FOOD AND DRUG ADMINISTRATION







                           ADVISORY COMMITTEE

                       IN JOINT SESSION WITH THE




                           ADVISORY COMMITTEE




                      Thursday, February 26, 2004


                               8:00 a.m.




                          Hilton Gaithersburg

                           620 Perry Parkway

                      Gaithersburg, Maryland 20877







         Peter A. Gross M.D., Chairman

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


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

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

         Ruth S. Day, Ph.D.

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

         Arthur A. Levin, M.P.H.

         Robyn S. Shapiro, J.D.

         Brian L. Strom, M.D., M.P.H.





         Roselyn E. Epps, M.D.

         Robert Katz, M.D.

         Paula Knudson, Consumer Representative

         Sharon S. Raimer, M.D.

         Eileen W. Ringel, M.D.

         Kathleen Y. Sawada, M.D.

         Jimmy D. Schmidt, M.D.

         Elizabeth S. Whitmore, M.D.

         Michael G. Wilkerson, M.D.


      CONSULTANTS (Voting):


         Wilma F. Bergfeld, M.D.

         Michael E. Bigby, M.D.

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

         Arthur H. Kibbe, Ph.D.

         Sarah Sellers, Pharm.D.

         Amarilys Vega, M.D., Ph.D.

         Jurgen Venitz, M.D., Ph.D.


      GUEST SPEAKER (Non-Voting):


         Richard K. Miller, Ph.D.



                        PARTICIPANTS (Continued)

      FDA STAFF:


         Jonca Bull, M.D.

         Steven Galson, M.D., M.P.H.

         John Jenkins, M.D.

         Sandra Kweder, M.D.

         Paul Seligman, M.D., M.P.H.

         Anne Trontell, M.D., M.P.H.

         Jonathan Wilkin, M.D.



                            C O N T E N T S




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


      Conflict of Interest Statement,

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


      Effectiveness of the Isotretinoin Risk Management

      Program for the Prevention of Fetal Exposure to

      Accutane and its Generic Equivalents and

      Consideration of whether Changes

      to this Isotretinoin Risk Management Program would

      be Appropriate:


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

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


      Background and Regulatory History,

         Jill Lindstrom, M.D., Division of Dermatologic

         and Dental Drug Products, FDA                          15


      Questions to the Speaker from Committee                   49


      Open Public Hearing:


         Robert A. Silverman, M.D.                              68


         Sidney Wolfe, M.D.,

         Public Citizen Research Group                          74


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

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


      Hoffmann-La Roche, Inc. Presentations:


         Introduction, Joanna Waugh, Group Director,

         Regulatory Affairs                                     90


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

         Global Head Drug Safety Risk Management                94


         Regulatory Overview, Joanna Waugh                      96



                      C O N T E N T S (continued)




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

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

         Management, Drug Safety Risk Management               101


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

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

         Global Head Drug Safety Risk Management               116


      Generic Firms' Presentations:


         Isotretinoin Risk Management Program, Background

         Information, Frank R. Sisto, Vice President,

         Corporate Regulatory Affairs,

         Mylan Laboratory, Inc.                                140


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

         Slone Epidemiology Center, Boston University          152


         Isotretinoin Enhanced Risk Management Program,

         Program Elements for which Advisory Committee

         Input is Requested, Robert W. Pollock, Vice

         President, Lachman Consultant Services, Inc.          169


      Questions to Roche and Generic Firms from Committee



      Isotretinoin Pregnancy Exposure: Spontaneous

      Reports 1 Year Pre- and 1 Year Post-Risk

      Management Program,

         Marilyn Pitts, Pharm.D.,

         Office of Drug Safety, FDA                            218


      Isotretinoin Pregnancy Prevention Program


         Allen Brinker, M.D., M.S.,

         Office of Drug Safety, FDA                            237


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

         Kaiser Permanente Drug Use Management                 265


      Questions to Kaiser from the Committee                   289



                      C O N T E N T S (Continued)




      Organization of Teratology Information Services,

         Interim Report, North American Isotretinoin

         Information and Survey Line, Richard Miller,

         Ph.D., University of Rochester                        296


      Questions to OTIS from the Committee                     313


      Risk Management Options for Pregnancy Prevention,

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


      Selecting Risk Management Tools: Considerations and

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

         Director, Office of Drug Safety, FDA                  338


      Questions to Speakers from the Committee                 366




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


  2                 Call to Order and Introductions


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


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


  5   Management Advisory Committee.  I would like to


  6   thank you all for coming this morning, and the


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


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


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


 10   of Internal Medicine at Hackensack University


 11   Medical Center and New Jersey Medical School.


 12             MS. JAIN:  Shalini Jain, Executive


 13   Secretary, FDA, Center for Drug Evaluation and


 14   Research.


 15             DR. WILKERSON:  Michael Wilkerson, MD.,


 16   private practice, Tulsa, Oklahoma.


 17             DR. RINGEL:  Eileen Ringel, I am in


 18   private practice in Waterville, Maine.


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


 20   Cognition Laboratory at Duke University and I am on


 21   the Drug Safety and Risk Management Committee.


 22             DR. KIBBE:  Art Kibbe, Chairman of the




  1   Pharmaceutical Sciences Department, Wilkes


  2   University School of Pharmacy and Chairman of the


  3   Pharmaceutical Sciences Advisory Committee to the


  4   FDA.


  5             DR. GARDNER:  Jackie Gardner, Professor of


  6   Pharmacy, University of Washington, and Drug Safety


  7   and Risk Management Advisory Committee.


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


  9   practice in Rockville, Maryland, and Clinical


 10   Assistant Professor of Dermatology at Georgetown


 11   University.


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


 13   a Masters in Public Health Candidate at Bloomberg


 14   School of Public Health.


 15             DR. TRONTELL:  Anne Trontell, Deputy


 16   Director of the Office of Drug Safety in the FDA


 17   Center for Drugs.


 18             DR. SELIGMAN:  Paul Seligman, Director of


 19   the Office of Pharmacoepidemiology and Statistical


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


 21             DR. WILKIN:  Jonathan Wilkin, Director of


 22   the Division of Dermatologic and Dental Drug




  1   Products in CDER, FDA.


  2             DR. BULL:  Good morning.  Jonca Bull,


  3   Director, Office of Drug Evaluation V in the Office


  4   of New Drugs, Center for Drug Evaluation and


  5   Research.


  6             DR. KWEDER:  Sandra Kweder, Deputy


  7   Director of Office of New Drugs in CDER.


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


  9   Director of the Center for Drug Evaluation and


 10   Research.


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


 12   representative on the Drug Safety Committee.


 13             DR. SAWADA:  Kathleen Sawada,


 14   dermatologist, private practice in Lakewood,


 15   Colorado.


 16             DR. VENITZ:  Jurgen Venitz, Associate


 17   Professor, Virginia Commonwealth University and


 18   Chair of the Clinical Pharmacology Subcommittee.


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


 20   Department of Biostatistics and Epidemiology at the


 21   University of Pennsylvania School of Medicine, and


 22   I am a member of the Drug Safety and Risk




  1   Management Committee.


  2             DR. BERGFELD:  I am Wilma Bergfeld,


  3   dermatologist and dermatopathologist, head of


  4   Clinical Research Department of Dermatology at the


  5   Cleveland Clinic.


  6             DR. RAIMER:  Sharon Raimer, Chairman of


  7   Dermatology at the University of Texas in


  8   Galveston.


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


 10   administrator for the University of Texas at


 11   Houston, and I am with the Dermatology Advisory


 12   Committee.


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


 14   dermatologist at Beth Israel Deaconess Medical


 15   Center and Harvard Medical School.


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


 17   epidemiologist with the Birth Defects Center at the


 18   Centers for Disease Control and Prevention.


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


 20   with the Institute for Safe Medication Practices,


 21   and I am with the Drug Safety and Risk Management


 22   Advisory Committee.




  1             DR. WHITMORE:  Beth Whitmore, I am in


  2   private practice in Wheaton, Illinois.


  3             DR. SHAPIRO:  Robyn Shapiro, I am


  4   Professor and Director of the Center for the Study


  5   of Bioethics at the Medical College of Wisconsin,


  6   and I am on the Drug Safety and Risk Management


  7   Advisory Committee.


  8             DR. EPPS:  Roselyn Epps, Chief of the


  9   Division of Dermatology in Children's National


 10   Medical Center, and also a member of the


 11   Dermatologic and Ophthalmic Drugs Advisory


 12   Committee.


 13             DR. SCHMIDT:  I am Jimmy Schmidt, in


 14   clinical practice from Houston, Texas and I am on


 15   the clinical faculty of University of Texas and


 16   Baylor Medical School.


 17             DR. CRAWFORD:  Good morning.  Stephanie


 18   Crawford, Associate Professor, University of


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


 20   member of the Drug Safety and Risk Management


 21   Advisory Committee.


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




  1   like to ask Shalini Jain to read the conflict of


  2   interest statement.


  3                  Conflict of Interest Statement


  4             MS. JAIN:  The following statement


  5   addresses the issue of conflict of interest with


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


  7   record to preclude even the appearance of such at


  8   this meeting.


  9             The topics to be discussed at today's


 10   meeting are matters of broad applicability.  Unlike


 11   issues before a committee in which a particular


 12   sponsor's product is discussed, issues of broad


 13   applicability involve many sponsors and their


 14   products.  All FDA participants have been screened


 15   for their financial interests as they may apply to


 16   the products and companies that could be affected


 17   by the committee's discussions.


 18             Based on this review, it has been


 19   determined that there is no potential for an actual


 20   or apparent conflict of interest at this meeting,


 21   with the following exception:  In accordance with


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




  1   a waiver that permits her to participate fully.


  2             A copy of the waiver statement maybe


  3   obtained by submitting a request to the Food and


  4   Drug Administration's Office of Management


  5   Programs, Division of Freedom of Information,


  6   HF1-35 5600 Fishers Lane, Rockville, Maryland


  7   20857.


  8             Because issues of broad applicability


  9   involve many sponsors and their products, it is not


 10   prudent to recite all potential conflicts of


 11   interest as they may apply to each member,


 12   consultant and guest speaker.  In addition, there


 13   will be no industry representatives at today's


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


 15   Administration has appointed industry


 16   representatives that currently serve on each of


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


 18   industry representative to the Drug Safety and Risk


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


 20   industry representative to the Dermatologic and


 21   Ophthalmic Drugs Advisory Committee, work with


 22   sponsors that are directly impacted by the matters




  1   before the committee.  FDA has contacted three


  2   industry representatives from other Center for Drug


  3   Evaluation and Research committees that have


  4   experience with risk management issues and with FDA


  5   advisory committee processes.  However, none were


  6   available to participate in this meeting.  Dr.


  7   Stemhagen and Mr. Kresel are present in the


  8   audience and attending as interested observers.


  9             Further, we would like to note that Dr.


 10   Louis Morris, a member of the Drug Safety and Risk


 11   Management Committee, has been recused from


 12   participating in today's meeting.  Dr. Morris is


 13   also present in the audience and attending as an


 14   interested observer.


 15             We would like to remind the FDA


 16   participants not to discuss the issues at hand


 17   outside the advisory committee meeting.  In the


 18   event that the discussions involve any other


 19   products or firms not already on the agenda for


 20   which FDA participants have a financial interest,


 21   the participant's involvement and exclusion will be


 22   noted for the record.  With respect to all other




  1   meeting participants, we ask in the interest of


  2   fairness that they address any current or previous


  3   financial involvement with any firm whose product


  4   they wish to comment upon.  Thank you.


  5             DR. GROSS:  Thank you.  The topic for


  6   discussion for the next two days is the


  7   effectiveness of the isotretinoin risk management


  8   program for the prevention of fetal exposure to


  9   Accutane and its generic equivalents, and to


 10   consider whether changes to this risk management


 11   program would be appropriate.  Dr. Steven Galson


 12   will give our committees the charge.  He is Acting


 13   Director of the Center for Drug Evaluation and


 14   Research.


 15                     Charge to the Committees


 16             DR. GALSON:  Thank you very much, Dr.


 17   Gross.  I want to thank all of the committee


 18   members for being here.  Your commitment to public


 19   service, indicated by the time commitment that you


 20   have agreed to make to this subject, is extremely


 21   important for the Food and Drug Administration and,


 22   indeed, very important for all the patients taking




  1   this drug and our decision-making process.


  2             Today and tomorrow you are going to hear


  3   details about the regulatory history of


  4   isotretinoin.  You are going to review data that


  5   has been collected over the last few years about


  6   the Pregnancy Prevention Program, and you are going


  7   to help us by giving us advice about where this


  8   program should go in the future.  These


  9   perspectives are extremely important to us.  We can


 10   spend a lot of time talking to each other and


 11   tossing ideas around about what is the best course


 12   of action but when we have outside observers who


 13   have taken a fresh look at these programs it is


 14   enormously helpful to us as we move down the path


 15   to make decisions.


 16             Isotretinoin has been on the market for


 17   about 22 years and it may take the record for the


 18   single drug with the most advisory committee


 19   meetings.  I don't know if that is true but it is


 20   certainly very close.  When Roche established the


 21   current S.M.A.R.T. program in consultation with the


 22   FDA in 2001, the agency established several goals




  1   for the program.  They were that no person should


  2   begin isotretinoin therapy if pregnant and that no


  3   pregnancy should occur while a woman is taking


  4   isotretinoin.


  5             I want to just note that although those


  6   were the goals, the agency is very cognizant of the


  7   fact that setting a zero goal as a metric for


  8   something that really depends on human behavior for


  9   success and is probably not possible to attain.  It


 10   is good to set that goal but when these issues are


 11   totally out of the control of manufacturers,


 12   physicians or the agency it is really impossible to


 13   actually meet that, and we have been criticized for


 14   saying our goal is zero.  I want to make it clear


 15   that we recognize that it is probably not


 16   attainable but we still think it is important to


 17   set these important goals because it helps us set


 18   the stage for figuring out what steps we want to


 19   take and we think that is very important.


 20             Setting these goals and establishing


 21   metrics to get there is very consistent with one of


 22   the evolving foundations of CDER's risk management




  1   program which is that risk management programs must


  2   be periodically evaluated for effectiveness.


  3   Efficiency in risk management is very important


  4   and, without measuring the effectiveness of the


  5   program and knowing whether we are getting adequate


  6   preventive power for the resources devoted we


  7   really don't know where to go in the future with


  8   this program, and it doesn't help us in terms of


  9   establishing and setting up new programs for


 10   additional drugs.


 11             Manufacturers of isotretinoin have been


 12   challenged by the agency to work together to


 13   minimize adverse events related to this drug, and


 14   we are really extremely heartened by the degree of


 15   collaboration that has taken place to date and by


 16   the way the manufacturers are working together to


 17   look towards the future.  We really expect this


 18   collaboration to continue and we think that the


 19   goal of minimized the teratogenic risk of this drug


 20   is something that we all share with all the


 21   manufacturers and we, again, want to congratulate


 22   and are very heartened by the degree to which these




  1   groups have been working together.  We look forward


  2   to hearing about how the S.M.A.R.T. program has


  3   worked and how the companies have been working in


  4   detail together.


  5             I want to just talk about the committee


  6   now.  We ask you to really remain focused on the


  7   purpose of this meeting, the risk management


  8   program for the prevention of fetal exposure.  We


  9   are aware that there are other important safety


 10   issues related to this drug but we really are going


 11   to focus on prevention of fetal exposure in this


 12   meeting.  We would like you to consider the data


 13   presented.  We want you to consider the past risk


 14   management programs and their achievements, and we


 15   are really looking forward to your recommendations


 16   as to whether the program, as it now exists, should


 17   continue; whether it is as effective as it could


 18   be; and how we should enhance it or establish new


 19   or different tools.  So, with that I will close and


 20   pass it back to the Chair.  Thank you very much.


 21   We are looking forward to a great meeting.


 22             DR. GROSS:  Thank you, Dr. Galson.  You




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


  2   next speaker is Jill Lindstrom, a medical officer


  3   for the Division of Dermatologic and Dental Drug


  4   Products at the FDA, who will talk about the


  5   background and regulatory history of this


  6   medication.


  7                Background and Regulatory History


  8             DR. LINDSTROM:  Good morning.


  9             [Slide]


 10             My objectives this morning are to set for


 11   you a clinical context for the use of isotretinoin;


 12   to outline the history of risk management efforts


 13   for this drug; to describe the current risk


 14   management plan in some detail; and to provide the


 15   committee with some rough guidelines for their


 16   assessment of the data that will be presented.


 17             [Slide]


 18             Isotretinoin is an oral retinoid that is


 19   indicated for the treatment of severe recalcitrant


 20   nodulocystic acne.  It is the only drug moiety


 21   approved for this indication, although there are


 22   other oral related products in development.  The




  1   innovator was approved in 1982 and three generic


  2   products have recently entered the market.


  3             [Slide]


  4             This patient has nodular acne, a


  5   devastating disease that can result in significant


  6   scarring and permanent disfigurement.  You can see


  7   that he has many lesions, to include large


  8   fluctuant nodules on his forehead, his cheeks, his


  9   chin and his nose.


 10             [Slide]


 11             This patient also has nodular acne and,


 12   again, you can see the many lesions on his face,


 13   the large fluctuant nodules extending down onto his


 14   trunk.


 15             [Slide]


 16             This is the same patient, a view of his


 17   back.


 18             [Slide]


 19             Again, a view of that patient's face prior


 20   to isotretinoin therapy--


 21             [Slide]


 22             --and following conclusion of a course of




  1   isotretinoin therapy--he is dramatically improved.


  2             [Slide]


  3             And a third clinical example of a patient


  4   with severe nodular acne.  Again, you can see the


  5   nodules, sinus track formation and scarring.  This


  6   is the patient prior to a course of isotretinoin


  7   therapy--


  8             [Slide]


  9             --and at completion of his course of


 10   therapy.


 11             [Slide]


 12             Because of its unique effectiveness,


 13   current practice standards have expanded the use of


 14   isotretinoin to the setting of non-nodular but


 15   still scarring acne.


 16             [Slide]


 17             This patient does not have nodules, does


 18   not have classic nodular acne.  She has severe


 19   papulopustular acne and her disease is scarring.


 20   You can also imagine that, in addition to the


 21   cutaneous morbidity, she has significant


 22   psychosocial morbidity from her disease.  This is




  1   her presentation prior to treatment with


  2   isotretinoin--


  3             [Slide]


  4             --and her result at conclusion of therapy.


  5             [Slide]


  6             And a second patient, again without


  7   nodular acne but with severe scarring papular acne.


  8   This is a front view--


  9             [Slide]


 10             --and a side view prior to treatment with


 11   isotretinoin--


 12             [Slide]


 13             --and the patient's result at conclusion


 14   of therapy, again dramatically improved.


 15             [Slide]


 16             Now, isotretinoin is unique among the


 17   therapies in the acne armamentarium in that it


 18   addresses all four of the known pathogenetic


 19   mechanisms of acne.  It decreases sebum production


 20   and shrinks the size of the sebaceous glands.  It


 21   normalizes follicular hyperkeratinization and


 22   reduces follicular plugging.  It decreases P. acnes




  1   colonization, although not through a direct


  2   antibacterial mechanism but probably through making


  3   the micro climate of the follicle inhospitable to


  4   the organism.  Finally, it is mildly


  5   anti-inflammatory.


  6             [Slide]


  7             These events can be seen in this


  8   histological specimen, this biopsy of a comedo


  9   prior to isotretinoin therapy.  You can see the


 10   dilated follicle filled with keratinous debris, the


 11   large sebaceous glands.  Not well appreciated in


 12   the black and white photograph is the


 13   perifollicular inflammation and the numerous


 14   bacteria in the follicle.


 15             [Slide]


 16             In a biopsy of a follicle following


 17   isotretinoin therapy the sebaceous glands--again, I


 18   regret that I don't have a pointer but the


 19   sebaceous glands are much smaller in size; the


 20   follicular lumen is narrow.  There is no follicular


 21   plugging and there is an absence of perifollicular


 22   inflammation.




  1             [Slide]


  2             Isotretinoin is also unique in that a


  3   course of therapy is temporally circumscribed.


  4   Other anti-acne agents have no long-term impact and


  5   are effective only while they are being used.  A


  6   course of isotretinoin, however, can result in


  7   complete and prolonged disease remission.  Thus,


  8   patients with severe scarring acne like the


  9   clinical examples that I just showed you prior to


 10   the approval of isotretinoin would have faced


 11   years, perhaps even decades, of therapy with oral


 12   antibiotics in combination with topical agents.


 13   Now such patients, after a course of isotretinoin


 14   therapy, will see their disease become quiescent


 15   and the progression of their disfigurement halted,


 16   and they are spared the risk, the expense and the


 17   inconvenience of years of oral and topical


 18   therapies.


 19             [Slide]


 20             However, isotretinoin does present its own


 21   risks.  It is a known human teratogen.  In utero


 22   exposure to isotretinoin can result in an increased




  1   risk of spontaneous abortion and premature births,


  2   as well as structural abnormalities.  Approximately


  3   28 percent of exposed fetuses will have sufficient


  4   stigmata at the time of birth to be diagnosed with


  5   retinoid embryopathy.  Additionally, many babies


  6   who are exposed to isotretinoin in utero will


  7   appear normal at birth and will go on later in life


  8   to manifest neurodevelopmental deficits.


  9             [Slide]


 10             What has been done to manage this risk?


 11   At the time of approval in 1982 it was understood


 12   from animal data that isotretinoin was likely a


 13   teratogen, and in labeling the drug was classified


 14   pregnancy category X.  Prescribers and patients


 15   were advised in the contraindications, warnings and


 16   precautions sections of labeling not to become


 17   pregnant while using the drug.


 18             [Slide]


 19             The first report of a human malformation


 20   following in utero exposure to isotretinoin was


 21   published in 1983.  In response, red warning


 22   stickers were distributed to pharmacies to be




  1   affixed to each isotretinoin prescription that was


  2   dispensed.  Additional reports of exposed


  3   pregnancies were received raising the concern both


  4   in the agency and the manufacturer.  Multiple "dear


  5   doctor" letters were issued to inform the medical


  6   community of this risk and the label was revised as


  7   information became available.


  8             [Slide]


  9             In 1988 the sponsor proposed a


 10   multi-tiered program to augment the risk management


 11   plan which they entitled the Pregnancy Prevention


 12   Program.  An advisory committee was convened to


 13   review this proposal.  There were, as I said,


 14   multiple components.  First, the label was altered


 15   to include warnings printed directly on the


 16   package, and the "avoid pregnancy" icon was


 17   introduced, the familiar red circle with the slash


 18   and the pregnant figure.  And, the packaging was


 19   changed to blister packaging.


 20             [Slide]


 21             The package insert was updated to include


 22   a boxed warning informing physicians and patients




  1   of a need for a negative pregnancy test seven days


  2   before treatment initiation; the importance of


  3   using two reliable forms of contraception; waiting


  4   to begin therapy until the second or third day of


  5   the next menses; and limiting the supply dispensed


  6   to 30 days; and the importance of repeating


  7   pregnancy testing and contraceptive counseling on a


  8   monthly basis.


  9             [Slide]


 10             An informed consent form for females was


 11   introduced in that program.  A kit for prescribers


 12   was provided to explain the details of the program,


 13   and the first iteration of the voluntary patient


 14   survey was introduced at that time.  Additionally,


 15   there was a tracking survey to assess prescriber


 16   use of the program.  That advisory committee


 17   recommended approval of the Pregnancy Prevention


 18   Program and the program was implemented in 1989.


 19             [Slide]


 20             What was the impact of the program?  It is


 21   somewhat difficult to say.  From the time of


 22   approval of isotretinoin in 1982 pregnancies have




  1   been reported to the agency.  At the time of the


  2   introduction of the Pregnancy Prevention Program we


  3   gained a new tool to gather information about


  4   pregnancy reports, the patient survey.  Those


  5   pregnancy reports are represented by the light blue


  6   bars from 1989 on.


  7             Both of these reporting mechanisms,


  8   spontaneous reports as well as reports through the


  9   survey, are voluntary reporting mechanisms and so


 10   it is difficult to ascertain an accurate pregnancy


 11   rate.  I want to remind you that this is a


 12   historical view prior to the implementation of the


 13   current risk management program, but what we can


 14   say is that the public health burden from exposed


 15   pregnancies continued to be large.


 16             [Slide]


 17             Additionally, during this time or during


 18   the '90s Accutane use was increasing significantly.


 19   Because of these reasons, the large public health


 20   burden from exposed pregnancies as well as the


 21   increasing use, an advisory committee was convened


 22   again to consider augmentation of the risk




  1   management plan.


  2             [Slide]


  3             This advisory committee was convened in


  4   September of 2000 and they determined that there


  5   was, indeed, a compelling need for augmentation of


  6   the risk management plan.  The agency agreed and


  7   this was communicated to the sponsor in a letter


  8   dated October 6, 2000.  This letter has been


  9   included in the briefing package for the committee.


 10             [Slide]


 11             In this letter risk management is


 12   addressed from two perspectives, both pregnancy


 13   prevention and potential neuropsychiatric adverse


 14   events.  Pregnancy prevention is the focus of this


 15   advisory committee.  However, since the letter was


 16   included in your packet and does address


 17   neuropsychiatric risk management I want to briefly


 18   update the committee on the status of risk


 19   management efforts with regards to potential


 20   neuropsychiatric risk.


 21             [Slide]


 22             Three points of action were recommended by




  1   the committee and communicated in that letter.


  2   First, that the informed consent be amended to


  3   inform patients of the potential for


  4   neuropsychiatric adverse events, and this has been


  5   done.  Second, it was advised that an educational


  6   program for prescribers be implemented, and this


  7   has also been done.  Third, it was recommended that


  8   a comprehensive research program be undertaken to


  9   include clinical trials.


 10             The sponsor submitted clinical protocols


 11   to investigate neuropsychiatric risk to the agency.


 12   When the agency reviewed them and gave the area


 13   some additional considered thought it was


 14   recognized that more basic science groundwork


 15   needed to be done before moving on to clinical


 16   trials, and this basic science groundwork is now


 17   being undertaken in collaboration with the National


 18   Institute for Mental Health.  As that data is


 19   accrued we will move on at the appropriate time to


 20   clinical trials.


 21             That is all I am going to say today about


 22   risk management of neuropsychiatric risk.  I want




  1   to remind both the committee and the public that it


  2   is not the subject of this advisory committee.


  3             [Slide]


  4             Moving on to pregnancy prevention, also


  5   addressed in that letter, two goals, as Dr. Galson


  6   already mentioned, were articulated.  The first,


  7   that no one should begin isotretinoin therapy if


  8   they are pregnant and the second, that effective


  9   pregnancy prevention would occur throughout the


 10   course of isotretinoin therapy.  Implied in these


 11   two goals is that we would have the ability to


 12   assess whether or not they have been achieved.


 13             [Slide]


 14             To achieve these two goals, five points of


 15   action were advised: augmentation of patient


 16   education; registration of all patients;


 17   registration of prescribers; implementation of a


 18   pregnancy registry; and linkage of prescription


 19   dispensing to adequate pregnancy testing.


 20             [Slide]


 21             The agency and the sponsor, having heard


 22   the committee's recommendations, entered into




  1   extensive discussions and negotiations in an


  2   attempt to design a plan that would incorporate the


  3   five points of action to achieve the two goals that


  4   had been articulated.


  5             However, obstacles were encountered,


  6   particularly regarding patient privacy issues and


  7   compliance with the newly passed Health Insurance


  8   Portability and Accountability Act.  Eventually,


  9   however, a plan was crafted and was approved in


 10   October, 2001.  The innovator was the only product


 11   on the market at that time and they named their


 12   risk management plan S.M.A.R.T., a System to Manage


 13   Accutane-Related Teratogenicity.  I will refer to


 14   their plan and the subsequent generic risk


 15   management plans as the current risk management


 16   plan so when I use the term the current risk


 17   management plan, you can think of that as


 18   interchangeable with S.M.A.R.T., S.P.I.R.I.T,


 19   I.M.P.A.R.T., etc.


 20             I want to now move and describe how the


 21   plan that was crafted sought to incorporate those


 22   five points of action and then I will describe for




  1   you the mechanics of the plan in some detail.


  2             [Slide]


  3             The first point of action articulated by


  4   the committee was a heightened educational program


  5   for each patient that included verifiable


  6   documented written informed consent.  This is


  7   fairly straightforward and is a component of the


  8   current risk management plan.


  9             [Slide]


 10             The second point was complete registration


 11   of all patients, both male and female.  This was


 12   intended to provide the denominator for


 13   ascertainment of the pregnancy rate.  However,


 14   registries raise issues regarding patient privacy.


 15   The sponsor proposed an alternative proposal to


 16   estimate the denominator using pharmacy databases


 17   and survey data.  This, of course, would avoid


 18   those patient privacy issues but the accuracy of


 19   the alternative proposal was dependent on


 20   increasing the survey response rate.  The sponsor


 21   felt that this would be achievable.


 22             [Slide]




  1             The third point of action was complete


  2   registration and certification of all prescribers.


  3   The sponsor objected that they did not have the


  4   authority to certify prescribers and so a plan of


  5   voluntary registration was devised in which


  6   prescribers self-attest that they possess the


  7   relevant competencies needed to safely prescribe


  8   isotretinoin.  Additionally, prescribers singed a


  9   commitment to use the current risk management plan.


 10   The sponsor does provide prescribers with


 11   information about the plan, but the responsibility


 12   for obtaining the necessary education to achieve


 13   the relevant competencies rests with the


 14   prescriber.  I will detail these competencies in a


 15   few moments.


 16             [Slide]


 17             The fourth point of action was a


 18   comprehensive plan to track fetal exposures to


 19   isotretinoin to include a formal pregnancy


 20   registry.  This was intended to provide the


 21   numerator for ascertainment of the pregnancy rate.


 22   Again, because it involved a registry, it raised




  1   concerns regarding patient privacy and issues


  2   regarding compliance with the newly passed HIPPA.


  3             Again, to avoid these obstacles and to


  4   speed the implementation of augmented risk


  5   management measures, the sponsor proposed


  6   extrapolation of the numerator from survey response


  7   data.  Accurate extrapolation from survey response


  8   data would require an increased survey response,


  9   which the sponsor identified as an increased


 10   response rate of greater than 60 percent.  Now,


 11   they did feel that this would be achievable and, in


 12   order to achieve the increased rate, they planned


 13   targeted education of prescribers to increase


 14   awareness of the survey and they increased


 15   reimbursement for patient participation by 300


 16   percent.


 17             [Slide]


 18             The final point of action advised by the


 19   committee was the linking of dispensing of


 20   isotretinoin to verification of adequate pregnancy


 21   testing.  This is accomplished in the current risk


 22   management plan through the use of yellow




  1   qualification stickers.  The physician verifies the


  2   negative pregnancy test and fills out the


  3   qualification sticker.  The patient takes the


  4   prescription with the qualification sticker to the


  5   pharmacist who then verifies that the patient has,


  6   indeed, been qualified.  However, in the current


  7   plan the pharmacist does not independently review


  8   the negative pregnancy test lab report.  Pharmacist


  9   participation in the current plan is voluntary but


 10   encouraged through the way that the plan is


 11   designed.


 12             [Slide]


 13             I want to take a moment now and describe


 14   in some detail the mechanics of how the current


 15   risk management plan works.  It can be a bit


 16   complex if you haven't used it yourself in a


 17   clinical setting.  The program begins with a


 18   physician who decides that they would like to


 19   prescribe isotretinoin and that they possess the


 20   relevant competencies necessary to do so.


 21             The physician will sign a one-time letter


 22   of understanding with the manufacturer, attesting




  1   that they do possess the necessary knowledge and


  2   experience in order to safely prescribe the drug,


  3   specifically that they are knowledgeable about the


  4   different forms of acne and its treatment; that


  5   they are knowledgeable about isotretinoin and its


  6   risks for teratogenicity; that they are


  7   knowledgeable about the risks for and the


  8   prevention of unplanned pregnancy; and finally,


  9   that they are knowledgeable about the current risk


 10   management plan and that they agree to use its


 11   mechanisms.


 12             When the manufacturer receives this signed


 13   letter of understanding, they then forward to the


 14   prescriber the qualification stickers and separate


 15   educational materials for both the prescriber as


 16   well as for patients.  Prescriber educational


 17   materials consist of things like best practices


 18   guides that inform the prescriber how to use the


 19   components of the current risk management plan.


 20   Educational materials for patients include things


 21   like brochures and videos.


 22             The physician then encounters a patient




  1   for whom they believe treatment with isotretinoin


  2   is indicated.  From this point forward, as I am


  3   describing the mechanics when I refer to a patient


  4   I am speaking specifically of a female patient.


  5   So, when the prescriber encounters a patient for


  6   whom isotretinoin is indicated the first thing that


  7   they will do, having made the preliminary decision


  8   to prescribe the drug, is obtain a screening


  9   pregnancy test.  They would also provide


 10   educational materials to the patient and the


 11   informed consent forms, which I will talk about in


 12   a minute.


 13             Also at this time, contraception


 14   counseling and contraception would be provided.


 15   This can be accomplished in one of two ways, the


 16   prescriber him or herself, if they possess the


 17   necessary expertise, can provide the counseling


 18   themselves or they can refer to a reproductive


 19   health specialist such as a gynecologist for


 20   provision of the contraception counseling and the


 21   contraception.  The female patient, unless they


 22   select complete abstinence, must be on two forms of




  1   contraception, at least one of which must be a


  2   primary form, for 30 days prior to the initiation


  3   of isotretinoin therapy.


  4             The patient reads the educational


  5   material, obtains the contraception counseling and


  6   the contraception and reads through the informed


  7   consent documents, signs those and returns them to


  8   the physician.  There are actually two informed


  9   consent documents.  The first is an informed


 10   consent/patient agreement which is given to both


 11   male and female patients.  This outlines the risks


 12   for teratogenicity, as well as the potential risk


 13   for psychiatric adverse events, and also elicits


 14   agreement from the patient that they will abide by


 15   the risk management principles of the current risk


 16   management program, such as that they will not


 17   share their isotretinoin with other people; they


 18   will not give blood until at least 30 days after


 19   the conclusion of their therapy; that they will


 20   return to their physician on at least a monthly


 21   basis.  The second informed consent document is


 22   specific for female patients and goes into much




  1   greater detail about the risks of unplanned


  2   pregnancy and the risk of teratogenicity with


  3   isotretinoin therapy.


  4             Both of those informed consent forms and


  5   the informed consent/patient agreement need to be


  6   signed and returned to the physician.


  7   Additionally, before prescribing isotretinoin the


  8   physician must obtain a second pregnancy test, this


  9   time timed to the woman's cycle within the first


 10   five days of the menses or, if the patient is


 11   amenorrheic, at least 11 days after the last


 12   episode of unprotected intercourse.  After these


 13   steps have been accomplished the physician then


 14   fills out the prescription form, affixes the


 15   qualification sticker and fills that out with the


 16   date of qualification signifying that two negative


 17   pregnancy tests have been obtained; that the


 18   patient understands the risk management program;


 19   that adequate contraception, either two forms or


 20   absolute abstinence, have been initiated.


 21             The patient then takes the prescription


 22   with the qualifying sticker affixed and filled out




  1   to the pharmacist.  The pharmacist verifies that


  2   the sticker has been affixed, has been properly


  3   completed, and also that the receipt of this


  4   sticker and the dispensing of the isotretinoin


  5   occur within seven days of the date of the


  6   physician's qualification of the patient.  If all


  7   of those criteria are met the pharmacist dispenses


  8   the isotretinoin along with a medication guide


  9   which is an information brochure for patients


 10   which, by law, must be dispensed each time


 11   isotretinoin is dispensed that describes in


 12   layman's language the risks of the drug and the


 13   steps that need to be taken to minimize those


 14   risks.


 15             The patient then initiates their course of


 16   isotretinoin therapy and on a monthly basis will


 17   return to the prescriber to be requalified.


 18   Requalification consists of repeating the pregnancy


 19   test and verifying that the test is negative;


 20   re-counseling the patient regarding contraception;


 21   and ensuring that the risk management program is


 22   being abided by.




  1             We receive data about the program from


  2   several sources, first, spontaneous adverse events


  3   reports come to the agency from physicians, the


  4   manufacturer, from patients as well as from


  5   pharmacists.  Additionally, the patient is


  6   encouraged to participate in the voluntary patient


  7   survey and data is gathered through that mechanism.


  8   Finally, pharmacies are surveyed and the


  9   prescriptions are audited to check for compliance


 10   with the sticker program.


 11             [Slide]


 12             The risk management plan, as I have


 13   described, was approved for the innovator in


 14   October of 2001.  Since that time three generic


 15   products have been approved and have entered the


 16   market.  Their risk management plans are identical


 17   in the essential elements that I have just


 18   described to the innovator plan.  So, again, when I


 19   speak of the current risk management plan, that


 20   would be interchangeable for either the innovator


 21   plan or the plan of the three generic products.


 22             [Slide]




  1             However, while the four risk management


  2   plans are identical in their essential elements and


  3   can be considered interchangeable, there are some


  4   differences that have caused marketplace confusion.


  5   Besides having different trade names for the four


  6   drugs, each manufacturer has elected to name their


  7   risk management program by a different name so for


  8   Accutane with have S.M.A.R.T., the System to Manage


  9   Accutane-Related Teratogenicity.  For Amnesteem we


 10   have S.P.I.R.I.T, the System to Prevent


 11   Isotretinoin-Related Issues of Teratogenicity.  For


 12   Sotret it is I.M.P.A.R.T., Isotretinoin Medication


 13   Program Alerting you to the Risks of


 14   Teratogenicity.  For Claravis it is A.L.E.R.T, the


 15   Adverse Event Learning and Education Program


 16   Regarding Teratogenicity.  Additionally, different


 17   survey contractors have been employed by the


 18   innovator who uses Degge/SI and the generic firms


 19   who all use the Slone Epidemiology Unit.  Finally,


 20   mid-course changes by the patient's pharmacy


 21   provider in brand of isotretinoin dispensed can


 22   result in patient confusion and perhaps multiple




  1   enrollment in the voluntary survey.


  2             [Slide]


  3             When this current risk management plan was


  4   approved the sponsor was instructed to submit a


  5   comprehensive report on the metrics of the program


  6   after one year of implementation.  This advisory


  7   committee has been convened to comment on those


  8   data.  The advisory committee in 2000 did not


  9   address benchmarks nor define success.  Indeed, to


 10   do so is challenging.  But at this time I want to


 11   provide you with some rough guidelines that you can


 12   use as you are thinking about three parameters in


 13   particular, the survey response rate, the sticker


 14   use and the number of fetal exposures.


 15             [Slide]


 16             The survey response rate, by the sponsor's


 17   own assertion, would need to be greater than 60


 18   percent.  The success of the current risk


 19   management program in terms of accurate estimation


 20   of that numerator for the pregnancy rate is


 21   dependent on this higher survey response rate.  The


 22   agency's approval of the current risk management




  1   plan was based on the sponsor's assertion that they


  2   would be able to achieve this threshold.


  3             [Slide]


  4             The qualification stickers serve as a


  5   surrogate endpoint for the use of the current risk


  6   management plan.  When the agency approved the plan


  7   it was understood that the stickers were an


  8   imperfect surrogate and, in fact, as the data has


  9   come in they may be more imperfect than we had


 10   realized, and other speakers will describe to you


 11   the linkage between the stickers and various


 12   components of the program such as pregnancy


 13   testing.  However, at the time of approval the


 14   sponsor was informed that because the sticker


 15   served as a surrogate, and an imperfect surrogate


 16   at that, the threshold for success would be very,


 17   very high and, in fact, would approach 100 percent


 18   in terms of sticker use.


 19             [Slide]


 20             Finally, and perhaps most importantly,


 21   fetal exposures--it would be difficult to identify


 22   an acceptable number for fetal exposures.  In




  1   considering what success would look like in terms


  2   of fetal exposures the committee may want to think


  3   of this in parallel with the two goals that were


  4   articulated by the 2000 advisory committee, the


  5   first goal being that no one initiate isotretinoin


  6   therapy if pregnant.  This goal, the responsibility


  7   for which rests largely on the shoulders of


  8   prescribers, may best be achievable.


  9             The second goal, that no one become


 10   pregnant while on isotretinoin therapy, is more


 11   complex because it depends on patient behavior.


 12   Again, in considering the threshold of success in


 13   terms of fetal exposure you may want to think of


 14   these two populations independently, and also in


 15   considering what risk management tools would impact


 16   these populations you may want to consider them


 17   separately as different tools may be appropriate.


 18             [Slide]


 19             In summary, isotretinoin is a uniquely


 20   effective drug for the treatment of severe,


 21   scarring acne, a truly devastating disease.  There


 22   has been a long history of risk management efforts




  1   to prevent fetal exposures to this drug which were


  2   built sequentially.  The current risk management


  3   program has introduced some new tools and the


  4   advisory committee is being asked to comment on the


  5   effectiveness of these new tools and the current


  6   program.


  7             I and my colleagues look forward to


  8   hearing your considered input on the data and how


  9   we can optimize the public health by ensuring that


 10   isotretinoin is available to the patients who


 11   needed it in a context that minimizes and best


 12   manages the risks.  So, I thank you for your


 13   attention this morning and I would be happy to take


 14   your questions.


 15             DR. GROSS:  Thank you very much, Dr.


 16   Lindstrom.  Before the questions, I would like to


 17   introduce an additional consultant who will be


 18   participating in our joint advisory committee


 19   session, Dr. Vega.  Dr. Vega, would you please


 20   introduce yourself?


 21             DR. VEGA:  Yes, good morning.  I am a


 22   Board-certified pediatrician with a Masters in




  1   Public Health and a Fellowship in


  2   Pharmacoepidemiology from the Food and Drug


  3   Administration.  I am also a former medical


  4   epidemiologist from the Office of Drug Safety, with


  5   extensive experience with the isotretinoin


  6   pregnancy prevention issue.  I presented at the


  7   last advisory committee the data on the different


  8   options to modify the Pregnancy Prevention Program.


  9   I currently work for PSI International in their


 10   adverse event reporting project.


 11                   Questions from the Committee


 12             DR. GROSS:  Thank you.  Now Dr. Lindstrom


 13   will entertain questions from the committees.  Yes?


 14             DR. CRAWFORD:  Dr. Lindstrom, thank you


 15   for the overview.  In terms of considering possible


 16   risk management tools to enhance pregnancy


 17   prevention, one thing I am not sure of after


 18   reading all the materials we were provided is


 19   whether the reasons for failure have been


 20   identified.  So, has there ever been any thought


 21   given to some type of failure mode analysis


 22   determining for those patients who do become




  1   pregnant, exactly what went wrong so efforts could


  2   be targeted on preventing those failures in the


  3   future?


  4             DR. LINDSTROM:  That is an excellent


  5   question.  The speakers that follow will be


  6   addressing the data and I believe also, as much as


  7   we know, the reasons for failures.  So, if you


  8   don't mind, I think I will defer the answer to that


  9   question to the presentations that will follow


 10   mine.


 11             DR. GROSS:  Dr. Gardner?


 12             DR. GARDNER:  Dr. Lindstrom, could you


 13   give us some idea of the epidemiology of the severe


 14   acne for which these drugs are both specifically


 15   indicated and also for which they are being used?


 16   For example, can you tell us the incidence or even


 17   the prevalence of the condition in the population


 18   and the distribution by gender and by age, if you


 19   know?


 20             DR. LINDSTROM:  I will do my best to


 21   answer that question.  Acne is extremely common,


 22   particularly in the adolescent age range.  The




  1   incidence has been reported to be 80 percent in the


  2   12-20 year-old group and falling to about 3 percent


  3   in the over 45 year-old age group.  You can sort of


  4   extrapolate the decrease during that time.


  5             DR. GARDNER:  Is that severe acne?


  6             DR. LINDSTROM:  No, that is all acne.


  7   There is not an ICD-9 code for severe acne so it is


  8   difficult--I don't actually know and I couldn't


  9   find, in preparing for this committee meeting, an


 10   incidence or a prevalence for severe acne.  I can


 11   tell you that recalcitrant nodular acne is not the


 12   majority of acne.  Severe scarring acne is a larger


 13   proportion of acne patients.  As a practicing


 14   dermatologist, it was not uncommon.  I saw scarring


 15   acne on essentially a daily basis but I don't have


 16   incidence or prevalence figures for you, other than


 17   the prevalence of acne in the population at large.


 18             DR. GROSS:  Sarah Sellers?


 19             DR. SELLERS:  A quick question on the


 20   qualification in the current program, the


 21   qualification sticker that goes to the pharmacy has


 22   a qualification date on it?




  1             DR. LINDSTROM:  Yes.


  2             DR. SELLERS:  And, is that date the date


  3   of the confirmed negative test?


  4             DR. LINDSTROM:  Yes, it is.  For


  5   initiation of therapy it would be the date of the


  6   second confirmed negative pregnancy test and for


  7   ongoing therapy it would be the date of the


  8   repeated negative pregnancy test.


  9             DR. SELLERS:  It is not the date that a


 10   sample was taken for a pregnancy test?


 11             DR. LINDSTROM:  No, I believe it is the


 12   date--I am sorry, I didn't follow actually your


 13   question.


 14             DR. SELLERS:  The qualification date is


 15   actually when the negative result is received--


 16             DR. LINDSTROM:  That is my understanding.


 17             DR. SELLERS:  --not the date a sample is


 18   drawn for analysis to go to the lab?


 19             DR. LINDSTROM:  Correct.


 20             DR. SELLERS:  Thank you.


 21             DR. GROSS:  Yes, Robyn??


 22             DR. SHAPIRO:  I guess I am curious about




  1   the HIPPA problem that you have found with some of


  2   the registry ideas.  Why couldn't the patients


  3   simply authorize release of particular information


  4   in order for them to get the drug and, therefore,


  5   make that information available?


  6             DR. LINDSTROM:  At the time of the prior


  7   advisory committee and at the time that the agency


  8   and the sponsor were working to craft the plan,


  9   HIPPA had just been approved and towards the end of


 10   that time period was being implemented.  In working


 11   with consul from the company as well as consul


 12   within the agency, working out the details of HIPPA


 13   compliance proved difficult and while it probably


 14   would have been achievable, it was taking a lot of


 15   time.  So, the sponsor proposed and the agency


 16   approved these alternative methods in order to have


 17   a plan in a more timely fashion that could be


 18   implemented that could augment the risk management


 19   program.  As understanding of compliance of HIPPA


 20   has matured, I think it would be much easier to


 21   navigate those waters at this time but at that time


 22   the Act had just been passed and was in the process




  1   of being implemented and understanding was not yet


  2   mature.


  3             DR. GROSS:  Dr. Bigby?


  4             DR. BIGBY:  I have two questions.  The


  5   first one is that you stated that some patients who


  6   take Accutane never have acne again.  Are you or


  7   someone else going to actually tell the committee


  8   what the actual numbers are in terms of the


  9   long-term efficacy of Accutane?


 10             DR. LINDSTROM:  What I had hoped to state


 11   was that patients may achieve complete and


 12   long-term remission. I have read different figures.


 13   Approximately 10-20 percent of patients who are


 14   treated with Accutane never require treatment with


 15   Accutane again.  Another way to state that would be


 16   that 10-20 percent of patients who undergo a course


 17   of isotretinoin therapy do require a second course


 18   of isotretinoin therapy.  Of the 80-90 percent that


 19   only require one course of isotretinoin therapy, a


 20   portion of those are then able to be maintained


 21   with no treatment at all.  A portion would require


 22   only topical therapy and some may require oral




  1   antibiotic therapy.


  2             DR. BIGBY:  I just think that it is


  3   important for the committee to know actually what


  4   those proportions are and I just hope somebody


  5   brings that data to the table.


  6             DR. LINDSTROM:  I don't have those


  7   numbers.  All I can tell you is that between 10-20


  8   percent of isotretinoin patients do undergo a


  9   second course of therapy.


 10             DR. BIGBY:  Well, those numbers do exist


 11   and I just hope it is sort of made known to the


 12   committee what those numbers are.


 13             The other question I had was of the


 14   pregnancies that occurred prior to S.M.A.R.T. and


 15   during S.M.A.R.T., is there any data about who the


 16   prescribers were?


 17             DR. LINDSTROM:  I am sorry, can you repeat


 18   your question?


 19             DR. BIGBY:  You presented information


 20   about pregnancies that occurred for the year prior


 21   to S.M.A.R.T. and during a year of S.M.A.R.T.  What


 22   I would like to know is who the prescribers of




  1   Accutane were for those women who got pregnant.


  2             DR. LINDSTROM:  Yes, actually I did not


  3   present any data about pregnancies during


  4   S.M.A.R.T.  My objectives at this point of the day


  5   were to set the historical context so the slide


  6   that I showed was that reported pregnancies to the


  7   agency were from 1982 through 1999.  Speakers later


  8   today will update you with the current pregnancy


  9   data, the more recent data during the


 10   implementation of the current risk management


 11   program.


 12             Now, there were two parts to your question


 13   and I only answered half.  Can you tell me again


 14   the second part of that question?


 15             DR. BIGBY:  No, you answered it.


 16             DR. LINDSTROM:  Okay.


 17             DR. GROSS:  Dr. Michael Cohen?


 18             DR. COHEN:  Earlier you mentioned that


 19   there may occasionally be some confusion between


 20   the various risk management programs for


 21   isotretinoin that exist and perhaps also the brand


 22   names.  Are you saying that that occasionally




  1   contributes to some of the problem that we are


  2   seeing with isotretinoin and the way that it is


  3   handled?  Also, who actually does the selection?


  4   Is it the prescriber or the pharmacist?  Is it a


  5   substitution that is made?  I didn't understand


  6   that.


  7             DR. LINDSTROM:  In stating the various


  8   names and alluding to confusion, my point is just


  9   to give the perspective of patients and


 10   prescribers.  It is a somewhat complex plan and


 11   there are various names out there, and to just make


 12   the committee aware that that is a potential source


 13   of confusion, the multiple names for the risk


 14   management plans.  I did not mean to imply that


 15   there should not be different trade names for the


 16   products of the various manufacturers but, rather,


 17   that the risk management plan having multiple names


 18   does present some confusion for patients.  The


 19   second part of your question?


 20             DR. COHEN:  Well, I guess I am a little


 21   bit confused about who actually selects the brand


 22   that will be used.  You mentioned that occasionally




  1   a patient can go from one brand to another--


  2             DR. LINDSTROM:  Right.


  3             DR. COHEN:  --does that contribute to any


  4   confusion that we should be concerned about?  I


  5   understand the plans are pretty much the same.


  6             DR. LINDSTROM:  Right.


  7             DR. COHEN:  They have the same baseline


  8   requirements but are there any errors that this


  9   contributes to that, you know, might have an


 10   adverse outcome that we should know about?


 11             DR. LINDSTROM:  Sure.


 12             DR. COHEN:  In other words, should there


 13   be one plan?


 14             DR. LINDSTROM:  I think that is an


 15   excellent question and one that the committee will


 16   need to be considering as the day goes forward.


 17   Other speakers will present to you the details of


 18   the data that has been obtained from the current


 19   risk management plan and will be in a better


 20   position to address confusion from the agency's


 21   perspective in terms of data collection from


 22   multiple plans.




  1             As far as whether a patient receives one


  2   particular manufacturer's isotretinoin or another,


  3   a physician can specify that as they write the


  4   prescription but I think in many instances it is


  5   the pharmacy provider that makes that determination


  6   of which patient receives which brand.  So, it is a


  7   little bit outside of the prescriber-patient


  8   relationship.


  9             DR. GROSS:  Dr. Kweder?


 10             DR. KWEDER:  Yes, I think I can clarify a


 11   little bit.  We do not have specific data on the


 12   frequency of switching between brands.  We have


 13   heard for patients and providers that this is a


 14   potential source of difficulty but we do not have


 15   data saying how common it is for patients to be


 16   required to switch mid-course.  Just like any


 17   medication, the source of imposing a change could


 18   be anything from the patient wanting a cheaper


 19   brand to the pharmacist pressing for that, or the


 20   physician or even the health insurance plan that


 21   will only pay a certain amount.


 22             DR. GROSS:  Dr. Trontell?




  1             DR. TRONTELL:  I was going to just


  2   elaborate on Dr. Kweder's remarks.  We don't yet


  3   have any data to document that confusion has


  4   occurred between these programs.


  5             DR. GROSS:  Thank you.  Dr. Whitmore, did


  6   you have a question?


  7             DR. WHITMORE:  The answer came up already,


  8   thank you.


  9             DR. GROSS:  Dr. Day?


 10             DR. DAY:  Was any provision made for


 11   providing the risk management plan for mail order


 12   prescriptions?  I assume that originally Accutane


 13   was available through mail order.


 14             DR. LINDSTROM:  The prior risk management


 15   plan did allow for mail order prescriptions.  For


 16   the current risk management plan, as I understand


 17   it, a mail order prescription might be challenging


 18   in that the drug needs to be dispensed within a


 19   seven-day window of qualification.  Not only that,


 20   but there are other features of the plan that might


 21   not happen.  So, it is not allowed.


 22             DR. GROSS:  Dr. Honein?




  1             DR. HONEIN:  I just want to follow-up with


  2   some questions on the multiple risk management


  3   programs.  I wondered if there was any data on how


  4   often women get one set of information from a


  5   prescriber and a different set of information from


  6   the pharmacist at the time it is dispensed, and if


  7   there are any reports of that contributing to


  8   confusion.


  9             DR. LINDSTROM:  The information that the


 10   patient receives from the pharmacist would be the


 11   medication guide which would be the same for all of


 12   the manufacturers' products, the innovator as well


 13   as the generic.  The pharmacy has the option of


 14   providing additional patient education information


 15   that is not part of the current risk management


 16   plan that would be in addition to that.


 17             DR. HONEIN:  Don't they get enrollment


 18   forms both from the prescriber and the pharmacy,


 19   and wouldn't those be different if they got


 20   different sets of material?


 21             DR. LINDSTROM:  Thank you.  That is a good


 22   point.  The enrollment forms are included with each




  1   prescription that is dispensed and the enrollment


  2   form for the innovator uses one contractor and the


  3   enrollment forms for the generics utilize a


  4   different contractor so you are correct that that


  5   would be another potential source of confusion for


  6   a patient.


  7             DR. GROSS:  Dr. Knudson?


  8             MS. KNUDSON:  I am curious about the age


  9   distribution of the women taking the drug.  I would


 10   like to know does the enrollment form or the survey


 11   form or the qualifying sticker carry the age?


 12             DR. LINDSTROM:  The qualifying sticker


 13   does not.  Age may be obtained by the pharmacy as


 14   part of an independent pharmacy data collection


 15   with age, date of birth and so forth to ensure that


 16   the correct prescription is dispensed to the


 17   correct patient.  Age is a component of the


 18   voluntary patient survey.


 19             DR. GROSS:  Dr. Ringel?


 20             DR. RINGEL:  This is a quibbling point


 21   from the "nothing in life is perfect" department.


 22   You mentioned that it should be possible to prevent




  1   initiation of isotretinoin therapy before a


  2   pregnancy, and there are ways you can actually


  3   manage it if you consider that there is a certain


  4   number of false-negative pregnancy tests,


  5   particularly early in pregnancy, and also there can


  6   be confusion with bleeding at implantation and


  7   bleeding for other reasons with menses.  If you put


  8   those together, in fact, it would be possible to be


  9   pregnant, despite all of our efforts, before


 10   initiating Accutane.


 11             DR. GROSS:  Dr. Strom?


 12             DR. STROM:  In the era of increasing


 13   computerized data entry, how would this risk


 14   management plan work?


 15             DR. LINDSTROM:  I am sorry, can you


 16   elaborate on your question?


 17             DR. STROM:  Sure.  The current risk


 18   management plan, as I understand it, relies on a


 19   sticker program.


 20             DR. LINDSTROM:  Yes.


 21             DR. STROM:  There is increasing use of


 22   computerized prescribing and a big push nationwide




  1   to increase that.


  2             DR. LINDSTROM:  Yes.


  3             DR. STROM:  How could this be


  4   operationalized?  How could this plan possibly work


  5   in that context?


  6             DR. LINDSTROM:  The current risk


  7   management plan does not allow for computerized


  8   prescriptions.


  9             DR. STROM:  Just to clarify, given the


 10   current environment in pharmacy, neither mail order


 11   nor computerized prescriptions are compatible with


 12   the current plan.


 13             DR. LINDSTROM:  Computerized prescriptions


 14   are not compatible with the current plan and I


 15   think mail order would be difficult with the


 16   current plan.  Again, I have set the historical


 17   context and described the current plan.


 18             DR. GROSS:  Dr. Kibbe?


 19             DR. KIBBE:  I have just a question about


 20   the two figures that you gave us and the data that


 21   is contained therein.  Have you taken the number of


 22   reports of pregnancies for the years from '91 to




  1   '99 and divided them by the number that you show


  2   for the number of female patients during those same


  3   years and gotten, even though it is an inaccurate


  4   number, at least an estimate of number of


  5   pregnancies per 1,000 patients over that time


  6   frame?


  7             DR. LINDSTROM:  I believe that you are


  8   bringing up the issue of pregnancy rate.  While the


  9   absolute number of pregnancies reported to the


 10   agency was relatively constant, the number of women


 11   receiving isotretinoin prescriptions was rising.  I


 12   don't want to belabor this point but there are two


 13   issues related to deriving a rate from the data


 14   that I showed.  First, pregnancy reporting is


 15   voluntary, both the spontaneous reports and those


 16   received through the survey.  They are voluntary.


 17   Both are voluntary mechanisms.  We know that


 18   adverse event reporting declines over time and we


 19   know that it does not capture all events so it is


 20   an imprecise number.


 21             Second, even if that numerator in terms of


 22   the number of pregnancies reported was reflective




  1   of the total number of exposed pregnancies that had


  2   occurred, even if that number, indeed, did stay


  3   flat the public health burden of those exposed


  4   pregnancies, of those affected babies, was not


  5   declining.  Those two slides were actually


  6   presented to the advisory committee in 2000, and


  7   for those reasons it was determined to be important


  8   to increase the risk management for this drug


  9   because the public health impact has remained


 10   significant.


 11             DR. KIBBE:  So, your answer is no?


 12             DR. LINDSTROM:  Yes.


 13             DR. GROSS:  Dr. Bull?


 14             DR. BULL:  I just wanted to remind you,


 15   going back to the issue of computerized


 16   prescriptions, that this whole risk management plan


 17   is predicated on a high level of interaction


 18   between the patient and the healthcare provider.


 19   These are non-refillable prescriptions.  The


 20   patient has to return to the healthcare provider


 21   for an interaction, hopefully a face-to-face


 22   evaluation of how the acne treatment is




  1   progressing, such that because of the fact that


  2   these are not prescriptions that are automatically


  3   refilled it is not a course of therapy where you


  4   are given a prescription that you renew for five


  5   months.  It is one where every month during that


  6   course of time there is a need to return to the


  7   healthcare provider of record.


  8             DR. GROSS:  I am going to take the


  9   prerogative of the chair and declare a break at


 10   this particular time.  We have no breaks scheduled


 11   for the morning and I think we will hold questions


 12   until a little bit later.  Thank you.  We will


 13   reconvene at 9:30.


 14             [Brief recess]


 15                       Open Public Hearing


 16             DR. GROSS:  Both the Food and Drug


 17   Administration and the public believe in a


 18   transparent process for information gathering and


 19   decision-making.  To ensure such transparency at


 20   the open public hearing session of the advisory


 21   committee meeting, which we are about to start, the


 22   FDA believes that it is important to understand the




  1   context of an individual's presentation.  For this


  2   reason, the FDA encourages you, the open public


  3   hearing speaker, at the beginning of your written


  4   or oral statement to advise the committee of any


  5   financial relationship that you may have with the


  6   sponsors of any products in the pharmaceutical


  7   category under discussion at today's meeting.  For


  8   example, the financial information may include the


  9   sponsor's payment of your travel, lodging or other


 10   expenses in connection with your attendance at the


 11   meeting.  Likewise, FDA encourages you at the


 12   beginning of your statement to advise the committee


 13   if you do not have any such financial


 14   relationships.  If you choose not to address this


 15   issue of financial relationships at the beginning


 16   of your statement it will not preclude you from


 17   speaking.


 18             We have two registered speakers for the


 19   morning, Dr. Robert A. Silverman is first.  Dr.


 20   Silverman?


 21             DR. SILVERMAN:  Dr. Gross, members of the


 22   advisory committee, thank you for giving me the




  1   opportunity to speak about the continued


  2   availability of isotretinoin.  My statement will


  3   focus on the benefits of this drug and the impact


  4   of pregnancy prevention risk management efforts on


  5   its availability to patients.


  6             I have been practicing pediatric


  7   dermatology for nearly two decades.  At first I was


  8   in Cleveland at Rainbow Babies and Children's


  9   Hospital.  Since 1989 I have maintained a private


 10   practice in Northern Virginia and a dermatology


 11   clinic in the Department of Pediatrics at


 12   Georgetown University.  For the record, I have not


 13   participated in any pharmaceutical company


 14   sponsored acne drug studies, nor am I taking any


 15   reimbursement from the AADA, and the only thing I


 16   have taken today is one bottle of water.


 17             [Laughter]


 18             I am a physician who treats patients, not


 19   a healthcare provider who sees clients.  I make the


 20   distinction to emphasize the trust and close


 21   relationship between a physician and patient that


 22   is necessary for obtaining the best results when




  1   treating acne while minimizing side effects of any


  2   of the medications that we use.  As a pediatrician,


  3   I recognize the social and psychological impact


  4   that an acne-scarred body image has on teenagers.


  5   I know of no drug that has changed the lives of my


  6   patients with acne more than isotretinoin.  It has


  7   been a Godsend to adolescents and to young adults


  8   with recalcitrant, nodular, nodulocystic and


  9   scarring disease.


 10             Unlike dermatologists entering the medical


 11   work force today, I remember how we used to treat


 12   severe nodulocystic acne.  One of the most painful,


 13   gruesome procedures that I learned in my training


 14   at the Children's Hospital in Boston was the


 15   incision and drainage of multiple purulent


 16   abscesses, like you saw earlier, on the faces of


 17   young men and women afflicted with recalcitrant


 18   nodulocystic acne.  The procedure is nearly a


 19   historical footnote since we have the availability


 20   of isotretinoin.


 21             There is not a week that goes by in my


 22   practice that a concerned parent, with facial scars




  1   themselves, brings in a preadolescent with minimal


  2   or no acne for anticipatory guidance in hopes of


  3   their child avoiding the same fate that they had


  4   when they were growing up.  Of course, the vast


  5   majority of these children never-ever reach the


  6   point of needing isotretinoin.  But for the few who


  7   progress and require it, I am thankful that I have


  8   the option to use this medication.  The reason I am


  9   here today is to keep this drug available to all


 10   people who need it.


 11             Let me share a story that perfectly


 12   illustrates the wonders that can be worked by this


 13   drug.  In 1982, when I was in Boston, the year that


 14   isotretinoin first became available in the United


 15   States, I met a beautiful young lady who had a


 16   beautiful complexion.  During that year she


 17   developed inflammatory acne that then rapidly


 18   progressed to severe painful, nodulocystic disease.


 19   She was being cared for by an excellent


 20   dermatologist at one of the nation's first and


 21   premier HMOs.  Minocycline, benzoyl peroxides,


 22   Retin-A and oral contraceptives made no difference




  1   in her appearance.


  2             Isotretinoin was not widely prescribed and


  3   it was not until 1986 when she saw her fourth


  4   dermatologist, after moving to Washington, D.C.,


  5   that Accutane was offered to her.  The years


  6   between 1982 and 1986 were for her filled with


  7   anxiety and self-consciousness.  I know this


  8   because this woman is now my wife.  She took


  9   isotretinoin safely.  She was aware of the


 10   teratogenic risks and used two forms of birth


 11   control.  We now have two healthy boys who were


 12   conceived well after my wife-to-be's finishing the


 13   drug.  This story is obviously close to my heart


 14   but it also illustrates the fact that female


 15   patients of childbearing potential can and do use


 16   isotretinoin safely.


 17             I have treated many teenaged girls and


 18   young women with isotretinoin.  I have personally


 19   prescribed isotretinoin since 1986 and have used it


 20   according to the risk management guidelines with


 21   utmost caution, and since the S.M.A.R.T. program


 22   has been in effect I have complied with it to the




  1   best of my ability.


  2             As a clinician in the trenches, I am


  3   familiar with the difficulties and weaknesses that


  4   were outlined that may impede optimal participation


  5   in the S.M.A.R.T. program.  Complicating and


  6   restricting access will only drive needy patients


  7   to obtain isotretinoin through illicit channels or


  8   those that circumvent well-established


  9   doctor-patient relationships.  This would be a


 10   travesty of monumental proportions.  In grade


 11   school I learned the acronym KIS--keep it simple.


 12   The more complicated you make the process of


 13   obtaining this medication the more mistakes are


 14   going to be made.


 15             I would be happy to help in any way that I


 16   can to keep this medication available to all who


 17   need it and to address the small, but unfortunate,


 18   number of pregnancies that have occurred while on


 19   this drug.  Thank you for your time and


 20   consideration and I would be happy to entertain any


 21   questions if we have a few seconds.  Thank you.


 22             DR. GROSS:  Thank you very much, Dr.




  1   Silverman.  The next speaker is Dr. Sidney Wolfe of


  2   the Public Citizen's Health Research Group.


  3             DR. WOLFE:  Helping out in this


  4   presentation is Dr. Sherri Shubin who is a


  5   pediatrician and currently doing a preventive


  6   medicine residency at Johns Hopkins.  She is


  7   spending part of her residency with us.


  8             [Slide]


  9             I will take a minute or so to go over the


 10   first couple of slides.  Our involvement really


 11   started shortly after the drug came on the market


 12   in September of '83.  We submitted a petition


 13   urging patient package inserts and black box


 14   warnings about birth defects and life-threatening


 15   adverse events.  Prior to approval, as many of you


 16   know, there was a pretty comprehensive program to


 17   make sure that no one who got the drug got


 18   pregnant, and a number of those strictures were


 19   dropped at the time of initial marketing and slowly


 20   some of them were reintroduced.


 21             On April 26, ADA testified before this


 22   committee describing Accutane as an imminent public




  1   health hazard and saying that unless certain


  2   restrictions were imposed it should really come off


  3   the market.  The restrictions are listed there, one


  4   of the most important of which is, of course,


  5   limiting prescribing to dermatologists who file


  6   sworn affidavits stating they will adhere to the


  7   stated indications for the drug.  That is supposed


  8   to be happening, not the sworn affidavit part but,


  9   obviously the amount of prescriptions belies the


 10   fact that that is what it is limited to.  We then


 11   filed a petition to the FDA in May of 1988 with


 12   recommendations, saying it should come off the


 13   market and only be allowed back on with these


 14   restrictions.


 15             [Slide]


 16             Just finishing up a little bit on that, we


 17   continued urging removal from the market unless


 18   restrictions were put in and, thus far, these


 19   restrictions just have not been put in.  Most


 20   recently, in September, 2000, we testified that at


 21   that time the issue of depression and suicide had


 22   arisen and again we proposed restrictions.




  1             [Slide]


  2             This is testimony before this committee by


  3   Dr. David Erickson, who was then Chief at the


  4   Centers for Disease Control and Prevention of the


  5   Genetics and Birth Control Branch.  His statements


  6   are very poignant because 15 years later the same


  7   issue is there: "The birth of babies with defects


  8   caused by fetal exposure to Accutane is


  9   unnecessary.  FDA decision to allow the marketing


 10   of Accutane is a failed regulatory experiment. A


 11   decision to depend on better contraception alone,


 12   without active intervention to reduce the number of


 13   users, is a decision to leave the number of


 14   affected babies at an unacceptably high level."


 15   Finally, one of his suggestions was, "perhaps a


 16   formal IND," investigational new drug, "would be a


 17   suitable mechanism to reduce the frequency of


 18   Accutane embryopathy."


 19             [Slide]


 20             Now, these are data from the package that


 21   was provided to you a couple of weeks ago--it


 22   should have been included.  This is an FDA




  1   presentation before this committee back in


  2   September of 2000.  What they said was that as of


  3   that time these are just the reported cases and, as


  4   several people said this morning and it understates


  5   the actual magnitude of the problem with 1,995


  6   exposed pregnancies; 1,214 elective abortions; 383


  7   live births; and 162 infants with birth defects.


  8             [Slide]


  9             These now are the more recent data from


 10   the first year of the S.M.A.R.T. program.  Again,


 11   the first two points are taken directly from the


 12   package that was handed out and 156,800


 13   "unique"--the phrase used in there--women were


 14   given the drug.  Secondly, the estimated pregnancy


 15   rate, and I am sure this is on the low side but


 16   that is what was in this information set is 0.35


 17   percent.  If you take that rate and apply it to the


 18   number of "unique" women given the drug in that


 19   first year it means that there have been 548


 20   pregnancies and this is 4.6 times higher than the


 21   voluntarily spontaneously reported pregnancies that


 22   are also listed in the package, which is a measure




  1   of the under-reporting.


  2             [Slide]


  3             Of the 61 pregnancies with known


  4   outcomes--remember, about half of them had outcomes


  5   unknown--48 of 61 or 78.7 percent resulted in


  6   elective abortions.  Again, if you apply this to


  7   the more likely estimate of the actual number of


  8   pregnancies, 548, this means that there would have


  9   been 431 elective abortions in that one year ending


 10   in March of 2003.


 11             [Slide]


 12             Again estimating the number of deliveries,


 13   of 61 pregnancies with known outcomes, 7 of 61 or


 14   11.5 percent resulted in deliveries.  There were


 15   some spontaneous abortions, and so forth that make


 16   up some of the other ones aside from the elective


 17   abortions.  Again, applying this to the 548


 18   estimated pregnancies, there would have been 63


 19   deliveries.  Using FDA's and the CDC's figure,


 20   which is probably on the low side, 25 percent birth


 21   defects and the 50 percent mental retardation is as


 22   close--there hasn't been any really careful study




  1   on it but applying those figures to this estimate,


  2   we are talking about 16 infants with birth defects


  3   and 31 with mental retardation just in that one


  4   year.


  5             [Slide]


  6             The reason the S.M.A.R.T. program and even


  7   the new Roche proposal do not seriously address the


  8   two major issues here are as follows:  In 1989 CDC


  9   estimated that there were no more than 4,000 women


 10   of childbearing age with severe cystic acne.  They


 11   did not even get into the recalcitrant or other


 12   therapy.  Adjusted for population growth because


 13   these were 1987 data, the number may now be 6,000.


 14   Given that there were 156,800 "unique" women of


 15   childbearing age who got the drug in that first


 16   year of S.M.A.R.T., this represents a 26-fold


 17   excess in prescribing over the number of on-label


 18   prescriptions.


 19             The second point is that unless there is


 20   something more than a sticker and an assurance but


 21   there is actually the provision of a lab test


 22   showing that the woman, in fact, was not pregnant




  1   and at least a description of the contraceptive


  2   methods--unless that happens, then people are going


  3   to have stickers that are misrepresenting what has


  4   actually happened.


  5             [Slide]


  6             The reason why we are about to file a


  7   petition in the next week or two asking for this


  8   drug to be taken off the market and made available


  9   through an IND is that there have been 20 years of


 10   failed voluntary and even more recently some


 11   mandatory restrictions, and they have led to


 12   actually a total of more pregnancy exposures


 13   because the actual amount of prescriptions has gone


 14   up.  I think it was estimated in '88 or '89 that


 15   there may be 70,000 "unique" women of childbearing


 16   age getting the drug and it is now some 150,000.


 17             As we recommended in '88 and the CDC


 18   itself suggested as an option the next year, as I


 19   showed you in Dr. Erickson's presentation, we now


 20   propose a ban on marketing with subsequent


 21   availability only under a tightly controlled IND as


 22   the only feasible way to significantly reduce




  1   prescriptions and pregnancy exposures.


  2             [Slide]


  3             These would be the main elements of the


  4   restrictions in an IND:  Photographic proof of


  5   severe cystic acne confirmed by an independent


  6   group of dermatologists.  Digital cameras make this


  7   kind of process relatively easy to set up.


  8             Secondly, a written record for each


  9   patient that there, in fact, is adequate previous


 10   treatment of the disease with antibiotics and other


 11   treatments and that there is recalcitrance to it.


 12             Third, a written statement of


 13   contraceptive practices and provision of a copy of


 14   this and a negative pregnancy test in order for the


 15   drug to be dispensed each time.


 16             [Slide]


 17             In summary, the S.M.A.R.T. program is


 18   clearly a failure.  Without these proposed IND


 19   restrictions, this administration and this advisory


 20   committee will continue to put its imprimatur on


 21   the reckless use of a drug that each year causes


 22   the need for hundreds of abortions and many




  1   seriously deformed infants with birth defects


  2   and/or mental retardation.  This is one of the two


  3   worst epidemics of preventable serious birth


  4   defects ever seen in the U.S.  I would just point


  5   out the other one is two defects where there is


  6   deficiency of folic acid, as you know.  The odds of


  7   neural tube defects are a couple of orders of


  8   magnitude lower than the odds of a birth defect


  9   with a live birth.  Of course, it is different not


 10   to have enough folic acid as opposed to be


 11   administering one of the more potent teratogens we


 12   have ever seen.  It is time to end the more than 20


 13   years of voluntary restrictions and some mandatory


 14   ones that have failed to reduce its prescribing for


 15   more than 20 times as many women as would be using


 16   the drug if it were limited to the approved


 17   indications.  Thank you.  I would be glad to try


 18   and answer any questions.


 19             DR. GROSS:  Thank you very much, Dr.


 20   Wolfe.  The final speaker in the open public


 21   hearing will be Dr. Sherri Shubin, who will read a


 22   letter from Dr. Furberg, which is in your packet.




  1             DR. SHUBIN:  Thank you.  I have no


  2   financial conflicts of interest.  As a member of


  3   the public, I would like to read the statement that


  4   was written by Dr. Curt Furberg, a member of this


  5   committee who could not be here today:


  6             Due to an unexpected family health


  7   problem, I will not be able to attend the upcoming


  8   advisory committee meeting on Accutane risk


  9   management.  Based on long observation and careful


 10   study, I feel very strongly about this issue and


 11   regret that I will not be there to express my views


 12   and participate in the committee's discussion and


 13   deliberation.  As a member of the committee, I


 14   would ask that the following be read aloud at the


 15   meeting after all testimony has been presented but


 16   before the committee begins its consideration and


 17   discussion of the issue and the questions presented


 18   it by the agency.


 19             To be candid, the history of Accutane is


 20   an example of inadequate and ineffective risk


 21   management by the FDA and the manufacturer of


 22   Accutane to the detriment of thousands of women. 




  1   Examples are numerous.  Although Accutane was a


  2   known animal teratogen and a suspected human


  3   teratogen at the time of its approval, the company


  4   did not recommend and the FDA did not insist upon


  5   labeling that emphasized the importance of


  6   contraception or abstinence while under treatment


  7   with the drug.  The consequences of this omission


  8   become more apparent when one understands that five


  9   women became pregnant while taking Accutane during


 10   pre-approval clinical trials despite following the


 11   contraception requirements of the study.


 12             In 1988, a highly publicized FDA advisory


 13   committee meeting was held to discuss the high


 14   level of pregnancy exposure to Accutane and the


 15   overuse of the product and its contribution to the


 16   pregnancy exposure problem.  The Pregnancy


 17   Prevention Program, PPP, emerged following this


 18   meeting as the primary means of managing Accutane's


 19   teratogenic risks.  Several advisory committee


 20   meetings were held to monitor the progress of the


 21   PPP between 1989 and 1991.  It was clear from these


 22   meetings that the majority of women taking Accutane




  1   were not volunteering to participate in the PPP,


  2   that even in the group that did volunteer pregnancy


  3   testing was infrequently performed and that


  4   pregnancy exposure to Accutane was still occurring


  5   at a high level.


  6             Remarkably, no advisory committee meeting


  7   on the Accutane pregnancy exposure and the


  8   performance of the PPP was convened until


  9   September, 2000.  At this meeting, it was shown


 10   that enrollment in the PPP was low and falling,


 11   that pregnancy testing was still often not being


 12   performed and that recommendations about


 13   contraception or abstinence were often not adhered


 14   to.  Even more alarming, the use of Accutane in


 15   women had increased three-fold during the preceding


 16   ten-year period when one would have expected it to


 17   decline substantially because of successful


 18   treatment of prevalent cases of severe nodular


 19   acne.  The committee's response to this evidence


 20   was to declare the PPP a failure and to recommend


 21   that a comprehensive risk management program that


 22   included patient and physician registration, as




  1   well as mandatory pregnancy testing, be


  2   established.  None of these has been implemented.


  3             Instead, the S.M.A.R.T. program was


  4   introduced.  It is an effort that added yellow


  5   stickers to the existing PPP, but had no means of


  6   determining if pregnancy testing was actually


  7   performed or of how many pregnancy exposures


  8   actually occurred.  Unfortunately, S.M.A.R.T. had


  9   the same basic design limitations as the PPP and


 10   this should have been recognized.  Now, after


 11   almost four years and thousands more of unnecessary


 12   pregnancy exposures to Accutane, this committee is


 13   once again asked to advise the FDA.


 14             Simply put, I believe that the system is


 15   not safe and cannot be used in a safe manner.  To


 16   minimize the number of pregnancy exposures to


 17   isotretinoin an IND-like process could be


 18   implemented that ensures universal pregnancy


 19   testing, registration of all pregnancy test results


 20   and incorporates a mechanism whereby the drug


 21   cannot be dispensed without a negative pregnancy


 22   test.  This coupling of a negative pregnancy test




  1   with dispensing of the drug would be analogous to


  2   the policy that has been successfully employed with


  3   the antipsychotic clozapine and has been summarized


  4   as "no blood, no drug."  An added benefit of such


  5   an approach would be that we would have more


  6   accurate information regarding the actual number of


  7   pregnancy exposures to the drug.  The numbers we


  8   have now, coming from a relatively small and


  9   self-selected group of volunteers, is undoubtedly a


 10   gross underestimate of reality.


 11             Other features of this IND-like approach


 12   could include limiting the number of


 13   isotretinoin-dispensing centers, mandatory


 14   pregnancy avoidance counseling at each visit and


 15   the proviso that dispensing centers would be


 16   audited periodically.  An important objective of


 17   our risk management should be to reduce the overuse


 18   of isotretinoin.  Therefore, I would recommend that


 19   the IND-like process I have briefly described


 20   include some means of documenting the presence of


 21   severe nodular acne in patients being considered


 22   for isotretinoin treatment.  In clinical trials for




  1   the approval of Accutane only patients with severe


  2   cystic acne were enrolled, and photographs of at


  3   least some of these patients were taken and used in


  4   advertisements and at professional meetings.


  5   Perhaps a photograph, documenting the patient's


  6   severe cystic acne, could be required prior to


  7   approval for treatment.


  8             The S.T.E.P.S. program for thalidomide has


  9   been talked about as a possible model for


 10   isotretinoin risk management, but it would not be


 11   adequate.  If my understanding is correct, there is


 12   actually no current coupling of a negative


 13   pregnancy test with dispensing of the drug and


 14   there is no central registry of the pregnancy test


 15   results.  Under this system, thalidomide


 16   prescribers answer several questions over the


 17   telephone in response to automated prompts in order


 18   to receive a number authorizing use of the drug for


 19   the next month.  This system is very similar to the


 20   yellow sticker system under S.M.A.R.T. in that it


 21   relies on prescriber self-attestation.  There is no


 22   validation that what the prescriber has answered is




  1   true and there is no comprehensive or reliable


  2   means of knowing how many pregnancy exposures have


  3   occurred.


  4             The occurrence of pregnancy exposures with


  5   the original Accutane pre-approval clinical trials


  6   and, more recently, within a clinical trial for


  7   another formulation of isotretinoin raises an


  8   uncomfortable question, should this drug have ever


  9   been released on the open market?  I think it was


 10   and is unethical to allow isotretinoin to be


 11   available for use outside of the protections that


 12   would be afforded by a controlled and documentable


 13   process of distribution.


 14             I do have copies of this statement for


 15   anyone who would like one.


 16             DR. GROSS:  Yes, there are copies of the


 17   statement in the committee's folders.  Thank you


 18   very much, Dr. Shubin.  Shalini Jain has a comment


 19   she would like to make now.


 20             MS. JAIN:  I just want to make a comment


 21   for a point of clarification with regards to Dr.


 22   Furberg's letter.  Dr. Shubin was reading the




  1   letter on behalf of Dr. Furberg.  In functioning as


  2   an FDA committee member representative, he has not


  3   been cleared for this meeting for purposes of


  4   conflict of interest but solely as a representative


  5   of the public today.  Thank you.


  6             DR. GROSS:  Thank you.  We will now move


  7   on to the next set of presentations.  From


  8   Hoffmann-La Roche, Joanna Waugh, Group Director for


  9   Regulatory Affairs, is first; Dr. Martin Huber,


 10   Vice President, Global Head, Drug Safety Risk


 11   Management; and Dr. Susan Ackermann Shiff, Global


 12   Head, Risk Management, Drug Safety Risk Management.


 13              Hoffmann-La Roche, Inc. Presentations


 14                           Introduction


 15             MS. WAUGH:  Good morning.


 16             [Slide]


 17             I am Joanna Waugh, from the Regulatory


 18   Affairs Department at Hoffmann-La Roche, Nutley,


 19   New Jersey.  Thank you to the FDA and the committee


 20   for giving us the opportunity to present today.


 21             [Slide]


 22             What I would like to do first is to just




  1   give you an overview of the framework of our


  2   presentation today.  Having heard the FDA


  3   presentation, there is some overlap with our


  4   presentation so we will go fairly rapidly through


  5   some of the areas where there is duplication.


  6             Following myself, Dr. Martin Huber will


  7   provide a brief overview of the risk/benefit


  8   profile for isotretinoin.  I will then briefly


  9   summarize a regulatory overview, focusing on risk


 10   management milestones for Accutane since its launch


 11   in the U.S. in 1982.  Dr. Susan Ackermann Shiff


 12   will then provide an overview of the S.M.A.R.T.


 13   program, comprising a description of what that


 14   program entails, as well as an assessment of some


 15   of the data with particular reference to metrics


 16   which were predetermined in agreement with FDA.


 17   Dr. Martin Huber will then review the pregnancy


 18   data from the S.M.A.R.T. program and move on to


 19   discuss our recommendations for program


 20   modification.


 21             [Slide]


 22             In addition to the team of presenters




  1   which are listed on the left-hand side of this


  2   slide, Roche does also have available, for


  3   responding to questions in the question and answer


  4   session, some additional colleagues, Miss Kay Bess


  5   from our Drug Safety Risk Management Department,


  6   Dr. Karen Blesch, from the same department, Miss


  7   Tammy Reilly, Vice President of Dermatology and


  8   Oncology, and Dr. Susan Sacks, from the Drug Safety


  9   Risk Management Department.


 10             [Slide]


 11             Additionally, we have available the


 12   following outside experts for responding to


 13   questions, Dr. Diane Berson, from Cornell


 14   University; Dr. Judith Jones, from the Degge Group;


 15   and Dr. Victor Strecher, from the University of


 16   Michigan School of Public Health.


 17             [Slide]


 18             As this slide shows and was referred to by


 19   the FDA in their presentation, the S.M.A.R.T. risk


 20   management program was approved in 2001 and it was


 21   subsequently implemented early in 2002.  Since 2002


 22   generic isotretinoin has also been available on the




  1   U.S. marketplace and this slide shows the


  2   respective manufacturers' products and risk


  3   management programs, which are all equivalent to


  4   the Accutane S.M.A.R.T. risk management program.


  5             [Slide]


  6             The conditions for the approval of the


  7   S.M.A.R.T. risk management program included the


  8   requirement to develop a backup program for a


  9   mandatory registry, as well as the understanding


 10   that a follow-up advisory committee would be


 11   convened when more data was available to discuss


 12   the effectiveness of the program, which is why we


 13   are here today.  When more data was available,


 14   Roche evaluated that data and developed a specific


 15   proposal for program enhancement based on the data


 16   we saw emerging.


 17             [Slide]


 18             In December of 2003, the FDA, Roche and


 19   the generic companies reviewed the data across our


 20   respective risk management programs.  Roche and the


 21   generic companies subsequently worked together on


 22   recommendations for program modification.  All




  1   companies agree on the need for one single program


  2   and the recommendation that you will hear put


  3   forward today is generally agreed to by all the


  4   companies.  The details of the implementation


  5   require some further refinement and discussion and


  6   we look forward to the discussion from the advisory


  7   committee today on the proposal that we will put


  8   forward to you.


  9             I will now hand over to Dr. Martin Huber.


 10                           Benefit/Risk


 11             DR. HUBER:  Good morning.


 12             [Slide]


 13             What I would like to briefly review for


 14   you is the benefit/risk.  As a first step in any


 15   risk management approach there needs to be an


 16   assessment of both the benefit and the risk that we


 17   are addressing.


 18             [Slide]


 19             Just to remind you, isotretinoin is


 20   indicated for severe recalcitrant nodular acne.  It


 21   is indicated only for patients who are unresponsive


 22   to conventional therapy, including systemic




  1   antibiotics.  Finally, it is indicated only for


  2   those females who are not pregnant and agree to not


  3   become pregnant.


  4             [Slide]


  5             The medical need for isotretinoin is


  6   because it is a serious disease with profound


  7   consequences.  Inadequately treated severe


  8   recalcitrant nodular acne can lead to disfiguring


  9   scarring.  Fortunately, it is a uniquely


 10   efficacious therapy for this condition and there


 11   are currently no alternative therapies for these


 12   patients.


 13             [Slide]


 14             To briefly remind you, this is the


 15   concern.  Inadequately treated SRNA can lead to


 16   disfiguring scarring which is life-long.


 17             [Slide]


 18             However, there is a specific challenge for


 19   isotretinoin, as has been indicated by the previous


 20   speakers.  Isotretinoin is known to be a human


 21   teratogen.  The majority of the female patients who


 22   use this drug are of childbearing potential. 




  1   Therefore, pregnancy prevention measures, including


  2   proactive risk management, are essential.  But the


  3   specific challenge of this program is that we must


  4   change the behavior of patients in order to have


  5   them comply better with these risk management


  6   programs.


  7             [Slide]


  8             The public health goals, as previously


  9   stated, remain the same.  Our vision is that no


 10   woman who is pregnant should receive isotretinoin


 11   therapy; no woman should become pregnant during or


 12   for one month after receiving isotretinoin therapy.


 13             [Slide]


 14             I will now turn it over to Miss Waugh who


 15   will review the regulatory history and the risk


 16   management program to date.


 17                       Regulatory Overview


 18             [Slide]


 19             MS. WAUGH:  The teratogenic risk of


 20   Accutane has been known since the approval of the


 21   drug in 1982 in the U.S.  Because of this known


 22   risk, we have taken a variety of risk management




  1   steps throughout the product life cycle with the


  2   aim of reducing pregnancies as far as possible.


  3   The proposed program that you will hear today


  4   includes risk management enhancements in response


  5   to data that we have seen in the S.M.A.R.T. risk


  6   management program.


  7             [Slide]


  8             This slide provides an overview of some


  9   examples of steps Roche has taken throughout the


 10   product life cycle to minimize pregnancies.  Since


 11   product launch in 1982, the product had a pregnancy


 12   category X, i.e., it was contraindicated in


 13   pregnant women.  In 1984 a black box warning was


 14   introduced to increase the prominence of warnings


 15   surrounding pregnancy.


 16             In 1988 the Pregnancy Prevention Program


 17   was introduced which FDA alluded to in the earlier


 18   presentation.  This was the first risk management


 19   program of its kind which used mechanisms over and


 20   above labeling as tools for risk management.  Some


 21   components of the Pregnancy Prevention Program are


 22   listed on this slide and I will just go through




  1   them briefly, the requirement for two forms of


  2   contraception to be used simultaneously for one


  3   month before, during and after Accutane treatment.


  4   Additionally, the requirement for negative monthly


  5   pregnancy testing; the addition of an "avoid


  6   pregnancy" symbol in the packaging.  Educational


  7   materials were introduced regarding contraceptives


  8   and pregnancy avoidance, and a female informed


  9   consent form was introduced.


 10             Further evaluation tools to assess the


 11   effectiveness of this program were introduced which


 12   included the Accutane survey.  This survey was


 13   developed by the Slone Epidemiology Center at


 14   Boston University and provided information about


 15   women's understanding of the risk issues related to


 16   teratogenicity, as well as some information about


 17   the pregnancy rate based on the number of women


 18   enrolled in the survey.


 19             [Slide]


 20             in 1990 we added information to the U.S.


 21   product information concerning a description of


 22   birth defects that could occur, as well as a




  1   recommendation that prescribing should be limited


  2   to a one-month supply.


  3             In 1994 the patient informed consent form


  4   was updated to include additional requirements.  In


  5   May of 2000, amongst additional requirements, one


  6   of the requirements was to have two negative


  7   pregnancy tests prior to the initial prescription.


  8             In September of 2000, as has been


  9   mentioned earlier, an advisory committee was


 10   convened which discussed pregnancy prevention.  I


 11   will come back to that in a little bit more detail


 12   later.  Subsequent to that advisory committee,


 13   Roche worked in collaboration with the FDA to


 14   determine how best to implement their


 15   recommendations.  The result of these discussions


 16   was the ultimate approval for the S.M.A.R.T. risk


 17   management program in October, 2001.


 18             [Slide]


 19             As I mentioned, the 2000 advisory


 20   committee discussed pregnancy prevention.  The


 21   recommendations from that advisory committee, as


 22   mentioned by the FDA, included the recommendation




  1   for the introduction of patient and prescriber


  2   registry.  In subsequent discussions with the


  3   agency, Roche put forward various proposals which


  4   included mandatory patient and prescriber


  5   registration.  In discussions with the agency about


  6   the best way to implement these recommendations and


  7   in view of some of the issues that FDA alluded to


  8   earlier, Roche and FDA agreed that the critical


  9   issue was to link a negative pregnancy test with


 10   each prescription and dispensing of Accutane.


 11             [Slide]


 12             The S.M.A.R.T. program introduced a link


 13   between dispensing and negative pregnancy testing


 14   via the Accutane qualification sticker.


 15   Additionally, the S.M.A.R.T. program included


 16   enhanced education, enhanced informed consent, and


 17   the requirement for prescribers who wish to


 18   prescribe Accutane to be registered into a


 19   database.


 20             [Slide]


 21             Dr. Susan Ackermann Shiff will now provide


 22   more details about the S.M.A.R.T. program.




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


  2             DR. ACKERMANN SHIFF:  Thank you.


  3             [Slide]


  4             What I would now like to briefly do is


  5   overview the S.M.A.R.T. program or the System to


  6   Manage Accutane-Related Teratogenicity.  The


  7   program was developed with and approved by the FDA,


  8   and went into effect on April 10 of 2002.


  9             [Slide]


 10             This high level overview slide provides


 11   two important features, first that the registered,


 12   qualified physician, the qualified patient and the


 13   pharmacist work together in the dispensing of the


 14   product.  Second, the qualification sticker is the


 15   one area where the negative pregnancy test and the


 16   dispensing of the product is linked.


 17             [Slide]


 18             Different from the Pregnancy Prevention


 19   Program, all prescribers must be enrolled in the


 20   program in order to prescribe the product.  A


 21   prescriber will read the guide to best practices,


 22   sign a letter of understanding and receive the




  1   qualification stickers.


  2             [Slide]


  3             When the prescriber signs the letter of


  4   understanding they attest to the fact that they


  5   know the risk and severity of fetal injury and


  6   birth defects; that they know how to diagnose and


  7   treat various forms of acne; that they know the


  8   risk factors of unplanned pregnancy and they will


  9   properly follow the S.M.A.R.T. procedures.  In this


 10   case, it includes education, pregnancy testing,


 11   contraception, informed consent and offering of the


 12   Accutane survey.


 13             [Slide]


 14             Once the prescriber has been registered


 15   within the system, they can educate the patient on


 16   the appropriate use of the product.  The "Be Smart,


 17   Be Safe, Be Sure" educational brochure that is


 18   shown on this slide contains elements of education


 19   about the product; contraceptive information; the


 20   two informed consents, the all-patient informed


 21   consent and the female patient informed consent; an


 22   enrollment card for the Accutane survey; and




  1   educational reinforcement.  The purpose of this


  2   brochure is that it be used at the initial office


  3   visit and all subsequent office visits.


  4             [Slide]


  5             As Roche understands that patients learn


  6   in different ways, we have also provided a variety


  7   of other educational materials.  There are story


  8   boards in both English and Spanish and two


  9   educational videos, one about contraception and one


 10   about the risks of unplanned pregnancy.  There are


 11   two 1-800 lines, one for Accutane information and


 12   one for contraception.  In addition, there is an


 13   "avoid" blister pack pregnancy symbol and a


 14   medication guide that is now packaged in the


 15   blister pack that has information about the product


 16   and is patient friendly.


 17             [Slide]


 18             There is also a patient education brochure


 19   for men that contains product information, informed


 20   consent and educational reinforcement.


 21             [Slide]


 22             The qualification sticker signifies that




  1   there is a qualification date that, in this case,


  2   is the date of the last negative pregnancy test,


  3   not the date that the pregnancy test was received.


  4   The pharmacist must dispense within seven days of


  5   the qualification date and can't dispense more than


  6   a 30-day supply.  No refills are allowed.  Both


  7   males and females have a qualification sticker


  8   attached to their prescription.


  9             [Slide]


 10             The qualification criteria or what the


 11   sticker represents on actual presentation is that


 12   the female patient has had the negative pregnancy


 13   testing, two at the start of therapy and one every


 14   month during therapy.  In addition, she has


 15   selected and committed to use two safe and


 16   effective forms of contraception.  She has signed


 17   all-patient informed consent and the female


 18   informed consent, and has been offered the


 19   opportunity to participate in the Accutane survey


 20   and knows of its importance.


 21             [Slide]


 22             Again, the qualification sticker is the




  1   actual sticker that links the dispensing of the


  2   product with the negative pregnancy test.  The


  3   pharmacist will allow no more than a 30-day supply;


  4   will dispense within seven days of the


  5   qualification date or the date of the last negative


  6   pregnancy test; and no refills are allowed.  In


  7   addition, no telephone, computerized or mail order


  8   prescriptions are allowed.  The pharmacist also has


  9   the opportunity to verify that the physician has


 10   been entered into the system by calling a 1-800


 11   number.


 12             [Slide]


 13             What I would like to do now is to review


 14   the data from S.M.A.R.T. year one, or April 1 of


 15   2002 through March 31, 2003.  In some cases I will


 16   be comparing these data to the year previous to


 17   S.M.A.R.T. or the last year of the Pregnancy


 18   Prevention Program which is April 1, 2001 through


 19   March 31, 2002.


 20             [Slide]


 21             We used three specific data sources to


 22   evaluate the S.M.A.R.T. program in year one.  The




  1   first is the prescription compliance survey; the


  2   second, the Accutane survey; and, three, pregnancy


  3   reports.  I will be reviewing the first two data


  4   sources and Dr. Huber will be reviewing the


  5   pregnancy reports in addition to the corresponding


  6   failure analyses.


  7             [Slide]


  8             The prescription compliance survey is a


  9   quarterly survey of a random sample of pharmacies


 10   pertaining to the use and completion of the


 11   qualification stickers.  In addition, Roche


 12   conducted a quarterly audit of anonymous Accutane


 13   prescriptions from a random sample of these


 14   participating pharmacies.  While I will not be


 15   discussing the quarterly audit, what I can say is


 16   that the results are consistent with the quarterly


 17   sample of the random sample of pharmacies.


 18             [Slide]


 19             There is one major objective of the


 20   prescription compliance survey, that is, to assess


 21   prescribers' and dispensing pharmacists' compliance


 22   with the appropriate use of the qualification




  1   sticker.


  2             [Slide]


  3             During our discussions with the FDA, we


  4   had decided on two specific sets of metrics with


  5   regard to the prescription compliance survey.  The


  6   first is that by the end of S.M.A.R.T. year one 90


  7   percent of all physicians would use the


  8   qualification stickers.  The secondary metrics


  9   included that 90 percent of all physicians would


 10   completely and correctly fill out the stickers, and


 11   that 90 percent of all prescriptions would be


 12   dispensed with a medication guide.  In October of


 13   2002 Roche started packaging the medication guides


 14   within the blister packs so the secondary metric is


 15   no longer applicable.


 16             [Slide]


 17             The results of the prescription compliance


 18   survey are as follows:  Over the six waves of the


 19   survey an average of 97 percent of all


 20   prescriptions had a qualification sticker affixed.


 21   Of those, 96 percent were correctly or completely


 22   completed.  There were no differences between the




  1   survey waves and there were no differences between


  2   the age of patient, the gender of patient, the


  3   location of the dispensing of the prescription or


  4   the payer type.  In conclusion, we have met and


  5   exceeded our metrics for stickers and the mechanics


  6   of the stickers are working well.  [Slide]


  7             Now I would like to review some of the


  8   high-level results from the Accutane survey.


  9             [Slide]


 10             As Ms. Waugh noted previously, the


 11   Accutane survey was developed by Slone Epidemiology


 12   Center of the Boston University School of Public


 13   Health.  It was initially implemented with the


 14   Pregnancy Prevention Program in 1989 and, to date,


 15   Roche has had two vendors for the survey.  From


 16   1989 to the presentation of these data, Slone


 17   Epidemiology Center was our primary research


 18   organization.  In October, 2002 we switched


 19   research organizations to SI International and the


 20   Degge Group.


 21             While I won't go into detail about the


 22   methodology of the survey, and I know that Dr.




  1   Mitchell is presenting later, what I do want to


  2   note is that there are two specific arms within the


  3   Accutane survey, the Accutane after treatment arm


  4   and the during and after treatment arm.  The


  5   presentation of these data deal only with the


  6   during and after treatment arm.  In addition, I


  7   would also like to note that the research


  8   organization SI/Degge did implement the


  9   questionnaire that was modified to include


 10   components of S.M.A.R.T.


 11             [Slide]


 12             There are four specific objectives of the


 13   Accutane survey.  It was a voluntary survey to


 14   determine female patient awareness of the


 15   teratogenic risks of Accutane.  In addition, it is


 16   used to measure compliance with key components of


 17   S.M.A.R.T., in this case informed consent, the


 18   medication guide, pregnancy testing, contraceptive


 19   use and the qualification sticker.  Historically,


 20   we have used data from the Slone Epidemiology


 21   Center to calculate a rate of pregnancy among


 22   female Accutane users and to identify risk factors




  1   that occur with pregnancy.


  2             [Slide]


  3             Again, during our discussions with the FDA


  4   we had agreed upon a variety of primary and


  5   secondary metrics, the primary metric being that 60


  6   percent of all women would enroll in the Accutane


  7   survey by the end of S.M.A.R.T. year one.  We have


  8   several data specific secondary metrics including


  9   female patient representativeness; recall of


 10   qualification sticker; recall of pregnancy test;


 11   medication guide; the use of two forms of safe and


 12   effective forms of contraception; and enrollment in


 13   the Accutane survey via the prescriber's office,


 14   from the blister pack or by calling a toll-free


 15   number.


 16             [Slide]


 17             Before I go on to specific review of the


 18   data, I would like to give you a high-level


 19   overview of our findings.  We were successful in


 20   increasing enrollment in the Accutane survey by


 21   approximately 10 percentage points but missed the


 22   60 percent metric.




  1             We found that females recalled the use of


  2   the qualification sticker and that percentage was


  3   almost 100 percent.  In addition, almost 100


  4   percent of all women knew the risks of taking


  5   Accutane while pregnant and were told to avoid


  6   pregnancy during Accutane.  However, they did not


  7   receive the pregnancy testing or were not using


  8   contraception according to the package insert.


  9             With regard to the enrollment rate, we


 10   calculated an enrollment rate by dividing the


 11   number of enrollees by the number of new patient


 12   female starts.  The result for the first year of


 13   S.M.A.R.T. is 28.2 percent of enrollment of all


 14   female Accutane users, which was up from 17 percent


 15   in pre-S.M.A.R.T. year one.  While, again, we


 16   increased the enrollment rate, we did not succeed


 17   in meeting the 60 percent metric.


 18             [Slide]


 19             However, when you look at the method of


 20   enrollment, we were very successful in shifting the


 21   method of enrollment from the blister pack to the


 22   physician's office.  Again, if you remember, the




  1   enrollment card is within the "Be Smart, Be Safe,


  2   Be sure" educational brochure and we see this as a


  3   marker that education was occurring within the


  4   physician's office.


  5             [Slide]


  6             When we asked females at the start of


  7   therapy what might Accutane do if it is taken


  8   during pregnancy, and did your doctor tell you the


  9   importance of avoiding pregnancy while on Accutane,


 10   almost 100 percent of all women indicated that it


 11   causes birth defects and that their physician told


 12   them the importance of avoiding pregnancy while on


 13   Accutane.


 14             [Slide]


 15             However, when we look at two important


 16   components of the S.M.A.R.T. program, pregnancy


 17   testing and contraceptive compliance, we found that


 18   only 64 percent of all women at the start of


 19   treatment indicated that they had received two


 20   pregnancy tests.  We were successful in reducing


 21   the women that reported no pregnancy tests from 18


 22   percent to approximately 9 percent, but a large




  1   proportion of women did not receive the pregnancy


  2   testing according to the package insert.


  3             [Slide]


  4             When we looked at the risk category at the


  5   start of treatment, we found that 50 percent of all


  6   women were not sexually active but 44 percent of


  7   all women reported some sort of sexual activity.


  8             [Slide]


  9             When we looked at sexual activity by use


 10   of two forms of contraception, we found that 41


 11   percent of these women indicated that they were not


 12   using two safe and effective forms of contraception


 13   at the start of their treatment.


 14             [Slide]


 15             When we looked at non-compliance with


 16   contraception by age, we noticed that females 12-19


 17   reported the highest percent of not sexual


 18   activity.  However, women 20-29, 30-39 and 40-44


 19   who were sexually active reported high levels of


 20   not using two forms of contraception, 20 percent,


 21   35 percent and 40 percent respectively.


 22             [Slide]




  1             We noted previously from the prescription


  2   compliance survey that a large percentage of


  3   prescriptions had the sticker affixed.  In this


  4   case, the percentage is similar, 97 percent of all


  5   women indicated that a qualification sticker was


  6   affixed to their prescription.  However, when we


  7   asked them about baseline pregnancy testing,


  8   receipt of two or more pregnancy tests and sexual


  9   activity by using two safe and effective forms of


 10   contraception, the percentages were no different


 11   between those women who reported a qualification


 12   sticker affixed to their prescription and those


 13   women who did not.  In fact, when we look at the 22


 14   cases of pregnancy, 20 of those cases of pregnancy


 15   occurred in women who claimed to have a


 16   qualification sticker attached to their


 17   prescription.


 18             [Slide]


 19             Further, when we looked at these same data


 20   during treatment, 21 percent of all women during


 21   treatment indicated that they had not received a


 22   pregnancy test.  Only 63 percent of these women




  1   indicated that they had received two or more


  2   pregnancy tests.  Again, during this time in the


  3   course of their treatment they should have received


  4   at least three pregnancy tests.


  5             [Slide]


  6             Forty percent of all women indicated they


  7   were sexually active during treatment.  However, 52


  8   percent of these women indicated that during


  9   treatment they were not using two safe and


 10   effective forms of contraception as outlined in the


 11   S.M.A.R.T. materials.


 12             [Slide]


 13             However again, we found that almost 100


 14   percent of all women said that they had seen a


 15   qualification sticker on their prescription during


 16   the course of their treatment.


 17             [Slide]


 18             In summary, we believe we were successful


 19   in increasing the enrollment of the Accutane survey


 20   by 10 percentage points, however, we did not meet


 21   the 60 percent metric set out.  We increased the


 22   proportion of patients enrolling vis-a-vis the




  1   prescriber's office.  For us, that was an


  2   indication that education is occurring within the


  3   prescriber's office.  And, we believe that the


  4   mechanics of the sticker are working well.


  5             [Slide]


  6             In addition, from the percentages in the


  7   Accutane survey, women do understand the need to


  8   avoid pregnancy and the consequences of becoming


  9   pregnant while on Accutane.  However, there was


 10   incomplete compliance with both pregnancy testing


 11   and with contraception.  In fact, we found little


 12   relationship between the qualification sticker,


 13   pregnancy testing and contraception.


 14             [Slide]


 15             Dr. Huber?


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


 17             [Slide]


 18             DR. HUBER:  I would now like to briefly


 19   review the pregnancy case reports that we have


 20   received at Roche and put them in perspective--as


 21   Dr. Crawford was asking earlier, the case value


 22   analysis basically.




  1             [Slide]


  2             First, I would like to go briefly through


  3   the methodology.  These reports come from multiple


  4   sources.  These are exposed pregnancies that are


  5   reported via either of the vendors for the Accutane


  6   survey or via spontaneous reports from healthcare


  7   professionals or consumers.


  8             [Slide]


  9             In order to compare the pregnancy numbers


 10   from S.M.A.R.T. and the pre-S.M.A.R.T. year we set


 11   up the following metrics so that the numbers would


 12   be somewhat comparable.  What we refer to here as


 13   pre-S.M.A.R.T. is that treatment was started so


 14   isotretinoin or Accutane was started between April


 15   1, 2001 to March 31, 2002.  But, because there are


 16   delays in receiving some of these reports, we


 17   allowed that the report was received by August 15,


 18   2002.  The S.M.A.R.T. data is essentially these


 19   same definitions but one year later.


 20             The other issue we have to deal with in


 21   the analysis of these data is that there are


 22   numerous reports that come in, in which there is no




  1   therapy date stated on the report.  We don't know


  2   when the therapy started.  In fact, when you review


  3   these, in some of these it is fairly explicit that


  4   the therapy was years ago.  So, we include this


  5   category of therapy start dates unknown and,


  6   because we don't have a therapy start date, we


  7   assign them to the period in which the report was


  8   received.


  9             [Slide]


 10             To give some context to these


 11   reports--there have been numerous questions about


 12   rates, etc.--what I would like to do is remind you


 13   of the overall use of the product.  First, the


 14   majority of these reports are from spontaneous


 15   reporting sources, not from the survey.  Also,


 16   overall Accutane use has been declining since 2000.


 17   I would like to focus on the estimated number of


 18   females treated.  This is female patients in total,


 19   not just childbearing, and this is Accutane.  So,


 20   you see 278,000, 253,000, 218,000.  I would like to


 21   note that generics were introduced in 2002.  So,


 22   when you see 2003 here, the 128,000 reflects purely




  1   the Accutane, not isotretinoin, data.


  2             [Slide]


  3             These are the pregnancy case reports we


  4   have received according to the cut-offs I defined


  5   earlier.  For pre-S.M.A.R.T. there was a total


  6   number of 150 pregnancies; for S.M.A.R.T., 183.  If


  7   we focus on those in which there is a treatment


  8   initiation date known to occur in the period, it is


  9   essentially 94 and 94.  Where the biggest increase


 10   has been is in this group of patients, these 89


 11   with treatment initiation date unknown.  I will go


 12   into a little more explanation of why we think this


 13   occurred in the next few slides.


 14             [Slide]


 15             We think it is unlikely that the true


 16   number of pregnancy case reports is a true


 17   increase.  In other words, we don't believe it is


 18   possible that an increased educational program,


 19   with increased monitoring and with the


 20   qualification sticker actually led to more exposed


 21   pregnancies.  Rather, as has been noted by several


 22   of the previous speakers, in a spontaneous




  1   environment there is a percentage of reports that


  2   you receive and a percentage you don't know about.


  3   We believe that this is most likely what is


  4   occurring here and that with the first year of


  5   S.M.A.R.T. we have actually seen an increased


  6   proportion of reporting.


  7             Why did that occur?  Of note, there was


  8   increased awareness among physicians with


  9   S.M.A.R.T.  There was also, as Dr. Ackermann noted,


 10   increased participation in the survey.  Finally,


 11   there is increased education and awareness among


 12   patients.


 13             [Slide]


 14             To go through the details of these cases


 15   now, I will start with what is the source of these


 16   reports.  We follow the convention of this in


 17   pre-S.M.A.R.T. with a known therapy start date;


 18   S.M.A.R.T. with a known therapy start date; this is


 19   pre-S.M.A.R.T. and S.M.A.R.T. with an unknown


 20   therapy start date cases.  This bottom color here


 21   is those cases that came in via the Accutane survey


 22   from either vendor.  The green is direct to Roche




  1   from a healthcare professional.  This orange is


  2   direct to Roche from consumers or others.


  3             What you see here is that the most


  4   substantial increase in number of pregnancy reports


  5   is this 10 to 33 in association with the Accutane


  6   survey.  Also consistent with increased awareness


  7   from consumers, while we didn't see an increase


  8   here, what we did see was a substantial increase


  9   from 19 to 30 of these cases coming to Roche from


 10   consumers that had this unknown therapy start date.


 11             [Slide]


 12             When we start looking at this, as has been


 13   noted, there are really two issues here.  There are


 14   those patients who are pregnant prior to starting


 15   Accutane therapy and then those patients who become


 16   pregnant on Accutane therapy.  These data try to


 17   break this down.  We looked specifically at the


 18   patients who were pregnant prior to starting


 19   Accutane therapy.  For the pre-S.M.A.R.T., of the


 20   150 pregnancies, 28 or 19 percent occurred in the


 21   pre-S.M.A.R.T. year; S.M.A.R.T. year one, 24 of 183


 22   or 13 percent occurred prior starting Accutane




  1   therapy.  If we look at the number that became


  2   pregnant while on Accutane therapy, 51 percent, 41


  3   percent with approximately the same numbers.


  4   Patients becoming pregnant within 30 days after


  5   stopping, 44 or 29 percent, 58 and 31 percent.  The


  6   biggest increase is in this unknown category but,


  7   as I stated earlier, this does include a large


  8   number of cases that had unknown treatment


  9   initiation and they also had unknown pregnancy


 10   date.


 11             [Slide]


 12             Looking at the demographics of these


 13   patients, these are the same patients, 153


 14   S.M.A.R.T., 183 S.M.A.R.T., broken down by age.  Of


 15   note, when you look at the 16-19 group or from


 16   19-29, 12-15 percent.  What is interesting is the


 17   age group 20-29 declined from 41 percent to 24


 18   percent but please note that 20-29 remains the


 19   largest category of patients, and 30-39 is


 20   essentially similar, 16 and almost 15 percent and


 21   once again a large number of unknown in S.M.A.R.T.


 22   year one.  The mean or median did not shift




  1   significantly.


  2             [Slide]


  3             Now coming to why are these people getting


  4   pregnant, we looked for evidence of educational and


  5   compliance understanding of patients.  These are


  6   not a linkage of survey data to these case reports.


  7   Rather, this information is gathered as part of our


  8   follow-up procedure for the pregnancy case reports.


  9             The green is yes, the orange is no and the


 10   light, pale color here is unknown.  What I would


 11   like to do is focus on the signed female informed


 12   consent, received a spiral notebook and enrolled in


 13   the Accutane survey.  The axis here is the number


 14   of pregnancy case reports that qualified for each


 15   category.  These are now the S.M.A.R.T. year one


 16   cases only.


 17             What we see here is that only three


 18   patients stated no to recall of a signed female


 19   informed consent.  Only five patients stated no to


 20   receiving a spiral notebook and this is in the


 21   group that is our worst outcome group in that they


 22   got exposed pregnancy, and seven said no to




  1   enrolling in the survey.  So, of those that


  2   answered, the interpretation of the data is they


  3   are getting the educational materials.  This is


  4   also consistent with what Dr. Ackermann talked


  5   about in the survey where 99 percent of the


  6   patients know they are not supposed to get


  7   pregnant.  They do receive the educational


  8   materials.


  9             [Slide]


 10             The problem, as we see it, is linking it


 11   to compliance with the behaviors in the program.


 12   Using the same format, this is once again


 13   S.M.A.R.T. year one, the number of pregnancy case


 14   reports are on this axis, two baseline pregnancy


 15   tests, monthly follow-up pregnancy tests, used two


 16   forms of contraception, and was the qualification


 17   sticker attached.


 18             I will start on the right first and 58


 19   versus zero recalled the qualification sticker and


 20   this is among the patients who became pregnant.


 21   What is most disturbing is that 16 said no to the


 22   question of baseline pregnancy tests; 8 said no to




  1   monthly follow-up pregnancy tests; and 6 said no to


  2   using two 2 forms of contraception.  So, what we


  3   detect in this data is a pattern of failure to


  4   comply with the educational materials that they


  5   received.


  6             [Slide]


  7             I would like to review briefly the methods


  8   of contraception in these cases.  Now we are


  9   pre-S.M.A.R.T. and S.M.A.R.T. and these were


 10   focusing on the 94 with the known start date in


 11   both groups.  Of note, 10 were pre-S.M.A.R.T.; 11


 12   of S.M.A.R.T. were using abstinence as a primary


 13   method of contraception.  Of note, of these 11


 14   cases that reported abstinence, 4 did report


 15   additionally using condoms.


 16             For the two forms of contraception, 17


 17   pre-S.M.A.R.T., which increased dramatically to 30


 18   in the S.M.A.R.T. reports, reported using two


 19   forms, one primary and one secondary.  No one


 20   reported in either year using two forms of


 21   secondary contraception.  With regards to one form


 22   of primary, 18 and 18; one form secondary, 14 and




  1   11.  Unknown declined from 27 to 19.


  2             [Slide]


  3             To put these numbers in perspective I am


  4   going to use some data from the Accutane survey.


  5   Dr. Mitchell will talk in more detail about these


  6   later.  But this is the one set of data we have in


  7   which we have a numerator--the number of


  8   pregnancies via the survey, and a denominator--the


  9   number of patients who enrolled in the survey.


 10   However, this applies only to the Slone Accutane


 11   survey participants.  We have not calculated this


 12   rate for year one of S.M.A.R.T. in the SI because


 13   there is an issue with the follow-up necessary to


 14   get the patients in and sufficient follow-up is not


 15   there yet.


 16             The other thing is that pregnancy rates


 17   get reported in multiple ways.  So, you are going


 18   to see some numbers potentially through the course


 19   of this day kind of flying around.  I would like to


 20   show you two ways to try and help you understand.


 21   One approach has used Accutane exposed pregnancies


 22   per 1,000 of the 140-day Accutane treatment




  1   courses.  Given that the normal treatment course is


  2   140 days, one approach has been to analyze the


  3   exposed pregnancies by treatment courses.  So, when


  4   you see the 140-day treatment course, this is what


  5   we are referring to.  The other way which you will


  6   see used is the number of Accutane exposed


  7   pregnancies per 1,000 patients per year.


  8             [Slide]


  9             On this slide we are looking at these data


 10   by both methods.  On the left vertical axis here,


 11   this is the number per treatment courses.  This is


 12   when we refer to the 140; zero on the bottom, 4 on


 13   the top.  This is the blue line, over time within


 14   the survey and enrollment date year 1989 to 2002