of
number of pregnancies reported was reflective
1 of the total number of exposed pregnancies that had
2 occurred, even if that number, indeed, did stay
3 flat the public health burden of those exposed
4 pregnancies, of those affected babies, was not
5 declining. Those two slides were actually
6 presented to the advisory committee in 2000, and
7 for those reasons it was determined to be important
8 to increase the risk management for this drug
9 because the public health impact has remained
11 DR. KIBBE: So, your answer is no?
12 DR. LINDSTROM: Yes.
13 DR. GROSS: Dr. Bull?
14 DR. BULL: I just wanted to remind you,
15 going back to the issue of computerized
16 prescriptions, that this whole risk management plan
17 is predicated on a high level of interaction
18 between the patient and the healthcare provider.
19 These are non-refillable prescriptions. The
20 patient has to return to the healthcare provider
21 for an interaction, hopefully a face-to-face
evaluation of how the acne treatment is
1 progressing, such that because of the fact that
2 these are not prescriptions that are automatically
3 refilled it is not a course of therapy where you
4 are given a prescription that you renew for five
5 months. It is one where every month during that
6 course of time there is a need to return to the
7 healthcare provider of record.
8 DR. GROSS: I am going to take the
9 prerogative of the chair and declare a break at
10 this particular time. We have no breaks scheduled
11 for the morning and I think we will hold questions
12 until a little bit later. Thank you. We will
13 reconvene at 9:30.
14 [Brief recess]
15 Open Public Hearing
16 DR. GROSS: Both the Food and Drug
17 Administration and the public believe in a
18 transparent process for information gathering and
19 decision-making. To ensure such transparency at
20 the open public hearing session of the advisory
21 committee meeting, which we are about to start, the
believes that it is important to understand the
1 context of an individual's presentation. For this
2 reason, the FDA encourages you, the open public
3 hearing speaker, at the beginning of your written
4 or oral statement to advise the committee of any
5 financial relationship that you may have with the
6 sponsors of any products in the pharmaceutical
7 category under discussion at today's meeting. For
8 example, the financial information may include the
9 sponsor's payment of your travel, lodging or other
10 expenses in connection with your attendance at the
11 meeting. Likewise, FDA encourages you at the
12 beginning of your statement to advise the committee
13 if you do not have any such financial
14 relationships. If you choose not to address this
15 issue of financial relationships at the beginning
16 of your statement it will not preclude you from
18 We have two registered speakers for the
19 morning, Dr. Robert A. Silverman is first. Dr.
21 DR. SILVERMAN: Dr. Gross, members of the
advisory committee, thank you for giving me the
1 opportunity to speak about the continued
2 availability of isotretinoin. My statement will
3 focus on the benefits of this drug and the impact
4 of pregnancy prevention risk management efforts on
5 its availability to patients.
6 I have been practicing pediatric
7 dermatology for nearly two decades. At first I was
8 in Cleveland at Rainbow Babies and Children's
9 Hospital. Since 1989 I have maintained a private
10 practice in Northern Virginia and a dermatology
11 clinic in the Department of Pediatrics at
12 Georgetown University. For the record, I have not
13 participated in any pharmaceutical company
14 sponsored acne drug studies, nor am I taking any
15 reimbursement from the AADA, and the only thing I
16 have taken today is one bottle of water.
18 I am a physician who treats patients, not
19 a healthcare provider who sees clients. I make the
20 distinction to emphasize the trust and close
21 relationship between a physician and patient that
necessary for obtaining the best results when
1 treating acne while minimizing side effects of any
2 of the medications that we use. As a pediatrician,
3 I recognize the social and psychological impact
4 that an acne-scarred body image has on teenagers.
5 I know of no drug that has changed the lives of my
6 patients with acne more than isotretinoin. It has
7 been a Godsend to adolescents and to young adults
8 with recalcitrant, nodular, nodulocystic and
9 scarring disease.
10 Unlike dermatologists entering the medical
11 work force today, I remember how we used to treat
12 severe nodulocystic acne. One of the most painful,
13 gruesome procedures that I learned in my training
14 at the Children's Hospital in Boston was the
15 incision and drainage of multiple purulent
16 abscesses, like you saw earlier, on the faces of
17 young men and women afflicted with recalcitrant
18 nodulocystic acne. The procedure is nearly a
19 historical footnote since we have the availability
20 of isotretinoin.
21 There is not a week that goes by in my
practice that a concerned parent, with facial scars
1 themselves, brings in a preadolescent with minimal
2 or no acne for anticipatory guidance in hopes of
3 their child avoiding the same fate that they had
4 when they were growing up. Of course, the vast
5 majority of these children never-ever reach the
6 point of needing isotretinoin. But for the few who
7 progress and require it, I am thankful that I have
8 the option to use this medication. The reason I am
9 here today is to keep this drug available to all
10 people who need it.
11 Let me share a story that perfectly
12 illustrates the wonders that can be worked by this
13 drug. In 1982, when I was in Boston, the year that
14 isotretinoin first became available in the United
15 States, I met a beautiful young lady who had a
16 beautiful complexion. During that year she
17 developed inflammatory acne that then rapidly
18 progressed to severe painful, nodulocystic disease.
19 She was being cared for by an excellent
20 dermatologist at one of the nation's first and
21 premier HMOs. Minocycline, benzoyl peroxides,
Retin-A and oral contraceptives made no difference
1 in her appearance.
2 Isotretinoin was not widely prescribed and
3 it was not until 1986 when she saw her fourth
4 dermatologist, after moving to Washington, D.C.,
5 that Accutane was offered to her. The years
6 between 1982 and 1986 were for her filled with
7 anxiety and self-consciousness. I know this
8 because this woman is now my wife. She took
9 isotretinoin safely. She was aware of the
10 teratogenic risks and used two forms of birth
11 control. We now have two healthy boys who were
12 conceived well after my wife-to-be's finishing the
13 drug. This story is obviously close to my heart
14 but it also illustrates the fact that female
15 patients of childbearing potential can and do use
16 isotretinoin safely.
17 I have treated many teenaged girls and
18 young women with isotretinoin. I have personally
19 prescribed isotretinoin since 1986 and have used it
20 according to the risk management guidelines with
21 utmost caution, and since the S.M.A.R.T. program
been in effect I have complied with it to the
1 best of my ability.
2 As a clinician in the trenches, I am
3 familiar with the difficulties and weaknesses that
4 were outlined that may impede optimal participation
5 in the S.M.A.R.T. program. Complicating and
6 restricting access will only drive needy patients
7 to obtain isotretinoin through illicit channels or
8 those that circumvent well-established
9 doctor-patient relationships. This would be a
10 travesty of monumental proportions. In grade
11 school I learned the acronym KIS--keep it simple.
12 The more complicated you make the process of
13 obtaining this medication the more mistakes are
14 going to be made.
15 I would be happy to help in any way that I
16 can to keep this medication available to all who
17 need it and to address the small, but unfortunate,
18 number of pregnancies that have occurred while on
19 this drug. Thank you for your time and
20 consideration and I would be happy to entertain any
21 questions if we have a few seconds. Thank you.
DR. GROSS: Thank you very much,
1 Silverman. The next speaker is Dr. Sidney Wolfe of
2 the Public Citizen's Health Research Group.
3 DR. WOLFE: Helping out in this
4 presentation is Dr. Sherri Shubin who is a
5 pediatrician and currently doing a preventive
6 medicine residency at Johns Hopkins. She is
7 spending part of her residency with us.
9 I will take a minute or so to go over the
10 first couple of slides. Our involvement really
11 started shortly after the drug came on the market
12 in September of '83. We submitted a petition
13 urging patient package inserts and black box
14 warnings about birth defects and life-threatening
15 adverse events. Prior to approval, as many of you
16 know, there was a pretty comprehensive program to
17 make sure that no one who got the drug got
18 pregnant, and a number of those strictures were
19 dropped at the time of initial marketing and slowly
20 some of them were reintroduced.
21 On April 26, ADA testified before this
committee describing Accutane as an imminent public
1 health hazard and saying that unless certain
2 restrictions were imposed it should really come off
3 the market. The restrictions are listed there, one
4 of the most important of which is, of course,
5 limiting prescribing to dermatologists who file
6 sworn affidavits stating they will adhere to the
7 stated indications for the drug. That is supposed
8 to be happening, not the sworn affidavit part but,
9 obviously the amount of prescriptions belies the
10 fact that that is what it is limited to. We then
11 filed a petition to the FDA in May of 1988 with
12 recommendations, saying it should come off the
13 market and only be allowed back on with these
16 Just finishing up a little bit on that, we
17 continued urging removal from the market unless
18 restrictions were put in and, thus far, these
19 restrictions just have not been put in. Most
20 recently, in September, 2000, we testified that at
21 that time the issue of depression and suicide had
arisen and again we proposed restrictions.
2 This is testimony before this committee by
3 Dr. David Erickson, who was then Chief at the
4 Centers for Disease Control and Prevention of the
5 Genetics and Birth Control Branch. His statements
6 are very poignant because 15 years later the same
7 issue is there: "The birth of babies with defects
8 caused by fetal exposure to Accutane is
9 unnecessary. FDA decision to allow the marketing
10 of Accutane is a failed regulatory experiment. A
11 decision to depend on better contraception alone,
12 without active intervention to reduce the number of
13 users, is a decision to leave the number of
14 affected babies at an unacceptably high level."
15 Finally, one of his suggestions was, "perhaps a
16 formal IND," investigational new drug, "would be a
17 suitable mechanism to reduce the frequency of
18 Accutane embryopathy."
20 Now, these are data from the package that
21 was provided to you a couple of weeks ago--it
should have been included. This
is an FDA
1 presentation before this committee back in
2 September of 2000. What they said was that as of
3 that time these are just the reported cases and, as
4 several people said this morning and it understates
5 the actual magnitude of the problem with 1,995
6 exposed pregnancies; 1,214 elective abortions; 383
7 live births; and 162 infants with birth defects.
9 These now are the more recent data from
10 the first year of the S.M.A.R.T. program. Again,
11 the first two points are taken directly from the
12 package that was handed out and 156,800
13 "unique"--the phrase used in there--women were
14 given the drug. Secondly, the estimated pregnancy
15 rate, and I am sure this is on the low side but
16 that is what was in this information set is 0.35
17 percent. If you take that rate and apply it to the
18 number of "unique" women given the drug in that
19 first year it means that there have been 548
20 pregnancies and this is 4.6 times higher than the
21 voluntarily spontaneously reported pregnancies that
also listed in the package, which is a measure
1 of the under-reporting.
3 Of the 61 pregnancies with known
4 outcomes--remember, about half of them had outcomes
5 unknown--48 of 61 or 78.7 percent resulted in
6 elective abortions. Again, if you apply this to
7 the more likely estimate of the actual number of
8 pregnancies, 548, this means that there would have
9 been 431 elective abortions in that one year ending
10 in March of 2003.
12 Again estimating the number of deliveries,
13 of 61 pregnancies with known outcomes, 7 of 61 or
14 11.5 percent resulted in deliveries. There were
15 some spontaneous abortions, and so forth that make
16 up some of the other ones aside from the elective
17 abortions. Again, applying this to the 548
18 estimated pregnancies, there would have been 63
19 deliveries. Using FDA's and the CDC's figure,
20 which is probably on the low side, 25 percent birth
21 defects and the 50 percent mental retardation is as
close--there hasn't been any really careful study
1 on it but applying those figures to this estimate,
2 we are talking about 16 infants with birth defects
3 and 31 with mental retardation just in that one
6 The reason the S.M.A.R.T. program and even
7 the new Roche proposal do not seriously address the
8 two major issues here are as follows: In 1989 CDC
9 estimated that there were no more than 4,000 women
10 of childbearing age with severe cystic acne. They
11 did not even get into the recalcitrant or other
12 therapy. Adjusted for population growth because
13 these were 1987 data, the number may now be 6,000.
14 Given that there were 156,800 "unique" women of
15 childbearing age who got the drug in that first
16 year of S.M.A.R.T., this represents a 26-fold
17 excess in prescribing over the number of on-label
19 The second point is that unless there is
20 something more than a sticker and an assurance but
21 there is actually the provision of a lab test
showing that the woman, in fact, was not pregnant
1 and at least a description of the contraceptive
2 methods--unless that happens, then people are going
3 to have stickers that are misrepresenting what has
4 actually happened.
6 The reason why we are about to file a
7 petition in the next week or two asking for this
8 drug to be taken off the market and made available
9 through an IND is that there have been 20 years of
10 failed voluntary and even more recently some
11 mandatory restrictions, and they have led to
12 actually a total of more pregnancy exposures
13 because the actual amount of prescriptions has gone
14 up. I think it was estimated in '88 or '89 that
15 there may be 70,000 "unique" women of childbearing
16 age getting the drug and it is now some 150,000.
17 As we recommended in '88 and the CDC
18 itself suggested as an option the next year, as I
19 showed you in Dr. Erickson's presentation, we now
20 propose a ban on marketing with subsequent
21 availability only under a tightly controlled IND as
only feasible way to significantly reduce
1 prescriptions and pregnancy exposures.
3 These would be the main elements of the
4 restrictions in an IND: Photographic proof of
5 severe cystic acne confirmed by an independent
6 group of dermatologists. Digital cameras make this
7 kind of process relatively easy to set up.
8 Secondly, a written record for each
9 patient that there, in fact, is adequate previous
10 treatment of the disease with antibiotics and other
11 treatments and that there is recalcitrance to it.
12 Third, a written statement of
13 contraceptive practices and provision of a copy of
14 this and a negative pregnancy test in order for the
15 drug to be dispensed each time.
17 In summary, the S.M.A.R.T. program is
18 clearly a failure. Without these proposed IND
19 restrictions, this administration and this advisory
20 committee will continue to put its imprimatur on
21 the reckless use of a drug that each year causes
need for hundreds of abortions and many
1 seriously deformed infants with birth defects
2 and/or mental retardation. This is one of the two
3 worst epidemics of preventable serious birth
4 defects ever seen in the U.S. I would just point
5 out the other one is two defects where there is
6 deficiency of folic acid, as you know. The odds of
7 neural tube defects are a couple of orders of
8 magnitude lower than the odds of a birth defect
9 with a live birth. Of course, it is different not
10 to have enough folic acid as opposed to be
11 administering one of the more potent teratogens we
12 have ever seen. It is time to end the more than 20
13 years of voluntary restrictions and some mandatory
14 ones that have failed to reduce its prescribing for
15 more than 20 times as many women as would be using
16 the drug if it were limited to the approved
17 indications. Thank you. I would be glad to try
18 and answer any questions.
19 DR. GROSS: Thank you very much, Dr.
20 Wolfe. The final speaker in the open public
21 hearing will be Dr. Sherri Shubin, who will read a
letter from Dr. Furberg, which is in your packet.
1 DR. SHUBIN: Thank you. I have no
2 financial conflicts of interest. As a member of
3 the public, I would like to read the statement that
4 was written by Dr. Curt Furberg, a member of this
5 committee who could not be here today:
6 Due to an unexpected family health
7 problem, I will not be able to attend the upcoming
8 advisory committee meeting on Accutane risk
9 management. Based on long observation and careful
10 study, I feel very strongly about this issue and
11 regret that I will not be there to express my views
12 and participate in the committee's discussion and
13 deliberation. As a member of the committee, I
14 would ask that the following be read aloud at the
15 meeting after all testimony has been presented but
16 before the committee begins its consideration and
17 discussion of the issue and the questions presented
18 it by the agency.
19 To be candid, the history of Accutane is
20 an example of inadequate and ineffective risk
21 management by the FDA and the manufacturer of
Accutane to the detriment of thousands of women.
1 Examples are numerous. Although Accutane was a
2 known animal teratogen and a suspected human
3 teratogen at the time of its approval, the company
4 did not recommend and the FDA did not insist upon
5 labeling that emphasized the importance of
6 contraception or abstinence while under treatment
7 with the drug. The consequences of this omission
8 become more apparent when one understands that five
9 women became pregnant while taking Accutane during
10 pre-approval clinical trials despite following the
11 contraception requirements of the study.
12 In 1988, a highly publicized FDA advisory
13 committee meeting was held to discuss the high
14 level of pregnancy exposure to Accutane and the
15 overuse of the product and its contribution to the
16 pregnancy exposure problem. The Pregnancy
17 Prevention Program, PPP, emerged following this
18 meeting as the primary means of managing Accutane's
19 teratogenic risks. Several advisory committee
20 meetings were held to monitor the progress of the
21 PPP between 1989 and 1991. It was clear from these
meetings that the majority of women taking Accutane
1 were not volunteering to participate in the PPP,
2 that even in the group that did volunteer pregnancy
3 testing was infrequently performed and that
4 pregnancy exposure to Accutane was still occurring
5 at a high level.
6 Remarkably, no advisory committee meeting
7 on the Accutane pregnancy exposure and the
8 performance of the PPP was convened until
9 September, 2000. At this meeting, it was shown
10 that enrollment in the PPP was low and falling,
11 that pregnancy testing was still often not being
12 performed and that recommendations about
13 contraception or abstinence were often not adhered
14 to. Even more alarming, the use of Accutane in
15 women had increased three-fold during the preceding
16 ten-year period when one would have expected it to
17 decline substantially because of successful
18 treatment of prevalent cases of severe nodular
19 acne. The committee's response to this evidence
20 was to declare the PPP a failure and to recommend
21 that a comprehensive risk management program that
included patient and physician registration, as
1 well as mandatory pregnancy testing, be
2 established. None of these has been implemented.
3 Instead, the S.M.A.R.T. program was
4 introduced. It is an effort that added yellow
5 stickers to the existing PPP, but had no means of
6 determining if pregnancy testing was actually
7 performed or of how many pregnancy exposures
8 actually occurred. Unfortunately, S.M.A.R.T. had
9 the same basic design limitations as the PPP and
10 this should have been recognized. Now, after
11 almost four years and thousands more of unnecessary
12 pregnancy exposures to Accutane, this committee is
13 once again asked to advise the FDA.
14 Simply put, I believe that the system is
15 not safe and cannot be used in a safe manner. To
16 minimize the number of pregnancy exposures to
17 isotretinoin an IND-like process could be
18 implemented that ensures universal pregnancy
19 testing, registration of all pregnancy test results
20 and incorporates a mechanism whereby the drug
21 cannot be dispensed without a negative pregnancy
test. This coupling of a negative
1 with dispensing of the drug would be analogous to
2 the policy that has been successfully employed with
3 the antipsychotic clozapine and has been summarized
4 as "no blood, no drug." An added benefit of such
5 an approach would be that we would have more
6 accurate information regarding the actual number of
7 pregnancy exposures to the drug. The numbers we
8 have now, coming from a relatively small and
9 self-selected group of volunteers, is undoubtedly a
10 gross underestimate of reality.
11 Other features of this IND-like approach
12 could include limiting the number of
13 isotretinoin-dispensing centers, mandatory
14 pregnancy avoidance counseling at each visit and
15 the proviso that dispensing centers would be
16 audited periodically. An important objective of
17 our risk management should be to reduce the overuse
18 of isotretinoin. Therefore, I would recommend that
19 the IND-like process I have briefly described
20 include some means of documenting the presence of
21 severe nodular acne in patients being considered
isotretinoin treatment. In clinical
1 the approval of Accutane only patients with severe
2 cystic acne were enrolled, and photographs of at
3 least some of these patients were taken and used in
4 advertisements and at professional meetings.
5 Perhaps a photograph, documenting the patient's
6 severe cystic acne, could be required prior to
7 approval for treatment.
8 The S.T.E.P.S. program for thalidomide has
9 been talked about as a possible model for
10 isotretinoin risk management, but it would not be
11 adequate. If my understanding is correct, there is
12 actually no current coupling of a negative
13 pregnancy test with dispensing of the drug and
14 there is no central registry of the pregnancy test
15 results. Under this system, thalidomide
16 prescribers answer several questions over the
17 telephone in response to automated prompts in order
18 to receive a number authorizing use of the drug for
19 the next month. This system is very similar to the
20 yellow sticker system under S.M.A.R.T. in that it
21 relies on prescriber self-attestation. There is no
validation that what the prescriber has answered is
1 true and there is no comprehensive or reliable
2 means of knowing how many pregnancy exposures have
4 The occurrence of pregnancy exposures with
5 the original Accutane pre-approval clinical trials
6 and, more recently, within a clinical trial for
7 another formulation of isotretinoin raises an
8 uncomfortable question, should this drug have ever
9 been released on the open market? I think it was
10 and is unethical to allow isotretinoin to be
11 available for use outside of the protections that
12 would be afforded by a controlled and documentable
13 process of distribution.
14 I do have copies of this statement for
15 anyone who would like one.
16 DR. GROSS: Yes, there are copies of the
17 statement in the committee's folders. Thank you
18 very much, Dr. Shubin. Shalini Jain has a comment
19 she would like to make now.
20 MS. JAIN: I just want to make a comment
21 for a point of clarification with regards to Dr.
Furberg's letter. Dr. Shubin was
1 letter on behalf of Dr. Furberg. In functioning as
2 an FDA committee member representative, he has not
3 been cleared for this meeting for purposes of
4 conflict of interest but solely as a representative
5 of the public today. Thank you.
6 DR. GROSS: Thank you. We will now move
7 on to the next set of presentations. From
8 Hoffmann-La Roche, Joanna Waugh, Group Director for
9 Regulatory Affairs, is first; Dr. Martin Huber,
10 Vice President, Global Head, Drug Safety Risk
11 Management; and Dr. Susan Ackermann Shiff, Global
12 Head, Risk Management, Drug Safety Risk Management.
13 Hoffmann-La Roche, Inc. Presentations
15 MS. WAUGH: Good morning.
17 I am Joanna Waugh, from the Regulatory
18 Affairs Department at Hoffmann-La Roche, Nutley,
19 New Jersey. Thank you to the FDA and the committee
20 for giving us the opportunity to present today.
What I would like to do first is to just
1 give you an overview of the framework of our
2 presentation today. Having heard the FDA
3 presentation, there is some overlap with our
4 presentation so we will go fairly rapidly through
5 some of the areas where there is duplication.
6 Following myself, Dr. Martin Huber will
7 provide a brief overview of the risk/benefit
8 profile for isotretinoin. I will then briefly
9 summarize a regulatory overview, focusing on risk
10 management milestones for Accutane since its launch
11 in the U.S. in 1982. Dr. Susan Ackermann Shiff
12 will then provide an overview of the S.M.A.R.T.
13 program, comprising a description of what that
14 program entails, as well as an assessment of some
15 of the data with particular reference to metrics
16 which were predetermined in agreement with FDA.
17 Dr. Martin Huber will then review the pregnancy
18 data from the S.M.A.R.T. program and move on to
19 discuss our recommendations for program
In addition to the team of presenters
1 which are listed on the left-hand side of this
2 slide, Roche does also have available, for
3 responding to questions in the question and answer
4 session, some additional colleagues, Miss Kay Bess
5 from our Drug Safety Risk Management Department,
6 Dr. Karen Blesch, from the same department, Miss
7 Tammy Reilly, Vice President of Dermatology and
8 Oncology, and Dr. Susan Sacks, from the Drug Safety
9 Risk Management Department.
11 Additionally, we have available the
12 following outside experts for responding to
13 questions, Dr. Diane Berson, from Cornell
14 University; Dr. Judith Jones, from the Degge Group;
15 and Dr. Victor Strecher, from the University of
16 Michigan School of Public Health.
18 As this slide shows and was referred to by
19 the FDA in their presentation, the S.M.A.R.T. risk
20 management program was approved in 2001 and it was
21 subsequently implemented early in 2002. Since 2002
generic isotretinoin has also been available on the
1 U.S. marketplace and this slide shows the
2 respective manufacturers' products and risk
3 management programs, which are all equivalent to
4 the Accutane S.M.A.R.T. risk management program.
6 The conditions for the approval of the
7 S.M.A.R.T. risk management program included the
8 requirement to develop a backup program for a
9 mandatory registry, as well as the understanding
10 that a follow-up advisory committee would be
11 convened when more data was available to discuss
12 the effectiveness of the program, which is why we
13 are here today. When more data was available,
14 Roche evaluated that data and developed a specific
15 proposal for program enhancement based on the data
16 we saw emerging.
18 In December of 2003, the FDA, Roche and
19 the generic companies reviewed the data across our
20 respective risk management programs. Roche and the
21 generic companies subsequently worked together on
recommendations for program modification. All
1 companies agree on the need for one single program
2 and the recommendation that you will hear put
3 forward today is generally agreed to by all the
4 companies. The details of the implementation
5 require some further refinement and discussion and
6 we look forward to the discussion from the advisory
7 committee today on the proposal that we will put
8 forward to you.
9 I will now hand over to Dr. Martin Huber.
11 DR. HUBER: Good morning.
13 What I would like to briefly review for
14 you is the benefit/risk. As a first step in any
15 risk management approach there needs to be an
16 assessment of both the benefit and the risk that we
17 are addressing.
19 Just to remind you, isotretinoin is
20 indicated for severe recalcitrant nodular acne. It
21 is indicated only for patients who are unresponsive
conventional therapy, including systemic
1 antibiotics. Finally, it is indicated only for
2 those females who are not pregnant and agree to not
3 become pregnant.
5 The medical need for isotretinoin is
6 because it is a serious disease with profound
7 consequences. Inadequately treated severe
8 recalcitrant nodular acne can lead to disfiguring
9 scarring. Fortunately, it is a uniquely
10 efficacious therapy for this condition and there
11 are currently no alternative therapies for these
14 To briefly remind you, this is the
15 concern. Inadequately treated SRNA can lead to
16 disfiguring scarring which is life-long.
18 However, there is a specific challenge for
19 isotretinoin, as has been indicated by the previous
20 speakers. Isotretinoin is known to be a human
21 teratogen. The majority of the female patients who
this drug are of childbearing potential.
1 Therefore, pregnancy prevention measures, including
2 proactive risk management, are essential. But the
3 specific challenge of this program is that we must
4 change the behavior of patients in order to have
5 them comply better with these risk management
8 The public health goals, as previously
9 stated, remain the same. Our vision is that no
10 woman who is pregnant should receive isotretinoin
11 therapy; no woman should become pregnant during or
12 for one month after receiving isotretinoin therapy.
14 I will now turn it over to Miss Waugh who
15 will review the regulatory history and the risk
16 management program to date.
17 Regulatory Overview
19 MS. WAUGH: The teratogenic risk of
20 Accutane has been known since the approval of the
21 drug in 1982 in the U.S. Because of this known
risk, we have taken a variety of risk management
1 steps throughout the product life cycle with the
2 aim of reducing pregnancies as far as possible.
3 The proposed program that you will hear today
4 includes risk management enhancements in response
5 to data that we have seen in the S.M.A.R.T. risk
6 management program.
8 This slide provides an overview of some
9 examples of steps Roche has taken throughout the
10 product life cycle to minimize pregnancies. Since
11 product launch in 1982, the product had a pregnancy
12 category X, i.e., it was contraindicated in
13 pregnant women. In 1984 a black box warning was
14 introduced to increase the prominence of warnings
15 surrounding pregnancy.
16 In 1988 the Pregnancy Prevention Program
17 was introduced which FDA alluded to in the earlier
18 presentation. This was the first risk management
19 program of its kind which used mechanisms over and
20 above labeling as tools for risk management. Some
21 components of the Pregnancy Prevention Program are
listed on this slide and I will just go through
1 them briefly, the requirement for two forms of
2 contraception to be used simultaneously for one
3 month before, during and after Accutane treatment.
4 Additionally, the requirement for negative monthly
5 pregnancy testing; the addition of an "avoid
6 pregnancy" symbol in the packaging. Educational
7 materials were introduced regarding contraceptives
8 and pregnancy avoidance, and a female informed
9 consent form was introduced.
10 Further evaluation tools to assess the
11 effectiveness of this program were introduced which
12 included the Accutane survey. This survey was
13 developed by the Slone Epidemiology Center at
14 Boston University and provided information about
15 women's understanding of the risk issues related to
16 teratogenicity, as well as some information about
17 the pregnancy rate based on the number of women
18 enrolled in the survey.
20 in 1990 we added information to the U.S.
21 product information concerning a description of
birth defects that could occur, as well as a
1 recommendation that prescribing should be limited
2 to a one-month supply.
3 In 1994 the patient informed consent form
4 was updated to include additional requirements. In
5 May of 2000, amongst additional requirements, one
6 of the requirements was to have two negative
7 pregnancy tests prior to the initial prescription.
8 In September of 2000, as has been
9 mentioned earlier, an advisory committee was
10 convened which discussed pregnancy prevention. I
11 will come back to that in a little bit more detail
12 later. Subsequent to that advisory committee,
13 Roche worked in collaboration with the FDA to
14 determine how best to implement their
15 recommendations. The result of these discussions
16 was the ultimate approval for the S.M.A.R.T. risk
17 management program in October, 2001.
19 As I mentioned, the 2000 advisory
20 committee discussed pregnancy prevention. The
21 recommendations from that advisory committee, as
mentioned by the FDA, included the recommendation
1 for the introduction of patient and prescriber
2 registry. In subsequent discussions with the
3 agency, Roche put forward various proposals which
4 included mandatory patient and prescriber
5 registration. In discussions with the agency about
6 the best way to implement these recommendations and
7 in view of some of the issues that FDA alluded to
8 earlier, Roche and FDA agreed that the critical
9 issue was to link a negative pregnancy test with
10 each prescription and dispensing of Accutane.
12 The S.M.A.R.T. program introduced a link
13 between dispensing and negative pregnancy testing
14 via the Accutane qualification sticker.
15 Additionally, the S.M.A.R.T. program included
16 enhanced education, enhanced informed consent, and
17 the requirement for prescribers who wish to
18 prescribe Accutane to be registered into a
21 Dr. Susan Ackermann Shiff will now provide
more details about the S.M.A.R.T. program.
1 Overview of the S.M.A.R.T. Program
2 DR. ACKERMANN SHIFF: Thank you.
4 What I would now like to briefly do is
5 overview the S.M.A.R.T. program or the System to
6 Manage Accutane-Related Teratogenicity. The
7 program was developed with and approved by the FDA,
8 and went into effect on April 10 of 2002.
10 This high level overview slide provides
11 two important features, first that the registered,
12 qualified physician, the qualified patient and the
13 pharmacist work together in the dispensing of the
14 product. Second, the qualification sticker is the
15 one area where the negative pregnancy test and the
16 dispensing of the product is linked.
18 Different from the Pregnancy Prevention
19 Program, all prescribers must be enrolled in the
20 program in order to prescribe the product. A
21 prescriber will read the guide to best practices,
sign a letter of understanding and receive the
1 qualification stickers.
3 When the prescriber signs the letter of
4 understanding they attest to the fact that they
5 know the risk and severity of fetal injury and
6 birth defects; that they know how to diagnose and
7 treat various forms of acne; that they know the
8 risk factors of unplanned pregnancy and they will
9 properly follow the S.M.A.R.T. procedures. In this
10 case, it includes education, pregnancy testing,
11 contraception, informed consent and offering of the
12 Accutane survey.
14 Once the prescriber has been registered
15 within the system, they can educate the patient on
16 the appropriate use of the product. The "Be Smart,
17 Be Safe, Be Sure" educational brochure that is
18 shown on this slide contains elements of education
19 about the product; contraceptive information; the
20 two informed consents, the all-patient informed
21 consent and the female patient informed consent; an
enrollment card for the Accutane survey; and
1 educational reinforcement. The purpose of this
2 brochure is that it be used at the initial office
3 visit and all subsequent office visits.
5 As Roche understands that patients learn
6 in different ways, we have also provided a variety
7 of other educational materials. There are story
8 boards in both English and Spanish and two
9 educational videos, one about contraception and one
10 about the risks of unplanned pregnancy. There are
11 two 1-800 lines, one for Accutane information and
12 one for contraception. In addition, there is an
13 "avoid" blister pack pregnancy symbol and a
14 medication guide that is now packaged in the
15 blister pack that has information about the product
16 and is patient friendly.
18 There is also a patient education brochure
19 for men that contains product information, informed
20 consent and educational reinforcement.
The qualification sticker signifies that
1 there is a qualification date that, in this case,
2 is the date of the last negative pregnancy test,
3 not the date that the pregnancy test was received.
4 The pharmacist must dispense within seven days of
5 the qualification date and can't dispense more than
6 a 30-day supply. No refills are allowed. Both
7 males and females have a qualification sticker
8 attached to their prescription.
10 The qualification criteria or what the
11 sticker represents on actual presentation is that
12 the female patient has had the negative pregnancy
13 testing, two at the start of therapy and one every
14 month during therapy. In addition, she has
15 selected and committed to use two safe and
16 effective forms of contraception. She has signed
17 all-patient informed consent and the female
18 informed consent, and has been offered the
19 opportunity to participate in the Accutane survey
20 and knows of its importance.
Again, the qualification sticker is the
1 actual sticker that links the dispensing of the
2 product with the negative pregnancy test. The
3 pharmacist will allow no more than a 30-day supply;
4 will dispense within seven days of the
5 qualification date or the date of the last negative
6 pregnancy test; and no refills are allowed. In
7 addition, no telephone, computerized or mail order
8 prescriptions are allowed. The pharmacist also has
9 the opportunity to verify that the physician has
10 been entered into the system by calling a 1-800
13 What I would like to do now is to review
14 the data from S.M.A.R.T. year one, or April 1 of
15 2002 through March 31, 2003. In some cases I will
16 be comparing these data to the year previous to
17 S.M.A.R.T. or the last year of the Pregnancy
18 Prevention Program which is April 1, 2001 through
19 March 31, 2002.
21 We used three specific data sources to
evaluate the S.M.A.R.T. program in year one. The
1 first is the prescription compliance survey; the
2 second, the Accutane survey; and, three, pregnancy
3 reports. I will be reviewing the first two data
4 sources and Dr. Huber will be reviewing the
5 pregnancy reports in addition to the corresponding
6 failure analyses.
8 The prescription compliance survey is a
9 quarterly survey of a random sample of pharmacies
10 pertaining to the use and completion of the
11 qualification stickers. In addition, Roche
12 conducted a quarterly audit of anonymous Accutane
13 prescriptions from a random sample of these
14 participating pharmacies. While I will not be
15 discussing the quarterly audit, what I can say is
16 that the results are consistent with the quarterly
17 sample of the random sample of pharmacies.
19 There is one major objective of the
20 prescription compliance survey, that is, to assess
21 prescribers' and dispensing pharmacists' compliance
with the appropriate use of the qualification
3 During our discussions with the FDA, we
4 had decided on two specific sets of metrics with
5 regard to the prescription compliance survey. The
6 first is that by the end of S.M.A.R.T. year one 90
7 percent of all physicians would use the
8 qualification stickers. The secondary metrics
9 included that 90 percent of all physicians would
10 completely and correctly fill out the stickers, and
11 that 90 percent of all prescriptions would be
12 dispensed with a medication guide. In October of
13 2002 Roche started packaging the medication guides
14 within the blister packs so the secondary metric is
15 no longer applicable.
17 The results of the prescription compliance
18 survey are as follows: Over the six waves of the
19 survey an average of 97 percent of all
20 prescriptions had a qualification sticker affixed.
21 Of those, 96 percent were correctly or completely
completed. There were no
differences between the
1 survey waves and there were no differences between
2 the age of patient, the gender of patient, the
3 location of the dispensing of the prescription or
4 the payer type. In conclusion, we have met and
5 exceeded our metrics for stickers and the mechanics
6 of the stickers are working well. [Slide]
7 Now I would like to review some of the
8 high-level results from the Accutane survey.
10 As Ms. Waugh noted previously, the
11 Accutane survey was developed by Slone Epidemiology
12 Center of the Boston University School of Public
13 Health. It was initially implemented with the
14 Pregnancy Prevention Program in 1989 and, to date,
15 Roche has had two vendors for the survey. From
16 1989 to the presentation of these data, Slone
17 Epidemiology Center was our primary research
18 organization. In October, 2002 we switched
19 research organizations to SI International and the
20 Degge Group.
21 While I won't go into detail about the
methodology of the survey, and I know that Dr.
1 Mitchell is presenting later, what I do want to
2 note is that there are two specific arms within the
3 Accutane survey, the Accutane after treatment arm
4 and the during and after treatment arm. The
5 presentation of these data deal only with the
6 during and after treatment arm. In addition, I
7 would also like to note that the research
8 organization SI/Degge did implement the
9 questionnaire that was modified to include
10 components of S.M.A.R.T.
12 There are four specific objectives of the
13 Accutane survey. It was a voluntary survey to
14 determine female patient awareness of the
15 teratogenic risks of Accutane. In addition, it is
16 used to measure compliance with key components of
17 S.M.A.R.T., in this case informed consent, the
18 medication guide, pregnancy testing, contraceptive
19 use and the qualification sticker. Historically,
20 we have used data from the Slone Epidemiology
21 Center to calculate a rate of pregnancy among
female Accutane users and to identify risk factors
1 that occur with pregnancy.
3 Again, during our discussions with the FDA
4 we had agreed upon a variety of primary and
5 secondary metrics, the primary metric being that 60
6 percent of all women would enroll in the Accutane
7 survey by the end of S.M.A.R.T. year one. We have
8 several data specific secondary metrics including
9 female patient representativeness; recall of
10 qualification sticker; recall of pregnancy test;
11 medication guide; the use of two forms of safe and
12 effective forms of contraception; and enrollment in
13 the Accutane survey via the prescriber's office,
14 from the blister pack or by calling a toll-free
17 Before I go on to specific review of the
18 data, I would like to give you a high-level
19 overview of our findings. We were successful in
20 increasing enrollment in the Accutane survey by
21 approximately 10 percentage points but missed the
1 We found that females recalled the use of
2 the qualification sticker and that percentage was
3 almost 100 percent. In addition, almost 100
4 percent of all women knew the risks of taking
5 Accutane while pregnant and were told to avoid
6 pregnancy during Accutane. However, they did not
7 receive the pregnancy testing or were not using
8 contraception according to the package insert.
9 With regard to the enrollment rate, we
10 calculated an enrollment rate by dividing the
11 number of enrollees by the number of new patient
12 female starts. The result for the first year of
13 S.M.A.R.T. is 28.2 percent of enrollment of all
14 female Accutane users, which was up from 17 percent
15 in pre-S.M.A.R.T. year one. While, again, we
16 increased the enrollment rate, we did not succeed
17 in meeting the 60 percent metric.
19 However, when you look at the method of
20 enrollment, we were very successful in shifting the
21 method of enrollment from the blister pack to the
physician's office. Again, if you
1 enrollment card is within the "Be Smart, Be Safe,
2 Be sure" educational brochure and we see this as a
3 marker that education was occurring within the
4 physician's office.
6 When we asked females at the start of
7 therapy what might Accutane do if it is taken
8 during pregnancy, and did your doctor tell you the
9 importance of avoiding pregnancy while on Accutane,
10 almost 100 percent of all women indicated that it
11 causes birth defects and that their physician told
12 them the importance of avoiding pregnancy while on
15 However, when we look at two important
16 components of the S.M.A.R.T. program, pregnancy
17 testing and contraceptive compliance, we found that
18 only 64 percent of all women at the start of
19 treatment indicated that they had received two
20 pregnancy tests. We were successful in reducing
21 the women that reported no pregnancy tests from 18
percent to approximately 9 percent, but a large
1 proportion of women did not receive the pregnancy
2 testing according to the package insert.
4 When we looked at the risk category at the
5 start of treatment, we found that 50 percent of all
6 women were not sexually active but 44 percent of
7 all women reported some sort of sexual activity.
9 When we looked at sexual activity by use
10 of two forms of contraception, we found that 41
11 percent of these women indicated that they were not
12 using two safe and effective forms of contraception
13 at the start of their treatment.
15 When we looked at non-compliance with
16 contraception by age, we noticed that females 12-19
17 reported the highest percent of not sexual
18 activity. However, women 20-29, 30-39 and 40-44
19 who were sexually active reported high levels of
20 not using two forms of contraception, 20 percent,
21 35 percent and 40 percent respectively.
1 We noted previously from the prescription
2 compliance survey that a large percentage of
3 prescriptions had the sticker affixed. In this
4 case, the percentage is similar, 97 percent of all
5 women indicated that a qualification sticker was
6 affixed to their prescription. However, when we
7 asked them about baseline pregnancy testing,
8 receipt of two or more pregnancy tests and sexual
9 activity by using two safe and effective forms of
10 contraception, the percentages were no different
11 between those women who reported a qualification
12 sticker affixed to their prescription and those
13 women who did not. In fact, when we look at the 22
14 cases of pregnancy, 20 of those cases of pregnancy
15 occurred in women who claimed to have a
16 qualification sticker attached to their
19 Further, when we looked at these same data
20 during treatment, 21 percent of all women during
21 treatment indicated that they had not received a
pregnancy test. Only 63 percent
of these women
1 indicated that they had received two or more
2 pregnancy tests. Again, during this time in the
3 course of their treatment they should have received
4 at least three pregnancy tests.
6 Forty percent of all women indicated they
7 were sexually active during treatment. However, 52
8 percent of these women indicated that during
9 treatment they were not using two safe and
10 effective forms of contraception as outlined in the
11 S.M.A.R.T. materials.
13 However again, we found that almost 100
14 percent of all women said that they had seen a
15 qualification sticker on their prescription during
16 the course of their treatment.
18 In summary, we believe we were successful
19 in increasing the enrollment of the Accutane survey
20 by 10 percentage points, however, we did not meet
21 the 60 percent metric set out. We increased the
proportion of patients enrolling vis-a-vis the
1 prescriber's office. For us, that was an
2 indication that education is occurring within the
3 prescriber's office. And, we believe that the
4 mechanics of the sticker are working well.
6 In addition, from the percentages in the
7 Accutane survey, women do understand the need to
8 avoid pregnancy and the consequences of becoming
9 pregnant while on Accutane. However, there was
10 incomplete compliance with both pregnancy testing
11 and with contraception. In fact, we found little
12 relationship between the qualification sticker,
13 pregnancy testing and contraception.
15 Dr. Huber?
16 Evaluation of S.M.A.R.T. Program
18 DR. HUBER: I would now like to briefly
19 review the pregnancy case reports that we have
20 received at Roche and put them in perspective--as
21 Dr. Crawford was asking earlier, the case value
2 First, I would like to go briefly through
3 the methodology. These reports come from multiple
4 sources. These are exposed pregnancies that are
5 reported via either of the vendors for the Accutane
6 survey or via spontaneous reports from healthcare
7 professionals or consumers.
9 In order to compare the pregnancy numbers
10 from S.M.A.R.T. and the pre-S.M.A.R.T. year we set
11 up the following metrics so that the numbers would
12 be somewhat comparable. What we refer to here as
13 pre-S.M.A.R.T. is that treatment was started so
14 isotretinoin or Accutane was started between April
15 1, 2001 to March 31, 2002. But, because there are
16 delays in receiving some of these reports, we
17 allowed that the report was received by August 15,
18 2002. The S.M.A.R.T. data is essentially these
19 same definitions but one year later.
20 The other issue we have to deal with in
21 the analysis of these data is that there are
numerous reports that come in, in which there is no
1 therapy date stated on the report. We don't know
2 when the therapy started. In fact, when you review
3 these, in some of these it is fairly explicit that
4 the therapy was years ago. So, we include this
5 category of therapy start dates unknown and,
6 because we don't have a therapy start date, we
7 assign them to the period in which the report was
10 To give some context to these
11 reports--there have been numerous questions about
12 rates, etc.--what I would like to do is remind you
13 of the overall use of the product. First, the
14 majority of these reports are from spontaneous
15 reporting sources, not from the survey. Also,
16 overall Accutane use has been declining since 2000.
17 I would like to focus on the estimated number of
18 females treated. This is female patients in total,
19 not just childbearing, and this is Accutane. So,
20 you see 278,000, 253,000, 218,000. I would like to
21 note that generics were introduced in 2002. So,
when you see 2003 here, the 128,000 reflects purely
1 the Accutane, not isotretinoin, data.
3 These are the pregnancy case reports we
4 have received according to the cut-offs I defined
5 earlier. For pre-S.M.A.R.T. there was a total
6 number of 150 pregnancies; for S.M.A.R.T., 183. If
7 we focus on those in which there is a treatment
8 initiation date known to occur in the period, it is
9 essentially 94 and 94. Where the biggest increase
10 has been is in this group of patients, these 89
11 with treatment initiation date unknown. I will go
12 into a little more explanation of why we think this
13 occurred in the next few slides.
15 We think it is unlikely that the true
16 number of pregnancy case reports is a true
17 increase. In other words, we don't believe it is
18 possible that an increased educational program,
19 with increased monitoring and with the
20 qualification sticker actually led to more exposed
21 pregnancies. Rather, as has been noted by several
the previous speakers, in a spontaneous
1 environment there is a percentage of reports that
2 you receive and a percentage you don't know about.
3 We believe that this is most likely what is
4 occurring here and that with the first year of
5 S.M.A.R.T. we have actually seen an increased
6 proportion of reporting.
7 Why did that occur? Of note, there was
8 increased awareness among physicians with
9 S.M.A.R.T. There was also, as Dr. Ackermann noted,
10 increased participation in the survey. Finally,
11 there is increased education and awareness among
14 To go through the details of these cases
15 now, I will start with what is the source of these
16 reports. We follow the convention of this in
17 pre-S.M.A.R.T. with a known therapy start date;
18 S.M.A.R.T. with a known therapy start date; this is
19 pre-S.M.A.R.T. and S.M.A.R.T. with an unknown
20 therapy start date cases. This bottom color here
21 is those cases that came in via the Accutane survey
from either vendor. The green is
direct to Roche
1 from a healthcare professional. This orange is
2 direct to Roche from consumers or others.
3 What you see here is that the most
4 substantial increase in number of pregnancy reports
5 is this 10 to 33 in association with the Accutane
6 survey. Also consistent with increased awareness
7 from consumers, while we didn't see an increase
8 here, what we did see was a substantial increase
9 from 19 to 30 of these cases coming to Roche from
10 consumers that had this unknown therapy start date.
12 When we start looking at this, as has been
13 noted, there are really two issues here. There are
14 those patients who are pregnant prior to starting
15 Accutane therapy and then those patients who become
16 pregnant on Accutane therapy. These data try to
17 break this down. We looked specifically at the
18 patients who were pregnant prior to starting
19 Accutane therapy. For the pre-S.M.A.R.T., of the
20 150 pregnancies, 28 or 19 percent occurred in the
21 pre-S.M.A.R.T. year; S.M.A.R.T. year one, 24 of 183
13 percent occurred prior starting Accutane
1 therapy. If we look at the number that became
2 pregnant while on Accutane therapy, 51 percent, 41
3 percent with approximately the same numbers.
4 Patients becoming pregnant within 30 days after
5 stopping, 44 or 29 percent, 58 and 31 percent. The
6 biggest increase is in this unknown category but,
7 as I stated earlier, this does include a large
8 number of cases that had unknown treatment
9 initiation and they also had unknown pregnancy
12 Looking at the demographics of these
13 patients, these are the same patients, 153
14 S.M.A.R.T., 183 S.M.A.R.T., broken down by age. Of
15 note, when you look at the 16-19 group or from
16 19-29, 12-15 percent. What is interesting is the
17 age group 20-29 declined from 41 percent to 24
18 percent but please note that 20-29 remains the
19 largest category of patients, and 30-39 is
20 essentially similar, 16 and almost 15 percent and
21 once again a large number of unknown in S.M.A.R.T.
year one. The mean or median did
3 Now coming to why are these people getting
4 pregnant, we looked for evidence of educational and
5 compliance understanding of patients. These are
6 not a linkage of survey data to these case reports.
7 Rather, this information is gathered as part of our
8 follow-up procedure for the pregnancy case reports.
9 The green is yes, the orange is no and the
10 light, pale color here is unknown. What I would
11 like to do is focus on the signed female informed
12 consent, received a spiral notebook and enrolled in
13 the Accutane survey. The axis here is the number
14 of pregnancy case reports that qualified for each
15 category. These are now the S.M.A.R.T. year one
16 cases only.
17 What we see here is that only three
18 patients stated no to recall of a signed female
19 informed consent. Only five patients stated no to
20 receiving a spiral notebook and this is in the
21 group that is our worst outcome group in that they
exposed pregnancy, and seven said no to
1 enrolling in the survey. So, of those that
2 answered, the interpretation of the data is they
3 are getting the educational materials. This is
4 also consistent with what Dr. Ackermann talked
5 about in the survey where 99 percent of the
6 patients know they are not supposed to get
7 pregnant. They do receive the educational
10 The problem, as we see it, is linking it
11 to compliance with the behaviors in the program.
12 Using the same format, this is once again
13 S.M.A.R.T. year one, the number of pregnancy case
14 reports are on this axis, two baseline pregnancy
15 tests, monthly follow-up pregnancy tests, used two
16 forms of contraception, and was the qualification
17 sticker attached.
18 I will start on the right first and 58
19 versus zero recalled the qualification sticker and
20 this is among the patients who became pregnant.
21 What is most disturbing is that 16 said no to the
question of baseline pregnancy tests; 8 said no to
1 monthly follow-up pregnancy tests; and 6 said no to
2 using two 2 forms of contraception. So, what we
3 detect in this data is a pattern of failure to
4 comply with the educational materials that they
7 I would like to review briefly the methods
8 of contraception in these cases. Now we are
9 pre-S.M.A.R.T. and S.M.A.R.T. and these were
10 focusing on the 94 with the known start date in
11 both groups. Of note, 10 were pre-S.M.A.R.T.; 11
12 of S.M.A.R.T. were using abstinence as a primary
13 method of contraception. Of note, of these 11
14 cases that reported abstinence, 4 did report
15 additionally using condoms.
16 For the two forms of contraception, 17
17 pre-S.M.A.R.T., which increased dramatically to 30
18 in the S.M.A.R.T. reports, reported using two
19 forms, one primary and one secondary. No one
20 reported in either year using two forms of
21 secondary contraception. With regards to one form
primary, 18 and 18; one form secondary, 14 and
1 11. Unknown declined from 27 to 19.
3 To put these numbers in perspective I am
4 going to use some data from the Accutane survey.
5 Dr. Mitchell will talk in more detail about these
6 later. But this is the one set of data we have in
7 which we have a numerator--the number of
8 pregnancies via the survey, and a denominator--the
9 number of patients who enrolled in the survey.
10 However, this applies only to the Slone Accutane
11 survey participants. We have not calculated this
12 rate for year one of S.M.A.R.T. in the SI because
13 there is an issue with the follow-up necessary to
14 get the patients in and sufficient follow-up is not
15 there yet.
16 The other thing is that pregnancy rates
17 get reported in multiple ways. So, you are going
18 to see some numbers potentially through the course
19 of this day kind of flying around. I would like to
20 show you two ways to try and help you understand.
21 One approach has used Accutane exposed pregnancies
1,000 of the 140-day Accutane treatment
1 courses. Given that the normal treatment course is
2 140 days, one approach has been to analyze the
3 exposed pregnancies by treatment courses. So, when
4 you see the 140-day treatment course, this is what
5 we are referring to. The other way which you will
6 see used is the number of Accutane exposed
7 pregnancies per 1,000 patients per year.
9 On this slide we are looking at these data
10 by both methods. On the left vertical axis here,
11 this is the number per treatment courses. This is
12 when we refer to the 140; zero on the bottom, 4 on
13 the top. This is the blue line, over time within
14 the survey and enrollment date year 1989 to 2002