text:
Peter Gross, M.D., Chair
Kimberly Topper, M.S., Executive Secretary
Wilma F. Bergfeld, M.D.
Michael E. Bigby, M.D.
Margaret Honein, Ph.D.
Arthur H. Kibbe, Ph.D.
Sarah Sellers, Pharm.D.
Amarilys Vega, M.D., Ph.D.
Jurgen Venitz, M.D., Ph.D.
Michael R. Cohen, R.Ph., M.S., D.Sc.
Stephanie Y. Crawford, Ph.D., MPH
Ruth S. Day, Ph.D.
Jacqueline S. Gardner, Ph.D., MPH
Arthur A. Levin, MPH (Consumer
Robyn S. Shapiro, J.D.
Brian L. Strom, M.D., MPH
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.
Jonca Bull, M.D.
John Jenkins, M.D.
Sandra Kweder, M.D.
Paul Seligman, M.D., MPH
Anne Trontell, M.D., MPH
Jonathan Wilkin, M.D.
Call to Order
Peter Gross, M.D. 4
Conflict of Interest Statement:
Kimberly Topper, M.S. 4
Effectiveness of the Isotretinoin Risk Management
Program for the Prevention of Fetal Exposure to
Accutane and its Generic Equivalents
Consideration of Whether Changes to this
Isotretinoin Risk Management Program would be
Open Public Hearing
Representative Bart Stupak 8
Gordon Day 21
LaDonna Williams 25
Boni Elewski, M.D. 29
Paul L. Smith 35
Debbie Banner 40
Carter Crosland 46
Lisa Crosland 51
Jeffrey Federman 57
Responses from Slone Epidemiology Center
Allen A. Mitchell, M.D. 66
Introduction of Questions:
Paul Seligman, M.D., MPH 101
Committee Discussion 106
FDA Presentation:
Kathleen Uhl, M.D. 183
Carl Kraus, M.D. 192
Anne Trontell, M.D., MPH 205
Hoffmann-La Roche Presentation:
Martin H. Huber, M.D. 208
Committee Discussion 243
2 Call to Order
3 DR. GROSS: We would like to begin by
4 reading the Conflict of Interest Statement
5 Conflict of Interest Statement
6 MS. TOPPER: The following announcement
7 addresses the issue of conflict of interest with
8 respect to this meeting and is made a part of the
9 record to preclude even the appearance of such at
10 this meeting.
11 The topics to be discussed at today's
12 meeting are matters of broad applicability. Unlike
13 issues before a committee in which a particular
14 sponsor's product is discussed, issues of broad
15 applicability involve many sponsors and their
16 products.
17 All FDA participants have been screened
18 for their financial interests as they may apply to
19 the products and companies that could be affected
20 by the committee's decisions. Based on this
21 review, it has been determined that there is no
potential for an actual or apparent conflict of
1 interest at this meeting with the following
2 exception:
3 In accordance with 18 U.S.C. 208(b)(3),
4 Dr. Ruth Day has been granted a waiver that permits
5 her to participate fully.
6 A copy of the waiver statement may be
7 obtained by submitting a written request to the
8 Food and Drug Administration's Office of Management
9 Programs, Division of Freedom of Information HFI-35
10 at 5600 Fishers Lane in Rockville, Maryland 20857.
11 Because issues of broad applicability
12 involve many sponsors and their products, it is not
13 prudent to recite all potential conflicts of
14 interest as they apply to each member, consultant,
15 and guest speaker.
16 There will be no industry representative
17 at today's meeting. As you are aware, the Food and
18 Drug Administration has appointed industry
19 representatives who currently serve on each of
20 these committees, but Annette Stemhagen, the
21 industry rep from the Drug Safety and Risk
Management Committee, and Peter Kresel, the
1 industry rep from Dermatologic and Ophthalmic Drugs
2 Advisory Committee, work with sponsors that are
3 directly impacted by the matter before the
4 committee.
5 FDA has contacted three other industry
6 representatives from other Center for Drug
7 Evaluation and Research Committees that have
8 experience in risk management and with the FDA
9 Advisory Committee process, however, none were
10 available to participate in this meeting.
11 Dr. Stemhagen and Mr. Kresel are present
12 in the audience and attending as interested
13 observers. Further, we would like to note that Dr.
14 Lou Morris, a member of the Drug Safety and Risk
15 Management Advisory Committee, has been recused
16 from participating in today's meeting. Dr. Morris
17 is also present in the audience and attending as an
18 interested observer.
19 We would like to remind the FDA
20 participants not to discuss issues at hand outside
21 the advisory committee meeting.
In the event that the discussions involve
1 any other products or firms not currently on the
2 agenda for which FDA participants have a financial
3 interest, the participants involvement and
4 exclusion will be noted for the record.
5 With respect to all other meeting
6 participants, we ask in the interest of fairness
7 that they address any current or previous financial
8 involvement with any firm whose product they may
9 wish to comment upon.
10 Thank you.
11 Open Public Hearing
12 DR. GROSS: We will begin with the open
13 public hearing.
14 Both the Food and Drug Administration and
15 the public believe in a transparent process for
16 information gathering and decisionmaking. To
17 ensure such transparency at the open public hearing
18 session of the Advisory Committee meeting, FDA
19 believes that it is important to understand the
20 context of an individual's presentation.
21 For this reason, FDA encourages you, the
open public hearing speaker, at the beginning of
1 your written or oral statement to advise the
2 committee of any financial relationship that you
3 may have with the sponsors of any products in the
4 pharmaceutical category under discussion at today's
5 meeting. For example, this financial information
6 may include the sponsor's payment of your travel,
7 lodging, or other expenses in connection with your
8 attendance at the meeting.
9 Likewise, FDA encourages you at the
10 beginning of your statement to advise the committee
11 if you do not have any such financial
12 relationships. If you choose not to address this
13 issue of financial relationships at the beginning
14 of your statement, it will not preclude you from
15 speaking.
16 The first speaker in the hearing will be
17 Representative Bart Stupak.
18 MR. STUPAK: Good morning. I do not have
19 any financial interests with anyone,
20 pharmaceuticals or any of the sponsors here today.
21 Thank you for the opportunity to allow me
22 to
address this Accutane Advisory Committee.
1 have submitted a written statement, so let me
2 highlight some parts of it.
3 The FDA has documented 366 pregnancy
4 exposures since the inception of the S.M.A.R.T.
5 program. Because the reporting of the pregnancy
6 exposures to isotretinoin is voluntary, there is no
7 way of knowing how many pregnancies have actually
8 occurred. In fact, Dr. Graham of the FDA has
9 actually estimated the yearly exposure rate may be
10 as high as 2,000, and that has recently been
11 revised, may be as high as 3,500 per year. This,
12 of course, does not include abortions.
13 It seems clear that the only way to
14 dramatically reduce the rate of pregnancy exposures
15 in Accutane patients is to regulate like the FDA
16 regulates Thalidomide.
17 A toothless, voluntary registry does not
18 work, and we all know it. The registry should be
19 mandatory for all female and male patients, for all
20 prescribers and dispensers of Accutane. There
21 should be real consequences for refusal to
participate in a program. I plan
to introduce that
1 legislation in the coming weeks.
2 For 22 years, we have seen the harm
3 Accutane can do to pregnant women and to our
4 children. How many more babies have to be born
5 with serious birth defects, how many more women
6 need to have miscarriages, and how many more
7 children have to die before the FDA implements
8 meaningful protections and restrictions on the use
9 of Accutane?
10 The risk of severe birth defects caused by
11 Accutane is undisputed. Let's take a look at the
12 history of this drug a little bit, because I don't
13 think anyone has ever focused on the full history
14 of this drug.
15 Go back to the Advisory Committee hearings
16 of 1988, 1989, and 1990. Roche had assured
17 Advisory Committees that Accutane would be
18 prescribed only to women with severe recalcitrant
19 cystic acne and pregnancy exposure rates would
20 dramatically decrease because the average
21 dermatologist would only see less than one female
22 per
year that would require Accutane therapy.
1 Therefore, they concluded it would be
2 limited to 5,000 new patients per year, and Roche's
3 advertising would focus, not on Accutane usage, but
4 future ads would, quote, "dramatically" focus on
5 "contraindication and proper use of pregnancy
6 prevention."
7 With those assurances, even the 1988
8 Advisory Committee, by consensus, considered
9 limiting the use, prescription and distribution in
10 four ways, but this consensus was never acted upon
11 and the committee concerns were largely forgotten
12 as Roche went on to make Accutane their second
13 highest selling drug.
14 Ten years later, the FDA and Roche
15 implemented the Pregnancy Prevention Program after
16 continued pregnancy exposures. In this program,
17 pharmacists, patients, and physicians were to work
18 together to decrease the pregnancy exposures to
19 Accutane.
20 Despite the PPP, the red stickers, the
21 voluntary consent form, and the NO pregnancy symbol
with the red line through it, Accutane pregnancy
1 exposures continued at unacceptable levels. In
2 fact, many patients, when they saw that pregnancy
3 with the line through it, the women actually
4 thought that Accutane was a form of birth control.
5 Not only did the number of female patients
6 receiving Accutane dramatically increase, so did
7 the off-label use of Accutane. It is estimated
8 that 90 percent of Accutane use is for off label,
9 and the FDA is of the opinion that many of the
10 prescribing physicians do not understand the
11 teratogenic effects of Accutane.
12 At the end of the September 2000 Advisory
13 Committee hearing, the Advisory Committee
14 recommended five conditions, and I am sure you are
15 all familiar with them.
16 The FDA agreed with the Advisory Committee
17 recommendations. FDA and Roche then began their
18 discussions on how to implement these
19 recommendations.
20 While the focus of these negotiations
21 centered on a pregnancy risk management program,
22 the
U.S. House of Representatives became involved
1 after the death of my son. In October of 2000, my
2 family and I went public with our concerns that
3 Accutane was associated with suicides in some
4 patients. Back then, Roche and the FDA claimed
5 there were 37 suicides. I believe there were at
6 least 54 associated with Accutane use.
7 Congressional hearings were held in
8 December of 2000 and again on December 11, 2002.
9 The December 2002 congressional Oversight and
10 Investigation Subcommittee hearing was attended by
11 12 members of the Energy and Commerce Committee.
12 The answers we sought were to the numerous
13 issues relating to Accutane, but included the
14 continued pregnancy exposure and the psychiatric
15 effects of Accutane. Committee members were
16 appalled when they learned that the FDA had
17 reversed its position and decided it was not
18 necessary to implement the September 2000 Advisory
19 Committee recommendations.
20 The FDA excuses of privacy and HIPAA
21 concerns for not implementing these recommendations
rang hollow with congressional committee members.
1 In the meantime, Roche continued to
2 aggressively market Accutane, growing to 1.51
3 million prescriptions in 2001.
4 The FDA negotiations with Roche produced
5 an agreement called the S.M.A.R.T. program.
6 S.M.A.R.T. did not fulfill the recommendations made
7 by the Advisory Committee. The S.M.A.R.T. program
8 began five months before the December 11, 2002
9 hearing.
10 Witnesses from the March of Dimes and the
11 Organization of Teratology Information Services,
12 OTIS, as we call them, testified that the
13 S.M.A.R.T. program would not achieve its
14 objectives, and the S.M.A.R.T. program did not go
15 far enough.
16 The OTIS representative further testified
17 that a partial review of their organization had
18 already revealed 17 cases of pregnancy exposure to
19 Accutane and that there was a lot of slippage in
20 the system.
21 At the hearing, the Chairman of our
committee asked the FDA, "What is your fallback
1 position if the S.M.A.R.T. program doesn't improve
2 things with the pregnancy exposures?"
3 Dr. Woodcock answered that for a variety
4 of reasons, FDA would evoke its authority under the
5 Food, Drug, and Cosmetic Act only as a last resort.
6 Members of the committee also learned
7 firsthand the FDA was dragging its feet. The FDA
8 failed to provide relevant documentation until the
9 day of the hearing, when they dropped off a number
10 of boxes filled with information requested by the
11 committee.
12 The FDA had evidence of the failings of
13 the S.M.A.R.T. program from its inception. Doctors
14 were pre-dating yellow stickers that signify the
15 female patient had received a negative pregnancy
16 test. Medical clinics were pre-dating
17 prescriptions so the patient could fill more than
18 one prescription within the seven-day limit of the
19 negative pregnancy test.
20 At least one patient was purchasing
21 Accutane with no pregnancy test, no prescriptions,
22 no
consent forms. Some health care plans,
1 electronically dispense their prescriptions, were
2 not using the yellow negative pregnancy sticker.
3 Pharmacies were not giving out the Med
4 Guides for Accutane, and that compliance with these
5 toothless regulations were not working. In fact,
6 approximately 50 percent of the doctors were not
7 using the informed consent forms because it's
8 voluntary.
9 The FDA withheld this information from our
10 committee at the December 11th hearing.
11 Now, Roche said they will support a
12 mandatory registry and submit a proposal. Please
13 understand my and a number of committee members
14 skepticism after going through the numerous
15 Advisory Committee hearings. I still do not
16 believe the FDA and Roche will ever institute a
17 registry and certification program similar to that
18 of S.T.E.P.S. for Thalidomide.
19 Equivalent effects call for equivalent
20 restrictions. There must be a mandatory
21 isotretinoin registry for patients, doctors, and
pharmacists. Pregnancies will
continue to occur if
1 any element is left out of the registry. There
2 must be consequences for failure to comply with any
3 part of the program.
4 FDA complains that if we do this, we will
5 send this drug to a black market. Since 1999,
6 myself and other members of Congress have tried to
7 address this issue on the Internet. We have asked
8 for the FDA to comment on our legislation, where
9 can we improve upon it. To date, FDA has not
10 answered.
11 The manufacturer of Accutane, Hoffmann-La
12 Roche, is just as culpable as the FDA in allowing
13 Internet and mail order of Accutane in the country.
14 Roche hides behind the FDA's inaction to complain
15 of Internet sales. Yet, their product coding
16 allows them to determine the exact location of
17 where products are shipped, to whom, and when.
18 We can cut down on these illegal sales, it
19 can be done. In fact, our committee has convinced
20 Purdue Pharma to stop shipping oxycotin to Mexico
21 as it is being brought back across the U.S. border.
Yet, when we pointed this out, what we have been
1 able to do in Mexico, and that Mexico does not have
2 the same regulatory scheme for Accutane as we have
3 in this country, Roche has refused to stop the
4 shipment of Accutane to Mexico.
5 Answers as to why Roche isn't really
6 serious about entering into a mandatory registry
7 for Accutane for patients is very clear. Roche did
8 all it could to defeat the registry for Accutane as
9 recommended by the September 2000 Advisory Panel.
10 In fact, the recommendations or the defeat
11 of those recommendations was a cause to celebrate
12 because, as Roche says, there is no psychiatric
13 registry.
14 Not only did Roche view the defeat of the
15 registry as a cause to celebrate, and they
16 protected their $450 million sales in Accutane,
17 Roche does not want any form of registry that would
18 provide insight into the psychiatric effects on
19 patients.
20 Roche is so fearful that a registry may
21 provide evidence of Accutane causing psychiatric
injury to young, developing brains that it will
1 stop at nothing to prevent the registry.
2 If you go back and take a look at the
3 history of this drug, Roche, in its initial
4 application to the FDA, they forgot to submit a
5 study, a study which was uncovered, which shows
6 that Accutane does adversely affect the central
7 nervous system in mice.
8 The committee has uncovered three more
9 studies, subsequent studies, that also suggest
10 Accutane does have some effect on the central
11 nervous system. Even the FDA, which has been
12 working with the National Institute of Mental
13 Health and the National Institute of Health has
14 kept from the Advisory Committee and the American
15 people their preliminary studies which do suggest a
16 causation between Accutane and psychiatric
17 injuries. Both the FDA and Roche have misled and
18 failed to protect the American people, unborn
19 children, and young adults from the devastating
20 effect of this drug.
21 I hope this time the FDA does not allow
22 the
manufacturers of Accutane and its generics to
1 come in and water down the recommendations that may
2 be made by this Advisory Committee.
3 I am not sure Congress is willing to let
4 them do that anymore. As I said earlier, I will be
5 introducing legislation to establish a mandatory
6 registry of patients, doctors, and pharmacists,
7 similar to that of the Thalidomide registry.
8 Within the documents provided by the FDA,
9 there is a statement provided by an exasperated FDA
10 investigator who cries out, how could the FDA grant
11 a patent extension on Accutane for use in young
12 patients with the devastation this drug has caused?
13 One begins to ask, what special powers or charm
14 does Roche have over the FDA?
15 It is time to put restrictions on the
16 users, prescribers, dispensers and marketers of
17 Accutane and its generics.
18 Thank you and if there is any questions, I
19 will be pleased to answer them.
20 DR. GROSS: Thank you very much,
21 Representative Stupak.
The second speaker is Gordon Day, who is
1 President-Elect of the Society of Dermatology
2 Physician Assistants.
3 MR. DAY: Good morning, Advisory Members.
4 My name is Gordon Day, and I am a
5 certified physician assistant, and I practice
6 dermatology in Sandy, Utah, a suburb of Salt Lake
7 City.
8 I am the President-Elect of the Society of
9 Dermatology Physician Assistants. The SDPA is a
10 national medical association of 900 members whose
11 mission is to improve patient care by providing
12 additional education and training for our members.
13 Physician assistants are but one group of
14 physician providers that prescribe isotretinoin.
15 We are an integral component of the medical team.
16 The collegial and dependent relationship we have
17 with dermatologists contributes directly to the
18 quality of diagnostic and therapeutic care
19 furnished to our patients.
20 The uniqueness of our position allows us
21 to spend more time with patients, providing
education on the therapeutic options for acne
1 treatment including the risks and benefits of
2 isotretinoin therapy. This also includes
3 contraceptive counseling.
4 Our Society firmly believes it is
5 necessary to assure the public that our members who
6 prescribe medications such as isotretinoin are
7 qualified to do so. Continuing medical education
8 and other life-long learning opportunities offered
9 by our Society include compliance with the
10 manufacturer-developed and FDA-approved risk
11 management program for fetal exposure.
12 It is also essential that medical
13 providers using isotretinoin be proactive in ways
14 that guarantee the continued availability of this
15 drug for qualified patients, and that is why I am
16 here today.
17 There are few other therapeutic options
18 available to us to effectively treat nodulocystic
19 acne. Additionally, it is important to the
20 dermatology health care team that patients be
21 compliant in all aspects of isotretinoin therapy,
including adherence to contraceptive practices
1 which are in place to minimize the likelihood of
2 adverse outcomes.
3 The importance of isotretinoin cannot be
4 emphasized strongly enough for our patients with
5 severe acne, who can avoid scarring and
6 disfigurement by use of this medication.
7 As a physician assistant in dermatology, I
8 see older patients on a daily basis who would have
9 benefited from isotretinoin, but whose bouts of
10 this severe acne occurred before this wonder drug
11 was approved for sale in the United States. They
12 will be scarred forever.
13 I have observed firsthand how patients
14 with severe cystic acne may be so concerned with
15 their appearance that it affects their daily
16 living, self-concept and quality of life. There
17 are patients I care for who will not go swimming
18 because of the severe cystic acne lesions and
19 scarring on their backs and shoulders.
20 I have female patients that have limited
21 outings socially because of their severe cystic
acne, and I have those patients who suffer from low
1 self-esteem and required psychiatric treatment
2 because of their severe acne. Isotretinoin is an
3 important tool for helping these patients when all
4 other options fail to improve their condition.
5 In the dermatology practice where I
6 provide care, in an attempt to avoid adverse
7 outcomes, I not only employ the S.M.A.R.T. program,
8 but also have developed a protocol that I and my
9 supervising physician, and other members of our
10 health care team use to make sure that all the
11 necessary risk management program components are
12 documented when using isotretinoin.
13 This enhanced protocol encompasses review
14 of side effect profiles, pregnancy testing,
15 contraceptive counseling, the completion of
16 time-specific laboratory testing, a thorough review
17 of the patient's own responsibilities,
18 participation in the survey, and completion of the
19 informed consent process.
20 It is an unfortunate fact that a small
21 number of fetal exposures still occur in female
isotretinoin patients, relative to the overall
1 number of female patients taking this drug.
2 Therefore, the Society of Dermatology
3 Physician Assistants would like to collaborate with
4 the American Academy of Dermatology Association and
5 the FDA on improving the effectiveness of the
6 current risk management program in ways that lead
7 to fewer adverse outcomes and safeguard patient
8 confidentiality and rights in the health care
9 system.
10 This process, once completed, should serve
11 as an educational tool for the patients, the
12 prescribers, and the pharmacists.
13 Thank you.
14 DR. GROSS: Thank you, Mr. Day.
15 The third speaker is LaDonna Williams,
16 Executive Director, Inflammatory Skin Disease
17 Institute.
18 MS. WILLIAMS: Good morning. I am LaDonna
19 Williams, and I am the Executive Director of the
20 Inflammatory Skin Disease Institute, a patient
21 advocacy group that provides education, public
awareness, and support to those patients with
1 inflammatory skin disease and their families.
2 Inflammatory skin disease is a broad
3 category of conditions ranging in severity. As you
4 can imagine, these diseases are very distressing to
5 those who have them, causing great discomfort and
6 real emotional distress.
7 You can learn more about inflammatory skin
8 disease by visiting our web site
9 www.isdi.online.org.
10 I feel it is important to be here today on
11 behalf of the patients who suffer from the
12 inflammatory skin disease acne. Severe acne is
13 characterized by papules, pustules and inflamed
14 nodules. Acne is a common skin disease and can be
15 a very serious medical condition.
16 For many Americans it is more than a
17 temporary cosmetic problem that can be treated by
18 over-the-counter lotions and creams.
19 For many Americans it is more than a
20 condition that can be treated by antibiotics, oral
21 contraceptives, or steroids. Indeed, for thousands
22 of
unfortunate Americans, acne can be a
1 life-altering and a socially terminal medical
2 condition for which isotretinoin is the only
3 effective method of treatment.
4 I am representing hundreds of acne
5 patients who cannot be here today. These patients
6 are both male and female, teenagers and adults who
7 have contacted me to express their strong support
8 for continued access to isotretinoin. This drug
9 literally worked wonders for them and they want to
10 make certain that it remains available for other
11 severe acne sufferers.
12 You have already reviewed reams of
13 briefing material and listened to hours of
14 testimony about the current risk management effort
15 to reduce fetal exposure to isotretinoin.
16 The Inflammatory Skin Disease Institute
17 agrees it is necessary to provide and improve a
18 program and reduce the number of pregnancies
19 associated with this drug keeping in mind I have
20 received numerous letters from teenagers and adults
21 stating how isotretinoin saved their skin and their
1 Many parents have written to me on behalf
2 of their children. One grateful mother told me how
3 isotretinoin improved her daughter's skin, and not
4 only made positive changes in her teenager's life,
5 but made positive changes in the whole family
6 because they could go out in public and do social
7 things together again.
8 I have received calls in my office from
9 patients and their parents explaining how academics
10 in high school has improved dramatically because
11 attendance became 100 percent after isotretinoin
12 cleared up their student's acne.
13 One patient had to consider to leave her
14 job that she loved very much because her acne was
15 so severe that her face was in a constant state of
16 being red, swollen, and painful, with disfiguring
17 pustules. Children were afraid of her, which in
18 turn made her withdrawn and depressed. She took
19 isotretinoin and she feels it saved her job, her
20 relationships, and her life.
21 I could go on and on with personal
accounts from patients for whom isotretinoin made a
1 positive difference in their lives. It is on their
2 behalf that I speak with you today.
3 I thank you for your time and your
4 attention in listening to these stories, and I hope
5 you will keep these testimonies in mind as you
6 debate the future direction of the isotretinoin
7 risk management program.
8 If I may close with somewhat of a cliche -
9 the effectiveness of isotretinoin goes beyond skin
10 deep. I hope that I have impressed upon this
11 committee how absolutely essential it is for this
12 drug treatment for acne to remain on the market,
13 and I hope I have impressed upon you how essential
14 it is for the qualified patients
15 Thank you.
16 DR. GROSS: Thank you.
17 The next speaker is Dr. Boni Elewski,
18 President of the American Academy of Dermatology,
19 the fourth speaker.
20 DR. ELEWSKI: Good morning, everyone.
21 My name is Dr. Boni Elewski. I am a
practicing dermatologist and Professor of
1 Dermatology in the Department of Dermatology at the
2 University of Alabama in Birmingham.
3 In addition to my medical duties, I am
4 also President of the American Academy of
5 Dermatology Association. On behalf of the 14,000
6 members of the Association, and our hundreds of
7 thousands of acne patients, I thank you for the
8 chance to speak with you about the current
9 pregnancy risk management program for isotretinoin.
10 The health, safety, and welfare of our
11 patients is of paramount importance to
12 dermatologists, as is the integrity of the
13 doctor-patient relationship. Indeed, because of
14 these concerns, our organization is committed to
15 optimizing the safety of our patients taking this
16 drug, as well as ensuring continued access to
17 isotretinoin for all qualified prescribers.
18 Education and communication with our
19 members and their patients about isotretinoin
20 compliance is essential to the safe use of this
21 drug.
The current risk management program has
1 been promoted in numerous education and
2 communication efforts, such as CME activities,
3 Member Alerts, articles on our web site, in our
4 official publication Dermatology World, and will be
5 augmented by new initiatives.
6 In addition, the Association hosted a
7 scientific consensus conference on the safe and
8 optimal use of isotretinoin to which key
9 decisionmakers in the FDA and the scientific
10 community were invited. The proceedings will be
11 published next month.
12 Recently, the Association sent a letter to
13 the FDA Commissioner with a list of web sites that
14 sell isotretinoin on line. We hope this
15 information will assist the agency with addressing
16 the problem of illicit sales of this powerful drug.
17 You have just heard a number of compelling
18 stories about the benefits of isotretinoin therapy.
19 I myself have treated hundreds of patients whose
20 quality of life has improved tremendously because
21 of this drug.
This is because acne is not simply a
1 cosmetic problem. In 1948, renowned dermatologist
2 Dr. Marion Sulzberger said, and I quote, "There is
3 no single disease which causes more psychic trauma,
4 more maladjustment between parents and children,
5 and general insecurity and feelings of inferiority
6 and greater sums of psychic suffering than does
7 acne." More than a half century later, his
8 observation still rings true.
9 When all other treatment options fail,
10 isotretinoin is the miracle drug that clears away
11 the redness, painful swelling, and lesions of
12 severe, nodulocystic acne, which may lead to
13 painful and disfiguring scars.
14 Unfortunately, a small number of women are
15 pregnant or become pregnant while taking this drug.
16 As always, our goal is to ensure both patient
17 safety and continued access to isotretinoin for all
18 qualified patients. For this reason, we would like
19 to offer the following recommendations for
20 improving the current risk management program.
21 First, the survey of female patients
should be mandatory, not voluntary.
We propose
1 that isotretinoin therapy be prescribed for
2 qualified female patients only if they participate
3 in the survey. Data generated by this mandatory
4 survey would be more complete. Of course, it is
5 the ultimate responsibility of the female patient
6 to comply with the birth control requirements of
7 the program and to avoid pregnancy.
8 Second, a single questionnaire and vendor
9 for the female patient survey should be designated.
10 The present situation with the generic
11 manufacturers using one questionnaire and vendor,
12 and Hoffmann-La Roche using another questionnaire
13 and vendor, is confusing to prescribers and
14 patients alike.
15 Furthermore, differences in the surveys
16 make it difficult to compare data. A single
17 questionnaire and vendor would minimize this
18 confusion, improve data gathering, and promote
19 patient safety and education, and ultimately
20 improve the health, safety, and welfare of our
21 patients taking this drug.
Third, the survey questionnaire should be
1 re-evaluated and simplified to obtain the pertinent
2 information to assess the risk management program.
3 Ultimately, this will improve the health, safety,
4 and welfare of our patients taking isotretinoin.
5 Fourth, the current risk management
6 program must be clarified and simplified to address
7 ongoing issues of concern for doctors and patients
8 alike.
9 And finally, it is crucial that program
10 materials warn patients to avoid Internet sales,
11 avoid re-use, or sharing of isotretinoin.
12 Let me close by saying, the preservation
13 of the doctor-patient relationship is crucial, and
14 may I add, an integral component to the risk
15 management system. As we strive to improve the
16 current risk management program for isotretinoin,
17 the American Academy of Dermatology Association's
18 guiding principle has always been, and will
19 continue to be, the health, safety and welfare of
20 our patients.
21 Thank you.
DR. GROSS: Thank you, Dr.
1 The next speaker, the fifth speaker, is
2 attorney Paul Smith.
3 MR. SMITH: Good morning. My name is Paul
4 Smith and I am an attorney practicing law in
5 Austin, Texas.
6 My practice relates exclusively to
7 pharmaceutical litigation and for the past two
8 years I have worked nearly full time on behalf of
9 families and individuals who have experienced
10 devastating and catastrophic side effects from
11 Accutane.
12 In connection with this privilege, I have
13 personally seen and known dozens of individuals and
14 families whose lives have been horribly altered as
15 a result of this powerful and dangerous drug.
16 The tragedy of a parent who has lost their
17 child to suicide and the tragedy of these parents
18 and babies who have to live with serious and
19 permanent birth defects is beyond description.
20 I understand that as my role, I am charged
21 with the responsibility to seek redress for these
people in the court system.
However, today, I am
1 stepping out of my role as a legal advocate, today,
2 I come before you as a member of the public who has
3 talked to and seen many who have been harmed by
4 Accutane.
5 Today, I am asking you to take a serious
6 and deliberate look at risk presented by this drug,
7 which has not, in my opinion, been fairly and
8 accurately examined.
9 You are fortunate to have the ability to
10 suggest and ensure that the tragedies that I have
11 seen in connection with this drug are substantially
12 reduced.
13 For over 20 years now, the FDA has made an
14 effort to regulate this product by adding warnings
15 and warnings in connection with this drug. This is
16 a laudable goal to try to ensure some safe use of
17 this product, however, as has been well established
18 and is beyond dispute today, the various programs
19 that have been instituted have failed miserably.
20 The admission and concession by Roche that
21 a registry is needed is too late for many. If
there is a registry, however, there are two
1 components which must be incorporated.
2 The first involves paternal exposure, that
3 is, where the father takes Accutane when the mother
4 conceives the fetus. This is limited to treatment
5 of the father with Accutane.
6 The second is the incredible failure of
7 Roche to consider the known psychiatric component
8 of the drug to impair complete compliance with any
9 rational program aimed at preventing fetal
10 exposures.
11 The dangers and risk of paternal exposure
12 is something that must be better studied and
13 understood. I point you to the Thalidomide
14 warnings which strongly advised male patients
15 taking Thalidomide to use contraceptive measures.
16 This is in dramatic contrast to the Accutane,
17 which suggests that there is no risk to the fetus
18 as the result of paternal exposure.
19 I have with me recently released documents
20 that indicates that Roche's own internal experts
21 has, in reviewing 13 potential paternal exposures,
found that in 5 of those cases, a possible
1 relationship could not be excluded.
2 This is a document that Roche fought hard
3 to keep from the public. I have it here with me.
4 It is sitting here for your review. I would
5 welcome and request that you get a copy of this and
6 review it thoroughly.
7 Carter Crosland, who is here with his
8 mother and father, is, in fact, one of the five
9 whose medical records were examined by the Roche's
10 internal geneticist. The Roche consultant
11 concluded that Carter's difficulties could very
12 well be related to Accutane embryopathy.
13 Roche's response to this phenomena and the
14 risk associated with paternal exposure is
15 inadequate. The public should be aware the
16 potential exposure does exist, and there should be
17 warnings specifically advising that there is
18 problem with paternal exposure.
19 We would strongly urge a registry that
20 includes males using Accutane that specifically
21 tracks their sexual activities.
The second issue for your consideration is
1 the inability of certain patients to comply with
2 warning and instructions as a direct result of
3 known psychiatric side effects presented by this
4 drug.
5 Only Roche disputes that Accutane may
6 cause depression and behavioral changes. It seems
7 to be well accepted within the rest of the
8 scientific community that there is a strong
9 relationship between Accutane and psychiatric
10 adverse events and depression.
11 I have seen nothing publicly which
12 suggests that Roche has even considered this
13 foreseeable and predictable phenomenon of pregnancy
14 secondary to impaired capacity as a result of
15 depression.
16 Debbie Banner is here to explain to you
17 how she got depressed and was unable to comply with
18 the program in effect at the time to prevent her
19 pregnancy.
20 I thank you for your attention and your
21 kind consideration and again the paternal exposure
study itself that was submitted to the FDA is here
1 for your review.
2 Thank you very much.
3 DR. GROSS: Thank you, Mr. Smith.
4 The sixth speaker is Debbie Banner.
5 MS. BANNER: Good morning. My name is
6 Debbie Banner. I am here with my husband Kevin. I
7 have known my husband since I was 17, and we have
8 been married for seven years. I appreciate this
9 opportunity to share with the members of this
10 honorable committee my horrifying experience with
11 the drug Accutane.
12 Starting today, we will offer one of the
13 answers to this question, why are girls continuing
14 to become pregnant while on Accutane despite the
15 warnings that Accutane causes birth defects?
16 I am afraid that one of the answers I will
17 propose today is one that neither the FDA, this
18 committee, or Hoffmann-La Roche has adequately
19 studied or considered.
20 I am also here to describe the nightmare
21 of having a child who has been born with Accutane
birth defects.
1 I became pregnant while on Accutane. I
2 survived this nightmare by the grace of God, strong
3 faith, a loving husband, and an overwhelming
4 commitment to my son.
5 I was devastated that I played a role in
6 causing my own child to be deformed. So, I vowed
7 to sacrifice everything to give him the best life I
8 could possibly give. Because I accepted my fate
9 humbly, I believe that is why God finally revealed
10 the other side of the story to me, the missing
11 piece of the puzzle.
12 On October 4th, 1996, my son Deven was
13 born. There is no medical doubt that his birth
14 defects are due to the effect of Accutane on him as
15 a developing fetus. He has been seen by the best
16 physicians and was diagnosed with Accutane
17 embryopathy.
18 Deven was diagnosed with an underdeveloped
19 cerebellum resulting in cerebral palsy and
20 hypotonia. At the age of 7, he is fed through a
21 feeding tube that is surgically inserted into his
stomach, he suffers from seizures.
1 After four eye surgeries, he has visual
2 perceptual problems. He has sensory integration
3 problems which manifest as autistic-like behaviors.
4 He has verbal expressive disorder, speech problems,
5 and requires physical therapy, occupational
6 therapy, and speech therapy.
7 He has a chronic history of pneumonia. He
8 requires special education services in school and
9 special accommodations. Along with these and other
10 medical problems, as well as fine motor and gross
11 motor impairments, it is likely that he will be
12 unable to take care of himself as an adult.
13 I was on Accutane in 1995 when I was 24
14 years old. I was an aerobics instructor and
15 attending school. I was working two jobs. I was
16 of healthy mind, body, and spirit, so when I first
17 visited the dermatologist, I was a happy person
18 although I had an acne problem.
19 Days after ingesting Accutane, I began to
20 react as if I were poisoned. I developed severe
21 headaches and sharp, piercing head pains. I was
nauseous day and night. I was
weak, dizzy,
1 confused, forgetful, suffering from hypersomnia and
2 severe crying spells.
3 Eventually, I developed suicidal thoughts.
4 I just wanted to sleep and never wake up again. I
5 was too sick when I was awake.
6 At the initiation of treatment, I had
7 chosen abstinence as my method of birth control. I
8 chose this for religious reasons and did not plan
9 to be sexually active again until I was married.
10 However, once in a state of severe
11 depression, I became mentally incapable of making
12 appropriate decisions. My thoughts were filled with
13 thoughts of suicide and death, which eventually
14 required psychiatric intervention.
15 At the time of conception, I was no longer
16 a patient that was reliable and capable of
17 complying with mandatory pregnancy prevention
18 procedures and reliable in carrying out
19 instructions.
20 The missing piece of the puzzle was given
21 to me when I learned that the psychiatric problems
that led to my pregnancy were a side effect of
1 Accutane.
2 Through my research, I have now met other
3 mothers who became pregnant on Accutane. I have
4 learned that depression was a factor in their
5 inability to comply with the warnings that, like
6 me, led to a nightmare of birth defects.
7 I have spoken to one mother who actually
8 attempted suicide while on Accutane and became
9 pregnant weeks later. To this day, there is no
10 instruction, education, or warning on how
11 psychiatric side effects of this drug may prevent
12 you, despite the best intentions, from complying
13 with the pregnancy prevention program.
14 It seems fundamental to me now, but how
15 can you educate someone that may not be able to
16 protect themselves. How can anyone including the
17 doctors who prescribe it believe that the drug
18 could do this when Roche refuses to admit that
19 there is a psychiatric component to the drug?
20 I am here to tell you from my own
21 experience, and experience told to me by other
mothers admitted in a cloud of shame and stigma
1 that depression can and does interfere with
2 pregnancy prevention even when patients have chosen
3 other forms of birth control.
4 Because women and girls are continuing to
5 become pregnant, I plead with this committee to
6 require that females of childbearing potential
7 receive an initial psychiatric evaluation and are
8 then monitored by a psychiatrist throughout
9 treatment.
10 To leave this decision to patients who may
11 be in denial and cannot protect themselves is to
12 guarantee more birth defects and abortions.
13 Because Accutane is such a powerful drug, it is
14 worth the extra effort and expense to save children
15 from a lifetime of deformity and pain and to
16 finally bring an end to the outrageous number of
17 Accutane abortions.
18 Warning is simply not enough when
19 psychiatric side effects are involved.
20 In conclusion, I want to express my
21 sympathy for people suffering from acne, but even
22 in
the very worst cases of acne, their suffering
1 cannot compare to the suffering endured daily by
2 children born with Accutane birth defects.
3 Thank you.
4 DR. GROSS: Thank you, Debbie, and Kevin
5 Banner.
6 The seventh speaker is Carter Crosland.
7 MR. CROSLAND: Good morning. My name is
8 Carter Crosland.
9 Today, you will hear my story. Not only
10 do I speak for myself, but also for the hundreds,
11 perhaps thousands of children whose voices will
12 never be heard. Those dreams and hopes will never
13 be realized. Today, I am their voice.
14 I was born January 22, 1985, in a small
15 rural town in central Utah, the first child of my
16 parents. As a young boy, I was told that I was a
17 miracle and that I had something important to share
18 with the world. I have been blessed with the
19 health, strength, and mental faculties to speak
20 before you today. Perhaps that is my purpose.
21 As a young boy, I dreamed of being a
wrestler. I loved sports and had
an unusual talent
1 for learning statistics. I played T ball with my
2 friends and they ran the bases for me while I
3 stopped the ball with my wheelchair tires.
4 And then the boys moved on to minors and
5 majors and I stayed behind. I became the batboy
6 and then the base ump. Then the coach, manager, or
7 anything else just to stay involved. The same was
8 true with football and wrestling. As I matured, I
9 realized I would be left behind again. Not only in
10 sports, but in every single aspect of my life.
11 My parents sacrificed to get me where I
12 am, and because they worked hard, we didn't qualify
13 for disability funding from the government. I was
14 too smart. I passed all the cognitive tests,
15 despite missing a third of my brain to a cyst.
16 I passed all the skills and vocabulary
17 tests. I could even pick up the blocks with my
18 mouth and put them in the holes quickly.
19 Therefore, by their standards, I wasn't disabled,
20 and I was at the end of the waiting list without
21 assistance.
I had generous people who helped me get
1 arms as a young boy, but we couldn't keep up with
2 the constant re-fitting and trips to the city. My
3 mom worked full time to keep insurance for me, but
4 she couldn't keep leaving work for sick kids and
5 trips to the prosthetic specialist, so I gave up on
6 the arms. They were too costly.
7 When I entered first grade, my mom quit
8 work, so that I could go on field trips, birthday
9 parties, and to the library with my friends. Where
10 I went, my chair went, and also my parents and my
11 van went. That made our financial situation even
12 worse, but I appreciated having my mom around.
13 I took drivers ed at 15 and passed with
14 flying colors, well, all except for the driving
15 test. You see, I can't afford the car for me to
16 drive and the school district can't provide it. I
17 completed high school and graduated with my class.
18 I was voted most preferred senior probably because
19 I had the gift of gab and I like to visit with
20 everyone.
21 My school built a ramp so that I could
participate in pomp and circumstance with my peers.
1 I now attend college and I am studying
2 communications. I hope to be a sports broadcaster
3 or work for some firm as a public relations guy.
4 My voice is the only asset I have that
5 puts me on the same playing field as those around
6 me. It is literally the only thing I can do on my
7 own. This is what I have accomplished so far in my
8 life against all odds. Now I would like to tell
9 you what I cannot do.
10 I room with a friend at college. I pay
11 him to help me bathe, get dressed, cook my meals,
12 charge my wheelchair, get my books, help me on
13 dates, drive my car, and anything else I want to
14 do. My friends lift me up the stairs to their
15 place or to any other place that is not accessible.
16 I have to plan for bathroom breaks because
17 I need help. My friend will get married soon, and
18 I will find another person and then another, and
19 another. My parents travel to bring me home and
20 back on weekends because I cannot afford a car that
21 I can drive on my own. My buddies take me shopping
22 and
help prepare and eat my meals. They
clean up
1 for me and do my wash.
2 Because I have all my mental faculties, my
3 dreams are the same as every other young man my age
4 - a car, a job, a girlfriend, and someday a wife
5 and family. I hope for these things, but I take it
6 one day at a time, and I don't know what the future
7 holds for me.
8 I keep being determined to make the best
9 of it and to find happiness in every small thing
10 around me. Some of these dreams I can realize now
11 if I could afford it. Money is a tremendous
12 limitation, nearly as limiting as my disability.
13 Please do not make money a factor in your decision
14 to research and regulate this drug.
15 They say that I don't fit into any
16 category or syndrome because of my intelligence. I
17 feel that my mental abilities are a gift from God
18 and are for a purpose. Today, I hope that purpose
19 is to bring this matter before you to your
20 attention.
21 I hope that you will look deep into your
heart and do everything you can to study, research,
1 and take every step possible to prevent this from
2 happening to one more child. Most are not as
3 fortunate as I am. Their voices will never be
4 heard. Please hear mine.
5 I thank you for your time.
6 DR. GROSS: Thank you, Mr. Crosland.
7 The eighth speaker will be Lisa Crosland.
8 MRS. CROSLAND: Ladies and gentlemen, good
9 morning. I am Lisa Crosland, and I am here with my
10 husband Russell and my son.
11 A first pregnancy is supposed to be a
12 happy time filled with anticipation and excitement,
13 but mine was neither. For me, I was a 19-year-old
14 in college, in love. We had big plans, big plans
15 and dreams that included marriage and children, but
16 things changed when Russell began using Accutane.
17 Our relationship became a disaster filled
18 with unkept promises and unpredictable behavior.
19 An engagement was broken and so was my heart, and
20 then I found out I was pregnant and alone.
21 Things went from bad to worse. I had
recurring nightmares that the baby inside me was
1 not right. I didn't grow enough, the baby banged
2 back and forth. An ultrasound at almost six months
3 confirmed my worst nightmare.
4 We were told that our baby had no arms and
5 legs, no sex organs. The child had a third of its
6 brain covered with fluid that was increasing. They
7 felt his eyes were too big and his head too large.
8 A large growing hernia and funny-shaped mouth was
9 also evident.
10 Most doctors felt the child would abort
11 itself. Others said that if it lived, it would be
12 on life support, unable to suck, and
13 institutionalized. I was devastated and so was
14 Russell. We prayed for a miracle that our child
15 would not suffer.
16 Our miracle was not what we expected, our
17 child lived, and today we are telling his story.
18 As parents, our first concern was why did this
19 happen, what did I do. Parents need to know why
20 this has happened to them.
21 I had lived what I thought was a clean and
healthy life. I did not smoke, I
did not drink or
1 use drugs. Every effort was made to determine what
2 I could have done to prevent this as a mother.
3 Yet, we turned up empty-handed.
4 The first time I heard the word Accutane
5 embryopathy was from a genetics counselor at the
6 University Hospital in Salt Lake City. Carter was
7 almost three months old and had just had his second
8 surgery. The doctor felt Carter's symptoms were
9 too similar to maternal Accutane exposure to
10 ignore.
11 I told her that I had never used the drug,
12 but his father had before, during, and after I
13 became pregnant. Carter has been worked up by the
14 best doctors and the best facilities. Everyone
15 wanted to know whether Russell or I carried some
16 odd genetic code that would cause this in the
17 future.
18 We looked everywhere, but there was
19 nothing else but Accutane. We reported an adverse
20 reaction to Hoffmann-La Roche, who responded that
21 this could not be the cause of our child's
deformities. A few years later I
spoke directly to
1 a doctor at Hoffmann-La Roche who told me that
2 there were a few other reports of paternal
3 exposure, but all could be attributed to another
4 cause.
5 I even asked for and received films and
6 study materials from Roche. You see, as we have
7 now learned from Roche's internal documents made
8 public only after Roche fought and lost the battle
9 to keep it private. Carter has all the clinical
10 signs of Accutane embryopathy.
11 Roche initially agreed that paternal
12 exposure to Accutane could not be ruled out. Why
13 then hasn't this been researched? Are kids like
14 Carter not worth it?
15 Since this time, I have seen warning
16 labels and adverse reports increase, more children
17 aborted and affected. I have studied and found
18 more and more similarities to things Carter was
19 experiencing in his life that other children whose
20 mothers were exposed were experiencing.
21 His mouth, his dental problems, his
problems with temperature regulation are just a few
1 of the less visible problems. Some children whose
2 only link is a mental I.Q. of under 85 have been
3 attributed to Accutane. I find it impossible not
4 to include Carter in this category simply because
5 his father was the user and he is normal in
6 intelligence.
7 Of course, it may very well be that women
8 who become pregnant from a father who has taken
9 Accutane may never put the issue together. The
10 possibilities of hundreds and thousands of
11 abortions simply attributed to poor development or
12 unwanted pregnancy may have occurred, with the
13 public being kept in the dark of these risks.
14 The fact that there has not been more
15 reporting of this issue does not mean that there is
16 not a serious risk and danger. It only means that
17 Roche has been successful in keeping this from the
18 public.
19 This drug Accutane has devastated my
20 family emotionally, physically, and financially.
21 It has been carelessly over-prescribed and
under-regulated. It has destroyed
our dreams and
1 shattered our lives, yet we stand before you today
2 united in our efforts to demand a change.
3 We want adequate research and funding into
4 the possibility of paternal exposure of retinoids.
5 We want the prescription of this drug for
6 dermatological reasons restricted to dermatologists
7 who are forced to prescribe it only as a last
8 resort for both men and women.
9 We want those greedy individuals who
10 facilitate unprescribed Internet sales of this drug
11 stopped and prosecuted.
12 Most of all, we want answers, not only for
13 ourselves, but for the hundreds of babies aborted
14 who may very well be exactly like Carter, but
15 discarded.
16 I cannot stand before you today and tell
17 you exactly how Accutane is responsible for my
18 son's disabilities, only that we know that it is.
19 Our family and many others have suffered long
20 enough at the hands of Hoffmann-La Roche. We urge
21 you to take a stand and ensure the safety of this
1 Thank you for your time.
2 DR. GROSS: Thank you, Mrs. Crosland.
3 Is there anyone from the public who wants
4 to speak at this point?
5 [No response.]
6 DR. GROSS: Hearing none, we will declare
7 a recess at this point, and we will reconvene at
8 9:15.
9 [Break.]
10 DR. GROSS: While we had closed our public
11 hearing, we are going to reopen it briefly. The
12 tenth speaker from earlier today, Jeffrey Federman
13 will speak.
14 MR. FEDERMAN: Good morning. My name is
15 Jeff Federman, and I am President of Paragon Rex, a
16 company that provides services to the
17 pharmaceutical industry.
18 For purposes of disclosure, we are not
19 engaged with the manufacturers involved in today's
20 meeting. In addition, my colleagues and I authored
21 a book about pharmaceutical risk management.
Let me begin my proposing that today's
1 proceedings provide two insights about what can
2 reasonably be expected about the design and
3 improvement of risk management programs.
4 The first focus is on the expectations of
5 rigor and precision. We are all associated with a
6 pharmaceutical industry that is famous for the
7 rigor and precision of its well-controlled clinical
8 trials. We expect to be able to determine drug
9 efficacy using scientific and statistical methods,
10 and would hope to bring a similar level of rigor to
11 pharmaceutical risk management.
12 Our colleagues in other risk-intensive
13 industries, such as nuclear energy and aerospace,
14 have much to teach us about applying a similar
15 degree of rigor to risk assessment and program
16 design. Validated well-established methodologies
17 exist to guide the design of risk management
18 programs in these industries.
19 Research of these practices, as well as
20 the disease management and adult learning
21 disciplines, suggest that effective drug risk
management may have several key elements.
1 1. Evidence-based assessment and design
2 process, perhaps such as failure mode and effects
3 analysis, or FMEA, that targets interventions to
4 address specific process-related causes of failure.
5 2. Redundancies that back up the
6 inevitable human failures.
7 3. Collaborative design with practicing
8 physicians to help program elements fit seamlessly
9 into their day-to-day practice of medicine.
10 4. Predictive modeling or pre-testing to
11 determine the likely effectiveness of any proposed
12 program and anticipate where program weaknesses may
13 exist.
14 5. Innovative implementation approaches,
15 perhaps such as scenario-based learning, that build
16 on the way clinicians and patients learn.
17 Finally, ongoing monitoring and
18 measurement with the anticipation that initial
19 programs change over time.
20 Certainly, rigorous design is achievable,
21 yet, in the world of every-day clinical practice,
where care is delivered based on the judgments and
1 knowledge and motivations of well-meaning men and
2 women, high precision in terms of predicting
3 program compliance and use may be an unrealistic
4 expectation at the time of program introduction.
5 This key difference between the controlled
6 clinical trial environment to which we are
7 accustomed and the realities of clinical practice
8 lead to a second expectation.
9 I suggest that expecting a definitive
10 precise or final design at the time of risk
11 management program introduction may not be
12 reasonable. Quality improvement standards in other
13 industries are built on the foundation of
14 continuous quality improvement, or CQI.
15 The concept of intervening with an initial
16 program, then, monitoring and measuring for early
17 opportunities to improve the program may be a more
18 achievable expectation.
19 The approach of showing continuous
20 movement towards a goal may require a frequency of
21 analysis and potential redesign occurring in
intervals of months, not years.
1 Today's discussions are another step in
2 the ongoing improvement of Roche's pioneering PPP
3 and enhanced S.M.A.R.T. programs. We support these
4 FDA initiatives and believe these hearings today
5 will help lead to the next generation of effective
6 pharmaceutical risk management programs that
7 incorporate both rigorous evidence-based program
8 design, as well as continuous quality improvement
9 to provide the degree of product we are all seeking
10 to achieve.
11 Thank you.
12 DR. GROSS: Thank you, Mr. Federman.
13 At this point, we will close the open
14 public hearing again, and we will move on to some
15 other orders of business.
16 Allen Mitchell, Director, Slone
17 Epidemiology Center, Boston University, will have a
18 few minutes to comment on some questions that were
19 raised yesterday.
20 DR. MITCHELL: Thank you very much, Dr.
21 Gross, and committee, I really appreciate your
offer of a few minutes to respond to some of the
1 concerns raised in the FDA review.
2 Yesterday, I mentioned that I was not here
3 on behalf or speaking for the FDA, and then this
4 morning's remarks, I just want to point out that
5 not only is that the case for these remarks, but I
6 am not speaking on behalf of the generic sponsors
7 or Hoffmann-La Roche. I guess that leaves me
8 speaking on behalf of the Slone Epidemiology
9 Center, which I think they will allow me to do.
10 This presentation has not been shared with
11 anyone other than our own group.
12 [Pause.]
13 DR. GROSS: We have a few questions from
14 yesterday. I would like to start with Dr. Day.
15 DR. DAY: Thank you. I did have questions
16 yesterday, however, I would like to defer that
17 comment and use it for an additional comment on the
18 questions today.
19 Would that be all right, Dr. Gross?
20 DR. GROSS: That's fine.
21 Dr. Bigby.
DR. BIGBY: I have a couple of
1 The first is to Hoffmann-La Roche.
2 The question was asked I think yesterday
3 about annual sales, and you found the number, but
4 didn't say what it was, the number of 450 million
5 came out today.
6 What are the annual sales of Accutane?
7 MS. REILLY: What year, sir?
8 DR. BIGBY: Last year.
9 MS. REILLY: In 2003, our U.S. net sales
10 were $144 million.
11 DR. BIGBY: Do you have any idea sort of
12 what you have spent in terms of legal fees and
13 lawsuits around the issue of teratogenicity?
14 MS. REILLY: No, sir, I do not.
15 DR. BIGBY: Is that an obtainable figure?
16 MS. REILLY: I would defer to our counsel.
17 DR. GROSS: Dr. Cohen, Michael, did you
18 have a question from yesterday?
19 DR. COHEN: No, I will hold it until a
20 discussion later.
21 DR. GROSS: Dr. Katz.
DR. KATZ: I wanted to ask Dr.
Huber, on
1 the people who enroll, what percentage of those,
2 how soon do they get a notice that they have
3 enrolled do they get a questionnaire, and what
4 percentage of the people that enroll fill out those
5 questionnaires, the two or three questionnaires
6 they get?
7 On the enrollment form, it says you will
8 get two or three questionnaires through the
9 treatment. So, what percentage of the people that
10 enroll get the questionnaires and answer them, and
11 how quickly do they get them?
12 DR. HUBER: I will refer to Dr. Blesch who
13 will answer your question.
14 DR. BLESCH: The Accutane survey is
15 divided into two sections. Eighty percent of the
16 patients who enroll, 80 percent get questionnaires
17 immediately upon enrollment. The other 20 percent
18 get a questionnaire approximately six months after
19 they enroll, and then a final questionnaire six
20 months after they finish treatment.
21 All Accutane-surveyed patients are
followed, continue to receive questionnaires until
1 six months after their treatment has stopped.
2 DR. KATZ: What percentage of patients who
3 you send that questionnaire to fill out the
4 questionnaire?
5 DR. BLESCH: I don't have that exact
6 number, but I believe it is about 80 percent.
7 DR. KATZ: Thank you.
8 DR. GROSS: Then, the last question from
9 yesterday was from Mr. Levin.
10 MR. LEVIN: I will defer questions until
11 later, but I do have one.
12 I am just curious what the sales for
13 Accutane for Roche were in 2002, prior to generic
14 entry into the market.
15 MS. REILLY: In 2002, that year to date
16 figure was 380 million.
17 DR. GROSS: Thank you.
18 Before proceeding, I would like to read a
19 comment that Dr. Jackie Gardner suggested I read,
20 and I concur.
21 We would like to publicly thank the people
22 who
came forward during the open public hearing
1 with their personal stories and acknowledge how
2 difficult that was.
3 Thank you.
4 Allen Mitchell.
5 Responses from Slone Epidemiology Center
6 DR. MITCHELL: Thank you. I think we have
7 things working.
8 [Slide.]
9 If I can follow up on Dr. Katz's question
10 from our survey, which is a similar design, the
11 response rate to the during and after treatment
12 questionnaires, the questionnaires that are sent to
13 women at the onset of therapy and the midst of
14 therapy is about 97 percent in our survey. It is
15 extremely high. That is both with mail and
16 telephone responses included.
17 I wanted to speak about the limitations of
18 the voluntary isotretinoin survey and perhaps some
19 of the non-limitations because it seems to us that
20 this is a critical issue in interpreting the data.
21 [Slide.]
Quickly, to review some of the questions,
1 and these are questions that we have posed as
2 potential limitations to this or any other survey
3 since 1988 when we first designed it, what is
4 success. The committee is struggling with this.
5 Of course, there were no pre- and
6 post-comparisons possible, and here we are talking
7 about the data up until the onset of S.M.A.R.T.
8 These are the 14 years of data preceding S.M.A.R.T.
9 What are the critical events that one
10 judges success by, is it pregnancies, live born
11 infants, infants with birth defects? Is the
12 critical outcome a rate of pregnancy, or is it an
13 absolute number?
14 One could imagine different scenarios with
15 very different responses to that final question.
16 [Slide.]
17 Two other limitations that we have
18 identified is that survey participation may provide
19 an unintended intervention and also that recall of
20 risk management may be biased among women who
21 become pregnant.
We were well aware of those two concerns
1 going into it, and to deal with those concerns, the
2 design, which is admittedly complicated, includes
3 two arms, the AT arm, which is the after therapy
4 only interview, if you will, and the DAT arm, which
5 is the during and after therapy interview with a
6 number of contacts with patients throughout the
7 course of therapy.
8 Those have varying degrees of patient
9 contact, and information in those arms is collected
10 either prospectively or retrospectively with
11 respect to some of these behaviors. So, we think
12 that we have been able to deal with those issues.
13 [Slide.]
14 There is another point about whether the
15 reporting of pregnancies among survey participants
16 is credible. We are, of course, concerned about
17 that. If women are avoiding pregnancy during
18 treatment, one would expect a rebound in pregnancy
19 rates following treatment. That seemed to us to be
20 an indirect measure of whether reports may be
21 accurate.
1 We have lifted this figure from our 1995
2 New England Journal paper, which summarized the
3 survey experience to date at that point, to
4 describe the pregnancy rates and outcomes during
5 and after isotretinoin therapy.
6 I think it becomes fairly clear that
7 during treatment now, which is lumped together, the
8 pregnancy rate is somewhere approximately 9 per
9 1,000 person years. We are using person years
10 here.
11 And as you can also see, elective
12 termination represents about 70 percent roughly of
13 those pregnancies. In the one month after
14 treatment, where the risk of malformation is
15 considerably reduced, and in our data doesn't show
16 much increase at all, but in that one month of
17 therapy, you begin to see the pregnancy rates
18 increase, and in the two months, three months, and
19 four months after therapy--and we only go out to
20 four months--what you find is a considerable
21 rebound in the pregnancy rates, which is what one
would expect if women are trying to avoid pregnancy
1 during the course of therapy.
2 But it is also interesting to point out
3 that by the time you get to the fourth month, the
4 proportion of pregnancies that result in elective
5 termination approximates what we see for the U.S.
6 population.
7 So, this provides some indirect assurance
8 that reporting is not terribly inaccurate.
9 [Slide.]
10 But what I want to focus on is the issue
11 of whether voluntary enrollment may compromise
12 representativeness, and, of course, one always
13 worries about that.
14 The response to that concern is to
15 maximize enrollment. We all know that, that is
16 basic epidemiology.
17 [Slide.]
18 The second approach is to compare the
19 survey population to the target population, and to
20 do that, using demographic characteristics, on the
21 one hand, and ideally, the risk factors in the two
groups, on the other hand.
1 [Slide.]
2 I think we should make the point and
3 understand clearly that enrolling 60 percent or
4 more of the target population does not, in itself,
5 assure that that population is representative.
6 Conversely, enrolling less than 60 percent
7 of the target population does not assure that the
8 sample is unrepresentative, and I think that there
9 has been a fair amount of assumption that because
10 the enrollment rates are below 60 percent,
11 therefore, the sample population is
12 unrepresentative.
13 [Slide.]
14 It is very difficult to make direct
15 comparisons in trying to respond to the question
16 about is the survey population a biased sample, and
17 we could spend days, as we have, we have spent
18 months over the past 14 years struggling with how
19 to evaluate this, the best we can do, and this is
20 based, not only in our own considerations, but
21 suggestions from FDA and from advisory committees
22 and
our own advisory committee that we have, is to
1 do some indirect comparisons.
2 These are necessarily limited and
3 imperfect, and I wish to make that very clear.
4 [Slide.]
5 Two parts of data that I want to present
6 were alluded to in the FDA review document. One
7 was a comparison we did using United Health Care
8 data, which is a large plan that had I think 14
9 different prescription plans under one umbrella.
10 What we were able to do through a
11 complicated process was to compare women who had
12 received a prescription for Accutane through that
13 plan, and look at those who enrolled in our survey
14 and those who didn't enroll.
15 [Slide.]
16 There were very few variables that we
17 could identify for comparison, but one of them was
18 age, and what we found was that the age among the
19 Accutane participants was somewhat younger by about
20 two years than it was in the population that didn't
21 enroll in the survey. This was actually compatible
with some anecdotal reports which we frankly didn't
1 believe from one of our colleagues at Roche at the
2 time.
3 This was back in the beginning of the
4 survey, in the '90s, who had said that in his
5 conversations with providers, he was finding a
6 number of them reporting to him that they tried to
7 have women participate in the survey if they felt
8 that woman was at increased risk, that they felt
9 that the survey would provide some additional
10 intervention or a component that would help
11 encourage compliance. It might do that indirectly,
12 but it certainly isn't the purpose of the survey.
13 [Slide.]
14 So, this was compatible in that one would
15 expect that women who are older would be at less
16 risk for pregnancy, and, indeed, when you stratify
17 these findings according to age, and now we are
18 looking at this time the participation rate in the
19 survey was estimated to be about 40 percent, what
20 we found was that that 40 percent rate was fairly
21 consistent across the three youngest age strata.
Where the participation rates were lowest were in
1 the oldest group of women, and, in fact, among the
2 women 50 to 59 years old, only 14 percent
3 participated, which would be compatible with the
4 either subselection or doctor's selection of women
5 at low risk saying don't both participating in the
6 survey, you are not at risk for pregnancy.
7 [Slide.]
8 The other data alluded to in the FDA
9 review, and that we have cited, and these are again
10 previously presented data, is a consumer survey
11 that was conducted by Roche identifying a number of
12 women who had been prescribed Accutane, and asking
13 them whether they enrolled in the survey or not,
14 and interestingly enough, the age difference was
15 again about two years, that the enrolled women
16 tended to be about two years younger than those who
17 didn't enroll in the survey.
18 Median education wasn't terribly
19 different, the source of their prescription wasn't
20 terribly different, indeed, the women in the
21 survey, 10 percent more than the women who weren't
22 in
the survey reported being sexually active, and
1 not surprisingly, along with that, higher rates of
2 contraception use.
3 Now, one of the things cited in the FDA
4 report was that, well, gee whiz, if you look at
5 this population, use of the birth control pill was
6 reported by 40 percent of the women enrolled in the
7 Slone survey, but only 16 percent among the women
8 who did not enroll.
9 On the face of it, there is no question
10 there is a difference there. It is not accounted
11 for by condom use or other barrier methods, but it
12 is striking that the surgical sterilization rates
13 were compensatorily different among the enrolled
14 and unenrolled women, and if you add up the highly
15 effective contraceptive methods as a percent, what
16 you find is that they are virtually identical in
17 terms of highly effective contraception use among
18 the women in the survey and the women who chose not
19 to participate in the survey.
20 [Slide.]
21 But again, even within this analysis,
there is about three times as many women--two and a
1 half times as many women on the pill in the survey,
2 suggesting that again, if anything, the survey
3 population may be at higher risk for pregnancy
4 since surgical sterilization is a highly effective
5 and more effective method than the pill.
6 [Slide.]
7 Finally, bringing us to the most recent
8 data, we compared the survey data, as did FDA,
9 versus isotretinoin users according to age--and
10 this is in the one year before S.M.A.R.T., and we
11 used the FDA data presented for advanced PCS as
12 representing the base population, the target
13 population, and we have provided the survey age
14 distributions on the left.
15 I think most observers would say that this
16 is actually, until you get to the older age groups
17 for sure, pretty representative, and while there is
18 a decrease in the proportion of participants who
19 are 15 years of age or under, that decrease is
20 relatively small, where again we see a deficit of
21 participation that is fairly consistent is again in
22 the
older women who are less at risk for pregnancy
1 by and large.
2 [Slide.]
3 And, indeed, when you compare the
4 pregnancies-- this is again in the year
5 pre-S.M.A.R.T.--reported by our survey, and the
6 total reported by FDA including the spontaneous
7 reports, we see striking similarities in the
8 distributions.
9 [Slide.]
10 So, in answer to the question is the
11 survey population a biased sample, to us, the
12 evidence does not suggest that the survey
13 population is biased towards women at low risk of
14 pregnancy.
15 Indeed, the indirect evidence, and I
16 stress it is indirect, suggests that, if anything,
17 the survey disproportionately includes women at
18 relatively high risk of pregnancy, and this pattern
19 has been observed consistently at various points in
20 the survey's history.
21 [Slide.]
That brings us back to this figure that we
1 showed in our presentation yesterday, where we
2 observed, again in the pre-S.M.A.R.T. era, 14 years
3 experience, a decrease in the pregnancy rate from
4 roughly 4-fold to a little bit over 1-fold, a
5 rather striking and consistent decrease over time.
6 [Slide.]
7 Well, if the survey has any value, we need
8 to consider what this means, and we think this
9 trend is unlikely to be explained by enrollment
10 biases, which would have to have changed over the
11 14-year period.
12 We have done all sorts of models as to how
13 one might account for this trend through biases,
14 and it is very difficult to come up with one.
15 [Slide.]
16 Rather, we think it may reflect continuing
17 improvements in the implementation of the risk
18 management program via its incorporation into
19 routine practice and I might add residency training
20 programs and the dermatology programs, so that our
21 summary view is that without respect to S.M.A.R.T.
specifically, we do think that the 14 years
1 experience preceding S.M.A.R.T. does reflect
2 incorporation of risk management elements to the
3 point where they have actually appeared to result
4 in a fairly substantial decrease in the pregnancy
5 rates.
6 I will be happy to take questions, and
7 thank you for your consideration.
8 DR. GROSS: Are there any questions? Yes.
9 DR. KIBBE: My question deals with the
10 characteristics of the individuals in the two
11 groups, those that undergo therapy and don't get
12 pregnant, and those that undergo therapy and end up
13 having either been pregnant when they start or end
14 up getting pregnant during the time frame.
15 I guess we could say that 99 percent of
16 the women who enroll in therapy are successful in
17 not having a pregnancy occur during that, and 1 or
18 2 percent do, but what characterizes the
19 differences between those two groups, because if we
20 want to improve what we do, we don't have to change
21 it for the 98 percent who go through the process
effectively, but if we could find some handle that
1 would help our clinicians identify individuals that
2 needed an additional activity or procedure, it
3 would help us a lot.
4 DR. MITCHELL: Actually, it is obviously a
5 relevant question. First of all, from these data
6 in the most recent years preceding S.M.A.R.T., the
7 pregnancy rate would be 99.9 percent, it's roughly
8 1 in 1,000. I don't mean to quibble, but it is
9 useful to keep that in mind.
10 What we would call the analysis you are
11 describing is a risk factor analysis. What one of
12 the public speakers called it was a failure mode
13 and effects analysis.
14 We are in the midst at the present time
15 frankly in doing a detailed analysis of exactly
16 that consideration. We have certainly identified
17 crudely that there are no gross characteristics
18 that appear to predict an increased risk of
19 pregnancy.
20 As one might expect, we have seen the
21 chosen method of birth control is directly related
22 to
the risk of pregnancy. We have seen that
1 typically effective methods are effective and the
2 typically ineffective methods are ineffective.
3 We have also seen and published in this
4 paper in 1995, our experience which indicates that
5 for any given mode of contraception, we provide
6 data to suggest considerably higher efficacy than
7 the generally published data on efficacy, and that
8 is because we think the motivation of this
9 population is unusually high.
10 What we are doing now is looking at all
11 the elements in the Pregnancy Prevention Program,
12 the pre-S.M.A.R.T. Pregnancy Prevention Program, to
13 see if we can identify any elements that do exactly
14 what you are describing, that characterize the
15 women who become pregnant and distinguish those
16 women from the women who did not become pregnant,
17 so that interventions could be targeted to that
18 population, and we are hoping to have that
19 completed--Dr. Trussel, James Trussel is going to
20 be joining us in that analysis as he has in the
21 past--and we hope to have completed in the next few
1 DR. KIBBE: A second question has to do
2 with my interest in the international experiences,
3 if you will, with this medication. Roche has said
4 that they have never had a country ask them to take
5 it off the market, but I can't imagine that there
6 aren't countries that are interested in eliminating
7 the risks.
8 Do you have any access to any data that
9 would help us understand how their interventions
10 differ from ours and how their risk ratios might
11 differ from ours, and how that might impact our
12 decisionmaking?
13 DR. MITCHELL: The short answer is no, we
14 don't have any data and we have certainly tried to
15 find such data. One of the concerns that we have is
16 that the way drugs are managed philosophically in
17 some other countries, and particularly one
18 scandinavian country with which I am aware, is very
19 different culturally from the U.S.
20 In one country, the attitude was that we
21 do what we do and after that it is not our concern,
22 and
they don't track the outcomes of exposures, not
1 pregnancy exposures, but even pregnancy rates.
2 I think the U.S. is frankly, uniquely
3 providing information that has a denominator.
4 Other countries have not, to our knowledge, taken
5 this concern nearly as seriously as it has been
6 taken in the U.S., and the result is that there is
7 very little data.
8 DR. GROSS: Thank you, Dr. Kibbe, for your
9 questions.
10 The next question comes from Dr. Honein.
11 DR. HONEIN: Yes. Dr. Mitchell, you
12 mentioned 38 to 45 percent survey enrollment based
13 on the United Health Care survey for 1990 to 1996.
14 Yesterday, the FDA presented data suggesting a 19
15 percent survey enrollment for the year prior to
17 Was there that much decline in enrollment
18 in the survey over that time period, or is this a
19 different methodology for calculating the estimated
20 survey participation?
21 DR. MITCHELL: The methodologies by which
22 you
calculate participation requires that you know
1 what the denominator is, and the denominator is the
2 number of unique women taking the drug.
3 The difficulty in establishing that
4 denominator, the difficulties are considerable, and
5 we have had a lot of debates over the years about
6 what is an appropriate denominator.
7 I mean if you simply divide the total
8 number of female scripts by 3.7, as the FDA used
9 the figure from one experience in the Seattle area,
10 you come up with one estimate of a denominator. If
11 you divide that by 4 prescriptions or 2
12 prescriptions, you get very different denominators.
13 The Kaiser data I think were closer to what we use.
14 But the fact is that we do suspect, based
15 on indirect evidence, that participation rates
16 declined over time, and it was really because of
17 our concern that we focused a lot of attention on
18 does the decline also reflect some differences in
19 the way women are enrolling.
20 What we think, although we can't prove, is
21 that the $10 incentive, which we identified at the
outset of the survey back in '89 as an incentive to
1 get women to participate in the survey through the
2 medication package which we came up with the idea
3 of putting the enrollment form in the medication
4 package to bypass the physicians who may not want
5 women to participate or may not encourage them.
6 So, we said, you know, make it like a
7 toaster rebate coupon and encourage women who might
8 be noncompliant to participate. But that was a $10
9 incentive back in 1989, and one of the reasons for
10 increasing the incentive in the most recent efforts
11 was to adjust, if you will, for inflation that $10
12 incentive. So, we do think that there has been a
13 decline.
14 DR. GROSS: The next question is from Dr.
15 Wilkerson.
16 DR. WILKERSON: Considering best practices
17 once again, considering the women that we have, the
18 ages, the methods of birth control that they have
19 employed and reasonable rates of success of those
20 programs, what would be your calculated rate of
21 pregnancies per 1,000 cases if everybody did
exactly what they were supposed to do and they used
1 the methods which are they using, what would this
2 rate actually look like? Instead of being 1 per
3 1,000 courses of therapy, how much would it go down
4 to?
5 DR. MITCHELL: Can I turn your question a
6 little bit?
7 DR. WILKERSON: It depends.
8 DR. MITCHELL: I can't give you the
9 answer. Okay, I can't give you the answer, but I
10 want to understand the question, so we could give
11 you the answer.
12 DR. WILKERSON: In other words, if you
13 take the current women and their methods of birth
14 control that they are currently using, use
15 optimally as real, everyday life people use them,
16 what would be the predicted rate of pregnancy per
17 1,000 courses or however you want to express this.
18 We know that methods fail, we know that.
19 That zero is not obtainable in this
20 process short of females not taking this drug right
21 now, but I mean best practices in normal settings,
what would be the predicted rate of pregnancy in
1 this setting.
2 DR. MITCHELL: I think I can parse that
3 question, to use an old term. One question is in
4 efficacy in the normal use of the method, and, in
5 fact, what our data suggests is that efficacy is
6 better than normal data would suggest. We can
7 spend a lot of time on defining on how best
8 efficacy was defined some years ago.
9 In the population we have observed, what
10 we see is roughly 1, 1.2 per 1,000. If all women
11 were on the pill, I could actually get you some of
12 those estimates, it's in the paper, but I think the
13 real question is what is the efficacy if women are
14 on two methods of contraception, which is what is
15 specified in the risk management program.
16 The difficulty in assessing that is trying
17 to find out whether women who report two methods
18 were reporting two simultaneous methods. Those
19 kinds of questions become extremely, not only
20 invasive, but they become extremely difficult to
21 ask, because you essentially have to understand if
22 a
woman is on the pill, did she take a pill every
1 day, if she was using the pill and the condom, did
2 she use the condom with every act of sexual
3 intercourse with the male partner.
4 One of the concerns is that women may be
5 interpreting the two methods, may be using two
6 methods, but forgetting the simultaneous. It is
7 conceivable, this is sort of the law of unintended
8 consequences that Dr. Trontell mentioned yesterday.
9 A concern we have, although we don't have data to
10 support it, is there going to be a fraction of
11 women who say, okay, I have got to use two methods,
12 I will use the pill a couple days a month and I
13 will use the condom when I think of it.
14 I don't mean to dodge your question. We
15 can give you contraceptive efficacy rates for any
16 single method that was reported, and it's in the
17 paper, in the New England Journal paper from '95,
18 but we can't answer the question any more directly
19 than that.
20 DR. GROSS: Dr. Kweder, do you want to
21 comment on that?
DR. KWEDER: Yes, basically, it is
1 to what Allen had to say. We have some slides that
2 display contraceptive method effectiveness rates as
3 generally understood, but there really are not data
4 that help us with the two methods simultaneously
5 used, and Allen's point is exactly what we have
6 struggled with, as well, does it mean, you know,
7 how many women actually interpret use of two
8 methods as simultaneous all the time. That, we
9 don't know.
10 DR. GROSS: The next question is from
11 Sarah Sellers.
12 DR. SELLERS: I am wondering if you have a
13 regional distribution of the study participants.
14 DR. MITCHELL: We do, and it is compatible
15 with the sales. I could get the slide out, I would
16 be happy to provide you. It will take me a couple
17 minutes to find it, but it is similar.
18 DR. SELLERS: Just one more follow-up, and
19 we may have addressed this yesterday, but has the
20 survey been validated at all with any medical
21 records or exam data?
DR. MITCHELL: Specifically, how
1 you--
2 DR. SELLERS: To confirm in particular any
3 way to validate voluntary reporting on pregnancies.
4 Primarily, that would be the only thing that we
5 could look at.
6 DR. MITCHELL: I think the concern is
7 false negatives, in other words, women who fail to
8 report pregnancies, and we have not done that.
9 That raises some privacy issues that are a little
10 tricky to get around.
11 Pregnancies that are reported are followed
12 up, and any pregnancy that is identified with any
13 suggestions of malformations, the records are
14 obtained if the woman will allow us to.
15 DR. TRONTELL: I would like to try and
16 address Dr. Sellers' question. I just wanted to
17 point one challenge in assessing pregnancy. Many
18 health plans do not cover termination of pregnancy,
19 so individuals who self-diagnose pregnancy and
20 elect to terminate outside their usual medical care
21 system will never be captured or ascertained.
DR. MITCHELL: Which is one of the
1 that we rely on voluntary reporting from
2 participants.
3 DR. GROSS: Thank you, Dr. Trontell.
4 Dr. Strom.
5 DR. STROM: I wanted to follow up on Dr.
6 Kibbe's question with a comment and then a question
7 to the company in follow-up. You were asking about
8 the international experience in particular.
9 Anecdotally, my colleagues in other
10 countries tell me that Accutane is seen as a
11 uniquely American problem, but that is not because
12 we are the only ones looking, but because we are
13 the only ones using it so widely, that other
14 countries don't use it anywhere nearly as widely as
15 we use it, so use is much less.
16 What I wonder about from the company is
17 whether you could give us sales data by population
18 for some selected countries, so, for example, to
19 try to nail down whether that anecdotal experience
20 is correct, in other words, what is the rate of use
21 in the U.S. population, how does that compare to
perhaps the English population or the Swedish
1 population or otherwise.
2 DR. HUBER: We do not have the data on
3 sales broken down by country here. That would take
4 us a little time to compile and we don't keep those
5 here in the U.S., so it would take us some time.
6 DR. STROM: But I think that is why you
7 are not seeing the sensitivity from other
8 countries.
9 DR. KIBBE: I think there is an underlying
10 social issue, too, and that general acceptability
11 of birth control methods in Sweden and some other
12 countries in Europe are going to be quite a bit
13 different than the United States. I am trying to
14 figure out what factors are out of the direct
15 control of the system that we have are impacting
16 it, that's all.
17 DR. GROSS: Thank you, Dr. Kibbe.
18 Dr. Whitmore has the last question.
19 DR. WHITMORE: Can you clarify, you had a
20 graph up there talking about the number of
21 pregnancies during Accutane and then for the
subsequent months after therapy, and I thought it
1 was 10 per 1,000 person years, is that correct?
2 DR. MITCHELL: It was about 9 during
3 therapy, 9 per 1,000 during the course of therapy
4 at that time.
5 DR. WHITMORE: So, just to clarify, that
6 would be 1 in 100 essentially as opposed to 1 in
7 1,000.
8 DR. MITCHELL: Well, yes, but I am sorry,
9 I accept your correction. I am confusing
10 different--our usual rate estimators per course,
11 per 1,000 courses, correct.
12 DR. WHITMORE: And that was person years,
13 and therapy can range anywhere from 24 to 48 weeks
14 depending how dosing is done essentially. I think
15 that is a point that need to be re-emphasized as
16 opposed to if birth control pills and a second form
17 of contraception were used effectively, maybe more
18 like 1 in 1,000 rate of pregnancy. I mean those
19 numbers are not correct, but I think just to give
20 us a ballpark idea.
21 One more question about your survey.
There is incentive to fill out the survey. For
1 teenagers, their parents probably make them fill it
2 out. For adults, there is a monetary reward for
3 doing it, and also there are probably some adults
4 who think oh, if I don't fill this out, something
5 bad is going to happen, or think that it is part of
6 all the program or something they need to do
7 particularly with all the PR about Accutane and
8 everything else.
9 So, I would say that a lot of people would
10 probably fill out the survey, fill it out because
11 of incentive reasons of some sort, and then I would
12 ask you, these women are signing a form that says I
13 will be abstinent or I will use two forms of
14 contraception throughout therapy.
15 What makes you think that a non-anonymous
16 survey is going to capture any information about
17 people actually not doing these things, they have
18 signed on a document saying they are going to do?
19 Also, reports about abortions, what makes
20 you think that these women who have signed this
21 document, if they do get an abortion, if they are
22 not
going to tell their doctor, what makes you
1 think they are going to report it to you?
2 DR. MITCHELL: Probably the fact that we
3 are dealing with human beings would be a large part
4 of that answer. We were similarly skeptical going
5 in, and remain somewhat skeptical, but less so.
6 What is very interesting is how often we
7 find women telling us things they have not told
8 their doctor. In fact, we did--and, Dr. Katz, you
9 had asked the question yesterday and I couldn't
10 remember what it was when we bumped into each
11 other, but it comes to mind now--and that question
12 is really how accurately do the data reflect what
13 the physician is doing.
14 We identified back in I think it was the
15 early '90s, a group of women who reported to us
16 that they had not had pregnancy testing prior to
17 the prescription of Accutane. From their enrollment
18 forms, we were able to identify the physicians who
19 were in that loop.
20 We called those physicians' offices to ask
21 sort of an anonymous survey question about we are
just calling from Boston University, we are
1 querying physicians about their practices with
2 respect to Accutane, and typically, very often the
3 person responding would be an office manager or the
4 office nurse rather than the physician.
5 We asked whether they routinely did, in
6 fact, do pregnancy testing as one of a number of
7 questions, and a surprising number--not a
8 surprising number--a large number of physicians
9 indicated that they routinely do pregnancy--I mean
10 the office nurse said oh, we always do pregnancy
11 testing, but a number of offices said to us we
12 don't.
13 Now, would you expect a physician's office
14 to tell a survey that they don't do pregnancy
15 testing? The converse is also the case, that when
16 we identify a woman who reports that she is
17 sexually active and does not use contraception, we
18 consider that woman at such great risk for
19 pregnancy that the design of the survey calls for
20 us to call that woman.
21 We call it reading the riot act. We call
that woman and say to her that the behaviors you
1 reported to us put you at high risk for pregnancy,
2 and we urge you to immediately call your physician,
3 stop taking the drug. Incidentally, would you also
4 be willing to allow us to talk to your doctor.
5 When the woman gives us permission to call
6 her doctor, you would assume that the doctor would
7 give you some response that would be compatible
8 with what the woman is reporting, and, in fact, I
9 can't give you the quantitative response, but there
10 were a disturbing number of times where the
11 physician would get on the phone with us, once the
12 woman gave us permission, and would go to the
13 medical record and read us from the medical record
14 that the woman said she was actively--so here was a
15 woman inviting us to find out, and what she was
16 doing was telling the survey--this is a long answer
17 to your question, but I think it deserves that--she
18 was telling us something that she wouldn't tell the
19 doctor.
20 So, the survey is actually in a position
21 to find out things that a woman wouldn't tell the
1 DR. WHITMORE: I had no idea that you
2 called patients. I think that is absolutely
3 fantastic.
4 DR. GROSS: Dr. Mitchell, thank you very
5 much for your presentation.
6 DR. MITCHELL: Thank you.
7 DR. GROSS: Dr. Katz.
8 DR. KATZ: I want to clarify. You call
9 the doctor's office, and you said some said they
10 didn't do any pregnancy testing, but you talked to
11 the office manager and most doctors' offices--I
12 happen to draw blood in the office, but most don't
13 draw blood in the office--so, the office manager
14 says no, we don't do pregnancy testing. They send
15 them to the laboratory, but they don't do it.
16 DR. MITCHELL: First of all, let me
17 explain this was a very biased sample. This was a
18 sample of women, a small sample of women who had
19 told us they had not gone through a compliant
20 process, so we are already dealing with a subset
21 that is hopefully small.
When we called--Dr. Katz, I can't remember
1 the specific questions, but we can get them for
2 you--we asked a series of questions of someone who
3 would be familiar with the offices practices, it
4 often was the nurse, but it represents only a very
5 small fraction, and we did incidentally try to
6 reach those doctors subsequently and get them
7 informed of what the appropriate practices were. I
8 don't mean to suggest that was a widespread
9 phenomena.
10 DR. GROSS: Thank you again, Dr. Mitchell.
11 We will now move on to Dr. Trontell, who
12 had some information to present to us that will be
13 helpful in our consideration of the questions.
14 DR. TRONTELL: There were some questions
15 yesterday about the specifics of the clozapine
16 program and also of the S.T.E.P.S. program. I am
17 thankful to the representative from Celgene who
18 came and provided information, which I will repeat,
19 and I will also invite that individual to come to
20 the microphone to supplement it.
21 But relative to the registration of
patients in the S.T.E.P.S. program, patients are
1 registered by their Social Security number. In the
2 event that that number is not unique, a second
3 unique number is assigned to those individuals.
4 So, the provision of patient anonymity in
5 S.T.E.P.S. it isn't truthfully there. If you have
6 their Social Security number, that can be readily
7 linked to an individual's name.
8 The other question that was asked was
9 about clozapine and the mechanism that led to its
10 institution. In fact, information provided to me
11 by one of the members of the Division of
12 Neuropharmacologic Drug Products told me, in fact,
13 that some of the experience that I cited with
14 agranulocytosis related to post-marketing
15 experience abroad where the product was marketed
16 with recommended monitoring for white counts and
17 prevention for agranulocytosis.
18 That rate was on the order of 1 to 2
19 percent, and that had been described in the era of
20 the clozapine national registry in practice with
21 mandatory monitoring of white count to be less than
22 1
percent, specifically 0.38 percent.
1 If there are additional questions, I would
2 invite the individuals who know each of those
3 registries to come to the microphone to address
4 them.
5 DR. GROSS: Hearing none, we will move on
6 now to Dr. Paul Seligman, Director of the Office of
7 Pharmacoepidemiology and Statistical Science at the
8 FDA, who will introduce the questions to us.
9 Introduction of Questions
10 DR. SELIGMAN: Good morning. I have been
11 asked to present the issues and questions for
12 consideration by the committee this morning and
13 this afternoon.
14 Please note that these questions are part
15 of the agenda that was distributed for the meeting
16 and can be found after the agenda.
17 Before I begin, I just want to take a
18 brief moment on behalf of myself and my colleagues
19 at the FDA to also thank the members of the public
20 this morning who were here to share their testimony
21 and their personal experiences.
The issues and questions fall into the
1 following sort of broad categories. We are asking
2 the committee today to evaluate the performance of
3 the current program and the data that have been
4 presented both yesterday and today, to consider
5 options for improvement of this current risk
6 management program, to consider how best to monitor
7 any recommended changes, and to consider benchmarks
8 for success as noted yesterday morning.
9 I think it was the first question out of
10 the gate by Dr. Bigby, as well as others this
11 morning, who have focused on how best to determine
12 whether subsequent changes or any program that
13 comes out of these deliberations should be
14 determined to be successful.
15 [Slide.]
16 The first issue that we ask the committee
17 to consider this morning is that based on the
18 reports and patient surveys, there does not appear
19 to be a meaningful decrease in the number of
20 pregnancies reported in women taking a course of
21 isotretinoin since implementation of the current
risk management program.
1 We would ask you then to discuss the
2 measurement and implementation factors that may
3 have contributed to these findings.
4 [Slide.]
5 The second issue is based on prescription
6 audits and patient surveys, use of the
7 qualification sticker is high. Patient surveys
8 suggest an inconsistent link between monthly
9 pregnancy testing and use of the stickers.
10 Reported pregnancies and patient surveys indicate
11 incomplete or inadequate birth control measures
12 among females.
13 Again, we ask you to please comment on
14 measurement and implementation aspects of the
15 current program that may have contributed to these
16 findings.
17 [Slide.]
18 Question 3. FDA's goals for the
19 Isotretinoin Pregnancy Prevention Risk Management
20 Program are that: no woman who is already pregnant
21 be prescribed and dispensed isotretinoin, and that
22 no
pregnancies should occur while on this therapy,
1 and that effective pregnancy prevention occur
2 throughout the course of treatment.
3 [Slide.]
4 In recommending any changes to the risk
5 management program, we ask the committee to
6 consider the potential tools and strategies in
7 light of the likelihood of effectiveness in further
8 reducing fetal exposure, the practical impact on
9 health care providers who prescribe and dispense
10 the product, and the impact on patients who must
11 navigate any such program.
12 [Slide.]
13 Given these factors, we are asking the
14 committee to consider the following options:
15 (a) Continue the current risk management
16 program without additional tools, and if this is
17 the recommendation, if so, what approaches do you
18 recommend to improve adherence with the program by
19 patients, physicians, pharmacists and others, such
20 as health educators?
21 [Slide.]
(b) Or to consider modification of the
1 current program with additional risk management
2 tools to reduce fetal exposure.
3 We list a number of them here, such as
4 programs to enhance education and interaction with
5 patients to identify and minimize high risk
6 behaviors; to tighten the linkage of prescriptions
7 dispensed by pharmacists with required check of
8 pregnancy test results; the registration of
9 patients, pharmacists, physicians and/or others
10 such as health educators; limiting the access or
11 distribution of the drug, or other tools. In
12 recommending the other tools, we would ask you to
13 describe them.
14 I should note that in the course of our
15 discussions and deliberations, other tools have
16 also been mentioned, but not listed here.
17 [Slide.]
18 Question 4. In order to adequately
19 monitor the risk management program, we ask the
20 following:
21 (a) Would it improve monitoring of risk
management program performance to register
1 patients, pharmacists, physicians, and other
2 relevant participants?
3 (b) If participants in such a risk
4 management program are registered, how can this be
5 more effectively done in a multi-source
6 environment, so that individuals are not registered
7 multiple times or double-counted?
8 [Slide.]
9 Finally, we are asking the committee to
10 identify critical benchmarks for determining the
11 success or failure of the pregnancy risk
12 management program, and suggest, for example, such
13 as reducing to zero the number of women who are
14 pregnant at the initiation of isotretinoin
15 treatment, and others.
16 I am happy to answer any questions about
17 these issues and provide any clarification as need
18 be.
19 DR. GROSS: Thank you, Dr. Seligman.
20 Committee Discussion
21 As Chair, I am going to make a suggestion
that we consider Question 3 last because that is
1 the recommendation of the committees on what the
2 program should be in the future.
3 Question 4, I suggest be considered before
4 3 because it talks about whether or not registers
5 would be helpful, and that may be part of the
6 ultimate plan that we come up with in Question 3,
7 and assessing success and failure is something that
8 we can also consider beforehand.
9 Is that okay with the committee if we do
10 it in that order, Question 1, 2, 4, 5, then 3?
11 Does anybody have any objections to that? Okay.
12 Why don't we begin with Question No. 1.
13 Based on the reports and patient surveys, there
14 does not appear to be a meaningful decrease in the
15 number of pregnancies reported in women taking a
16 course of isotretinoin since implementation of the
17 current risk management program.
18 Data has been presented on that. Please
19 discuss measurement and implementation factors that
20 may have contributed to these findings. If I may
21 be so bold as to say that insufficient data has
been presented to answer that part of the question,
1 but let's hear what committee members think on
2 those issues.
3 Dr. Gardner.
4 DR. GARDNER: As a non-clinician, it would
5 help me greatly to understand what happens in the
6 clinician's office in terms of the implementation
7 of these processes both from the standpoint of
8 physician and patient burden, and also the
9 logistics we heard yesterday, a scenario of trying
10 to get a pregnancy test, is it the result or a new
11 request, and so on.
12 Could the clinicians comment on how these
13 processes are implemented in practice for example?
14 DR. GROSS: Any dermatologist want to--Dr.
15 Katz.
16 DR. KATZ: We will walk you through it
17 from the beginning. First of all, the patient has
18 been seen multiple times previously, on every other
19 treatment we know, different antibiotics starting
20 with the least risk of inducing and most used for
21 decades, and then antibiotics with a high risk
1 Then, the patient is evaluated, and if it
2 is a minor, the parent is in the office initially,
3 a complete discussion of all side effects are done,
4 and then the female patient, one can't portray in
5 this meeting the doctor-patient contact and the
6 validity of patient response, reliability of
7 patient, we can't project that here, but the
8 physician assesses that, as well.
9 Then, you give the patient a choice of
10 having a parent leave the room, so you can discuss
11 the contraception end. We ask them if they are
12 using contraceptives, and it is burdensome going
13 through this entire thing, then, of all the side
14 effects involved.
15 All risks are mentioned and if it is
16 decided to go ahead with the Accutane, in female
17 patients, baseline bloodwork is done, CBC, hepatic
18 profile, lipids, and HCG pregnancy test, and they
19 are told to come back at the time of the next
20 period for another pregnancy test, or they can get
21 that done, since they are not coming, that might be
22 in
10 days, they wouldn't have to come back to the
1 office, they can go to the lab and get the
2 laboratory test. They will often fax it, and then
3 they can come by and get a prescription with the
4 yellow stickers.
5 They are told to come back in two weeks
6 and then every four weeks through the course of
7 treatment. Bloodwork is obtained each time, and
8 then they are given a prescription again. They are
9 reminded each time about the necessity of two means
10 of pregnancy.
11 They are asked about the side effects, how
12 they are feeling as far as generally, and once
13 again you can't project everything. You are
14 looking at their face to see how they are doing.
15 With all this said and done, you remind the patient
16 each time about the necessity of two means of
17 contraception.
18 A lot of times people say yes, it happened
19 to me, to bear on this question further, how can
20 these adverse effects be reduced, it can't be to
21 zero because a patient says that she is not
sexually active, and each time she remarks a little
1 bit, she said I told you that last time, and each
2 time I remind her, she reminds me that, doctor, I
3 told you I am not sexually active, and then two
4 weeks later she calls me and says she missed her
5 period. This happens. So, how do you eliminate
6 that?
7 Now, it so happens, then, we got a
8 pregnancy test, she wasn't pregnant, she had just
9 missed a period. But she was concerned because
10 obviously, she wasn't sexually inactive. So, these
11 are the problems that face us, and that is why this
12 is going to happen anyway.
13 Does that answer your question?
14 DR. GARDNER: Thank you.
15 DR. GROSS: Dr. Crawford has a question.
16 DR. CRAWFORD: A follow-up either to Dr.
17 Katz or any other member of the committee. Other
18 than actual pregnancy testing, what would be
19 different with the male patient prescribed
20 isotretinoin?
21 DR. KATZ: No, except that contraception
isn't discussed, which might bring up some points
1 that came up with the male patients, but, no, that
2 is not discussed.
3 DR. GROSS: That is an issue we will need
4 to consider later on, whether male contraception
5 should be recommended.
6 At this point, I would like to encourage
7 the committees to specifically stick to the
8 question.
9 The first part of the Question 1, does
10 anybody disagree with the statement, the statement
11 being there does not appear to be a meaningful
12 decrease in the number of pregnancies? Does
13 anybody disagree with that? Yes.
14 DR. BERGFELD: I would like to speak to
15 that. This was a new program, the S.M.A.R.T.
16 program for the dermatologists, and when they were
17 asked to participate, the American Academy of
18 Dermatology put in place very intensive teaching
19 courses at all of their meetings to inform the
20 dermatologists of their behaviors.
21 We were also visited by the company in our
offices in which the S.M.A.R.T. programs were
1 introduced to us. We then had didactic sessions to
2 go through what our responsibilities were to be in
3 this program, and we were requested, and it was
4 inferred, that unless we signed up, we would not be
5 prescribing this drug and that we would be out of
6 order to prescribe this drug.
7 So, in my practice at the Cleveland
8 Clinic, we did abide by what we felt was the best
9 thing for our patients, we became informed, we
10 abided by the sticker qualifications, and we did
11 somewhat what you did, Dr. Katz. We used the forms
12 that are given to us to go over with the patients.
13 But what I would like to say about this is
14 that what happened was that the compliance of the
15 dermatologists went up with informed consent and
16 education of the patient.
17 I think that is reflected by the fact that
18 you have decreased numbers of prescriptions being
19 written overall, but a constant number of
20 pregnancies, and I think there has just been an
21 increased reporting that has gone on because of the
educational program.
1 I think when you open or begin a new
2 program, this is what you would expect, and I would
3 think that what we here do today would be to
4 enhance this program to make it more efficient and
5 improve it, so the reporting continues and the
6 education continues, with the ultimate objective to
7 reduce the pregnancies to zero if possible.
8 DR. GROSS: Okay. I am still trying to
9 answer Question No. 1. Let me take the prerogative
10 of the Chair and say there does not appear to be a
11 meaningful decrease in the number of pregnancies.
12 Would anybody disagree with that? Dr.
13 Whitmore.
14 DR. WHITMORE: The one thing that you
15 asked was are there contributing factors.
16 DR. GROSS: That is the second part of the
17 question. Let's do the first part first.
18 Otherwise, we are never going to get through the
19 day.
20 Does anybody disagree? Dr. Ringel.
21 DR. RINGEL: I think the real honest
answer is that we really don't know.
We don't know
1 if Dr. Bergfeld's comment about the number being
2 artificially high because of increased reporting is
3 true.
4 On the other hand, if that number really
5 reflects the actual rate, that is problematic
6 because the rate should have decreased, in fact,
7 because there were decreased numbers of
8 prescriptions written.
9 I think the only thing that this shows is
10 we don't have the answer to that, and we really
11 need a registry.
12 DR. GROSS: So, we have one dissenter.
13 Does anybody else dissent on the statement there
14 does not appear to be a meaningful decrease in the
15 number of pregnancies? Dr. Bigby.
16 DR. BIGBY: The suggestion has been raised
17 should we consider as an objective, the rate or the
18 absolute number, so if, in fact, you could show,
19 and you could probably do this, that the rate had
20 actually decreased and the absolute numbers in the
21 hundreds, is that a success. That is the point I
think we should think about, so maybe rate isn't
1 what we should be looking at.
2 DR. GROSS: Could I see a show of hands on
3 the question there does not appear to be a
4 meaningful decrease in the number of pregnancies?
5 We are never going to get through the program. We
6 are going to be stuck on Question 1 until 5:00 p.m.
7 To me, the answer seems obvious. Yes.
8 DR. SCHMIDT: Yesterday, on page 70 in
9 this Pregnancy Rate and Accutane Survey, this, I
10 thought was meaningful that it decreased, that
11 there was almost like a 2- to 4-fold decrease in
12 some of the slides that were shown in the decrease
13 in pregnancy rate.
14 I want to add one other thing to back up
15 Wilma. You know, people are very, very anal about
16 doing these different things in the offices.
17 At least in Houston, I mean we really bend
18 over backwards to do everything and cross out t's
19 and dot our i's on these, and from a clinical
20 experience, I took a straw vote at one of our major
21 meetings, our Thursday morning conference, and
since this S.M.A.R.T. program started, I could only
1 identify in this group one pregnancy that had
2 occurred at least in our group, which probably
3 includes a lot of people doing a lot of Accutane.
4 DR. STROM: To bring it to resolution, I
5 think the problem is an issue of terminology and
6 people are confusing numbers and rates. The
7 question is there does not appear to be a
8 meaningful decrease in the number of pregnancies
9 reported. I think it is very clear that is the
10 case. That is based on spontaneous reports, the
11 numbers are roughly even.
12 All of the issues everybody is raising are
13 correct in terms of issues of reporting that maybe
14 that the rates have gone down despite the fact that
15 the numbers haven't, and I think those are the two
16 things that people have confused.
17 But the question says not a meaningful
18 decrease in the numbers, and those numbers are
19 based on spontaneous reports, that is clearly the
20 case. The numbers are roughly the same.
21 MR. LEVIN: I just want to add to Brian's
comment that I think what people are responding to
1 is the second part. I mean the issue of whether we
2 are seeing better reporting, more accurate
3 reporting or actually that things are remaining the
4 same is a question of measurement, and that is in
5 the second part of the question.
6 DR. GROSS: So, a show of hands on the
7 first part of the question.
8 DR. DAY: Excuse me. Could I ask a
9 clarification? I know these questions have been set
10 for some time, but is there a way for us to ever
11 modify it, so that we could have a second part that
12 we could vote that the number has not decreased,
13 but that we do not have sufficient evidence about
14 the rate or the rate has or has not? Can we
15 address number and rate in this question?
16 Otherwise, some of us will be uncomfortable in
17 voting quickly one way or another to get it off our
18 agenda.
19 DR. GROSS: Sure, there is no reason. I
20 think we should answer the question, then, if you
21 want to put another statement, there is no reason
22 we
can't do that.
1 DR. TRONTELL: May I offer some
2 clarification from the Agency? We do our best to
3 express the questions clearly, but our intent in
4 this question was, in fact, to engage the committee
5 is some discussion on the issue of ascertainment of
6 pregnancy, some of which have already been raised
7 in some of the remarks around the table.
8 We would appreciate some discussion or
9 closure around it, not so much an issue of debating
10 whether or not the numbers have changed. We can
11 make our assessment of that, but the issue of
12 ascertainment, as well as implementation are what
13 we would like the committee to address.
14 DR. GROSS: So, ascertainment really
15 relates to the second part of the question.
16 A show of hands on the number of
17 pregnancies. Do all people think the number of
18 pregnancies appear not to have decreased
19 meaningfully? A show of hands that they agree that
20 is the case.
21 [Show of hands.]
DR. GROSS: Those who disagree?
1 DR. KIBBE: Abstentions? I think the data
2 is inconclusive and I will not vote one way or the
3 other when the date is unreliable.
4 DR. GROSS: Fine. So, the majority agree
5 and there is one abstention.
6 DR. KWEDER: Dr. Gross, if there is a
7 vote, we would appreciate it if you could record it
8 for the record in the instances when you do vote.
9 Thank you.
10 DR. GROSS: For the record, the group
11 agrees there does not appear to be a meaningful
12 decrease.
13 Do you want to go around the room, is that
14 what you mean by record?
15 MS. TOPPER: For the record, we are
16 required to go around the room individually and
17 have each person record their vote. If you will
18 say your name and you agree or disagree, we will
19 need to have that. Thank you.
20 DR. GROSS: Art, do you want to start?
21 MR. LEVIN: Arthur Levin. I agree.
DR. SAWADA: Kathy Sawada. I agree.
1 DR. VENITZ: Jurgen Venitz. I agree.
2 DR. STROM: Brian Strom. I agree.
3 DR. BERGFELD: Wilma Bergfeld. I agree
4 with the number, but I do not agree with the rate.
5 I believe the rate has gone down.
6 DR. GROSS: You believe the rate has gone
7 up?
8 DR. BERGFELD: Down.
9 DR. RAIMER: Sharon Raimer. I am going to
10 abstain. I don't think we have good enough data.
11 DR. GROSS: So, that is an abstention?
12 DR. RAIMER: Abstention.
13 MS. KNUDSON: Paula Knudson. I agree.
14 DR. BIGBY: Michael Bigby. I agree with
15 the statement that there hasn't been a meaningful
16 decrease in the number of pregnancies reported. I
17 do think that there is information that the actual
18 rate has decreased.
19 DR. HONEIN: Peggy Honein. I agree.
20 DR. COHEN: Michael Cohen. I agree.
21 DR. WHITMORE: Beth Whitmore. I agree
there has not been a meaningful decrease.
1 MS. SHAPIRO: Robyn Shapiro. I agree and
2 also observe that by asking for numbers as opposed
3 to rates, there seems to be an implied goal about
4 what we should be looking for, whether intended or
5 not.
6 DR. EPPS: Roselyn Epps. I agree.
7 DR. SCHMIDT: Jimmy Schmidt. I agree.
8 DR. CRAWFORD: Stephanie Crawford. I
9 agree there has not been a meaningful decrease in
10 the absolute number.
11 DR. GROSS: Peter Gross. I agree.
12 DR. WILKERSON: Michael Wilkerson. I
13 agree with the question.
14 DR. RINGEL: Eileen Ringel. I agree also.
15 DR. VEGA: Amarilys Vega. I think that we
16 don't have sufficient data.
17 DR. GROSS: So, that is an abstention?
18 DR. VEGA: Yes, sir.
19 DR. DAY: Ruth Day. I agree with the
20 decrease in number reported and make no claims
21 about anything else, numbers that may have
occurred, as well as changes in rate.
1 DR. KIBBE: Arthur Kibbe. I abstain on
2 the basis that the data is not conclusive, nor is
3 this an appropriate question.
4 DR. GARDNER: Jackie Gardner. I agree.
5 DR. KATZ: Robert Katz. I agree.
6 DR. SELLERS: Sarah Sellers. I agree.
7 DR. GROSS: Thank you all.
8 Now, for the more difficult part--that was
9 easy, believe it or not--please discuss measurement
10 and implementation factors. This is really where
11 the expertise of the committee could be enormously
12 helpful.
13 Any suggestions, comments?
14 Robyn Shapiro.
15 MS. SHAPIRO: I agree with your earlier
16 comment that there is insufficient data to weigh in
17 on that.
18 DR. GROSS: Anyone else? Art.
19 MR. LEVIN: I guess I am just confused by
20 what the rate, when talking about rates, where we
21 are. If I look at P70 of the Roche presentation,
which is sourced at Slone and tracks the number of
1 pregnancies per 1,000 Accutane treatment courses
2 and the number of pregnancies per 1,000 patients
3 per year, there does seem to be a decrease, but
4 where we get down to is around the number 3, and we
5 have just heard from 4 to 3. Over the period of
6 1989 to the year 2002, and if we sort of track
7 into, you know, sort of approximate on this graph
8 where the first prevention program came into effect
9 and then where S.M.A.R.T. came into effect, which
10 is probably not on this graph actually. You know,
11 we see recent history.
12 But we just heard of a rate of 1, I think,
13 in the presentation from Slone. So, I am just
14 personally somewhat confused as to the different
15 presentations of what the rate issue is, whether it
16 is in the course of treatment or per patient year
17 what we are discussing here.
18 DR. GROSS: Sarah.
19 DR. SELLERS: I would just like to remind
20 everyone that we are talking about a reporting
21 rate, we are not talking about an incidence rate,
22 and
the primary objective of the risk management
1 program is to decrease the number of pregnancies,
2 not to decrease the reporting rate.
3 These are reported pregnancies and the
4 number of reported cases are small in comparison to
5 what we believe are the overall number of
6 pregnancies that may be occurring and exposures
7 during pregnancy.
8 So, a meaningful decrease in a reporting
9 rate, in my opinion, has very little validity in
10 the discussion of decreasing pregnancy exposures.
11 DR. GROSS: Thank you.
12 So far we have been talking about
13 measurement on this question. How about
14 implementation factors, implementation factors that
15 may have contributed to a lack of a decrease in the
16 number of pregnancies? Dr. Katz.
17 DR. KATZ: Just to take one second to
18 reiterate an anecdote--I won't reiterate it--but to
19 remind you we don't have part of not being able to
20 improve on it although we have to keep trying and
21 use every effort is the human fallibility and that
22 was
my only point in mentioning that little
1 anecdote. You can't completely control human
2 behavior, nor can we unfortunately 100 percent
3 control physician behavior and how much time
4 somebody is spending with a patient, and so forth.
5 So, some of it, we are not going to be
6 able to reduce it to zero.
7 DR. GROSS: A point well taken.
8 DR. KATZ: It was also pointed out
9 yesterday, with all the stringent requirements that
10 one might consider adding, that still doesn't
11 eliminate pregnancies. It will capture the numbers
12 better and it may be a reminder, an education
13 reminder, but if somebody is going to tell the
14 doctor that they are sexually inactive, you can't
15 force them to take birth control pills. There is a
16 certain limit to what we can do.
DR. GROSS: Exactly. There is going to be <