1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

 

                      FOOD AND DRUG ADMINISTRATION

 

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

 

                    DRUG SAFETY AND RISK MANAGEMENT

 

                           ADVISORY COMMITTEE

                       IN JOINT SESSION WITH THE

 

                   DERMATOLOGIC AND OPHTHALMIC DRUGS

 

                           ADVISORY COMMITTEE

 

 

 

                      Thursday, February 26, 2004

 

                               8:00 a.m.

 

 

 

                          Hilton Gaithersburg

                           620 Perry Parkway

                      Gaithersburg, Maryland 20877

                                                                 2

 

                              PARTICIPANTS

 

      DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE:

 

         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.

 

      DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY

      COMMITTEE:

 

         Roselyn E. Epps, M.D.

         Robert Katz, M.D.

         Paula Knudson, Consumer Representative

         Sharon S. Raimer, M.D.

         Eileen W. Ringel, M.D.

         Kathleen Y. Sawada, M.D.

         Jimmy D. Schmidt, M.D.

         Elizabeth S. Whitmore, M.D.

         Michael G. Wilkerson, M.D.

 

      CONSULTANTS (Voting):

 

         Wilma F. Bergfeld, M.D.

         Michael E. Bigby, M.D.

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

         Arthur H. Kibbe, Ph.D.

         Sarah Sellers, Pharm.D.

         Amarilys Vega, M.D., Ph.D.

         Jurgen Venitz, M.D., Ph.D.

 

      GUEST SPEAKER (Non-Voting):

 

         Richard K. Miller, Ph.D.

                                                                 3

 

                        PARTICIPANTS (Continued)

      FDA STAFF:

 

         Jonca Bull, M.D.

         Steven Galson, M.D., M.P.H.

         John Jenkins, M.D.

         Sandra Kweder, M.D.

         Paul Seligman, M.D., M.P.H.

         Anne Trontell, M.D., M.P.H.

         Jonathan Wilkin, M.D.

                                                                 4

 

                            C O N T E N T S

 

                                                              PAGE

 

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

 

      Conflict of Interest Statement,

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

 

      Effectiveness of the Isotretinoin Risk Management

      Program for the Prevention of Fetal Exposure to

      Accutane and its Generic Equivalents and

      Consideration of whether Changes

      to this Isotretinoin Risk Management Program would

      be Appropriate:

 

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

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

 

      Background and Regulatory History,

         Jill Lindstrom, M.D., Division of Dermatologic

         and Dental Drug Products, FDA                          15

 

      Questions to the Speaker from Committee                   49

 

      Open Public Hearing:

 

         Robert A. Silverman, M.D.                              68

 

         Sidney Wolfe, M.D.,

         Public Citizen Research Group                          74

 

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

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

 

      Hoffmann-La Roche, Inc. Presentations:

 

         Introduction, Joanna Waugh, Group Director,

         Regulatory Affairs                                     90

 

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

         Global Head Drug Safety Risk Management                94

 

         Regulatory Overview, Joanna Waugh                      96

                                                                 5

 

                      C O N T E N T S (continued)

 

                                                              PAGE

 

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

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

         Management, Drug Safety Risk Management               101

 

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

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

         Global Head Drug Safety Risk Management               116

 

      Generic Firms' Presentations:

 

         Isotretinoin Risk Management Program, Background

         Information, Frank R. Sisto, Vice President,

         Corporate Regulatory Affairs,

         Mylan Laboratory, Inc.                                140

 

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

         Slone Epidemiology Center, Boston University          152

 

         Isotretinoin Enhanced Risk Management Program,

         Program Elements for which Advisory Committee

         Input is Requested, Robert W. Pollock, Vice

         President, Lachman Consultant Services, Inc.          169

 

      Questions to Roche and Generic Firms from Committee

                                                               174

 

      Isotretinoin Pregnancy Exposure: Spontaneous

      Reports 1 Year Pre- and 1 Year Post-Risk

      Management Program,

         Marilyn Pitts, Pharm.D.,

         Office of Drug Safety, FDA                            218

 

      Isotretinoin Pregnancy Prevention Program

      Evaluation,

         Allen Brinker, M.D., M.S.,

         Office of Drug Safety, FDA                            237

 

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

         Kaiser Permanente Drug Use Management                 265

 

      Questions to Kaiser from the Committee                   289

                                                                 6

 

                      C O N T E N T S (Continued)

 

                                                              PAGE

 

      Organization of Teratology Information Services,

         Interim Report, North American Isotretinoin

         Information and Survey Line, Richard Miller,

         Ph.D., University of Rochester                        296

 

      Questions to OTIS from the Committee                     313

 

      Risk Management Options for Pregnancy Prevention,

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

 

      Selecting Risk Management Tools: Considerations and

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

         Director, Office of Drug Safety, FDA                  338

 

      Questions to Speakers from the Committee                 366

 

                                                                 7

 

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

 

  2                 Call to Order and Introductions

 

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

 

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

 

  5   Management Advisory Committee.  I would like to

 

  6   thank you all for coming this morning, and the

 

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

 

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

 

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

 

 10   of Internal Medicine at Hackensack University

 

 11   Medical Center and New Jersey Medical School.

 

 12             MS. JAIN:  Shalini Jain, Executive

 

 13   Secretary, FDA, Center for Drug Evaluation and

 

 14   Research.

 

 15             DR. WILKERSON:  Michael Wilkerson, MD.,

 

 16   private practice, Tulsa, Oklahoma.

 

 17             DR. RINGEL:  Eileen Ringel, I am in

 

 18   private practice in Waterville, Maine.

 

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

 

 20   Cognition Laboratory at Duke University and I am on

 

 21   the Drug Safety and Risk Management Committee.

 

 22             DR. KIBBE:  Art Kibbe, Chairman of the

 

                                                                 8

 

  1   Pharmaceutical Sciences Department, Wilkes

 

  2   University School of Pharmacy and Chairman of the

 

  3   Pharmaceutical Sciences Advisory Committee to the

 

  4   FDA.

 

  5             DR. GARDNER:  Jackie Gardner, Professor of

 

  6   Pharmacy, University of Washington, and Drug Safety

 

  7   and Risk Management Advisory Committee.

 

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

 

  9   practice in Rockville, Maryland, and Clinical

 

 10   Assistant Professor of Dermatology at Georgetown

 

 11   University.

 

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

 

 13   a Masters in Public Health Candidate at Bloomberg

 

 14   School of Public Health.

 

 15             DR. TRONTELL:  Anne Trontell, Deputy

 

 16   Director of the Office of Drug Safety in the FDA

 

 17   Center for Drugs.

 

 18             DR. SELIGMAN:  Paul Seligman, Director of

 

 19   the Office of Pharmacoepidemiology and Statistical

 

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

 

 21             DR. WILKIN:  Jonathan Wilkin, Director of

 

 22   the Division of Dermatologic and Dental Drug

 

                                                                 9

 

  1   Products in CDER, FDA.

 

  2             DR. BULL:  Good morning.  Jonca Bull,

 

  3   Director, Office of Drug Evaluation V in the Office

 

  4   of New Drugs, Center for Drug Evaluation and

 

  5   Research.

 

  6             DR. KWEDER:  Sandra Kweder, Deputy

 

  7   Director of Office of New Drugs in CDER.

 

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

 

  9   Director of the Center for Drug Evaluation and

 

 10   Research.

 

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

 

 12   representative on the Drug Safety Committee.

 

 13             DR. SAWADA:  Kathleen Sawada,

 

 14   dermatologist, private practice in Lakewood,

 

 15   Colorado.

 

 16             DR. VENITZ:  Jurgen Venitz, Associate

 

 17   Professor, Virginia Commonwealth University and

 

 18   Chair of the Clinical Pharmacology Subcommittee.

 

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

 

 20   Department of Biostatistics and Epidemiology at the

 

 21   University of Pennsylvania School of Medicine, and

 

 22   I am a member of the Drug Safety and Risk

 

                                                                10

 

  1   Management Committee.

 

  2             DR. BERGFELD:  I am Wilma Bergfeld,

 

  3   dermatologist and dermatopathologist, head of

 

  4   Clinical Research Department of Dermatology at the

 

  5   Cleveland Clinic.

 

  6             DR. RAIMER:  Sharon Raimer, Chairman of

 

  7   Dermatology at the University of Texas in

 

  8   Galveston.

 

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

 

 10   administrator for the University of Texas at

 

 11   Houston, and I am with the Dermatology Advisory

 

 12   Committee.

 

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

 

 14   dermatologist at Beth Israel Deaconess Medical

 

 15   Center and Harvard Medical School.

 

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

 

 17   epidemiologist with the Birth Defects Center at the

 

 18   Centers for Disease Control and Prevention.

 

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

 

 20   with the Institute for Safe Medication Practices,

 

 21   and I am with the Drug Safety and Risk Management

 

 22   Advisory Committee.

 

                                                                11

 

  1             DR. WHITMORE:  Beth Whitmore, I am in

 

  2   private practice in Wheaton, Illinois.

 

  3             DR. SHAPIRO:  Robyn Shapiro, I am

 

  4   Professor and Director of the Center for the Study

 

  5   of Bioethics at the Medical College of Wisconsin,

 

  6   and I am on the Drug Safety and Risk Management

 

  7   Advisory Committee.

 

  8             DR. EPPS:  Roselyn Epps, Chief of the

 

  9   Division of Dermatology in Children's National

 

 10   Medical Center, and also a member of the

 

 11   Dermatologic and Ophthalmic Drugs Advisory

 

 12   Committee.

 

 13             DR. SCHMIDT:  I am Jimmy Schmidt, in

 

 14   clinical practice from Houston, Texas and I am on

 

 15   the clinical faculty of University of Texas and

 

 16   Baylor Medical School.

 

 17             DR. CRAWFORD:  Good morning.  Stephanie

 

 18   Crawford, Associate Professor, University of

 

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

 

 20   member of the Drug Safety and Risk Management

 

 21   Advisory Committee.

 

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

 

                                                                12

 

  1   like to ask Shalini Jain to read the conflict of

 

  2   interest statement.

 

  3                  Conflict of Interest Statement

 

  4             MS. JAIN:  The following statement

 

  5   addresses the issue of conflict of interest with

 

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

 

  7   record to preclude even the appearance of such at

 

  8   this meeting.

 

  9             The topics to be discussed at today's

 

 10   meeting are matters of broad applicability.  Unlike

 

 11   issues before a committee in which a particular

 

 12   sponsor's product is discussed, issues of broad

 

 13   applicability involve many sponsors and their

 

 14   products.  All FDA participants have been screened

 

 15   for their financial interests as they may apply to

 

 16   the products and companies that could be affected

 

 17   by the committee's discussions.

 

 18             Based on this review, it has been

 

 19   determined that there is no potential for an actual

 

 20   or apparent conflict of interest at this meeting,

 

 21   with the following exception:  In accordance with

 

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

 

                                                                13

 

  1   a waiver that permits her to participate fully.

 

  2             A copy of the waiver statement maybe

 

  3   obtained by submitting a request to the Food and

 

  4   Drug Administration's Office of Management

 

  5   Programs, Division of Freedom of Information,

 

  6   HF1-35 5600 Fishers Lane, Rockville, Maryland

 

  7   20857.

 

  8             Because issues of broad applicability

 

  9   involve many sponsors and their products, it is not

 

 10   prudent to recite all potential conflicts of

 

 11   interest as they may apply to each member,

 

 12   consultant and guest speaker.  In addition, there

 

 13   will be no industry representatives at today's

 

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

 

 15   Administration has appointed industry

 

 16   representatives that currently serve on each of

 

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

 

 18   industry representative to the Drug Safety and Risk

 

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

 

 20   industry representative to the Dermatologic and

 

 21   Ophthalmic Drugs Advisory Committee, work with

 

 22   sponsors that are directly impacted by the matters

 

                                                                14

 

  1   before the committee.  FDA has contacted three

 

  2   industry representatives from other Center for Drug

 

  3   Evaluation and Research committees that have

 

  4   experience with risk management issues and with FDA

 

  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

 

                                                                15

 

  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

 

                                                                16

 

  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

 

                                                                17

 

  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

 

                                                                18

 

  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

 

                                                                19

 

  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

 

                                                                20

 

  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

 

                                                                21

 

  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

 

                                                                22

 

  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

 

                                                                23

 

  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

 

                                                                24

 

  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.

 

                                                                25

 

  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

 

                                                                26

 

  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

 

                                                                27

 

  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

 

                                                                28

 

  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

 

                                                                29

 

  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

 

                                                                30

 

  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

 

                                                                31

 

  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

 

                                                                32

 

  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

 

                                                                33

 

  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

 

                                                                34

 

  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]

 

                                                                35

 

  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

 

                                                                36

 

  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

 

                                                                37

 

  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

 

                                                                38

 

  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

 

                                                                39

 

  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

 

                                                                40

 

  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

 

                                                                41

 

  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

 

                                                                42

 

  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.

 

                                                                43

 

  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]

 

                                                                44

 

  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

 

                                                                45

 

  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

 

                                                                46

 

  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

 

                                                                47

 

  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

 

                                                                48

 

  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

 

                                                                49

 

  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

 

                                                                50

 

  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

 

                                                                51

 

  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?

 

                                                                52

 

  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

 

                                                                53

 

  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

 

                                                                54

 

  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

 

                                                                55

 

  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

 

                                                                56

 

  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

 

                                                                57

 

  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

 

                                                                58

 

  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.

 

                                                                59

 

  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?

 

                                                                60

 

  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?

 

                                                                61

 

  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

 

                                                                62

 

  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

 

                                                                63

 

  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

 

                                                                64

 

  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

 

                                                                65

 

  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

 

                                                                66

 

  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

 

                                                                67

 

  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

 

                                                                68

 

  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

 

                                                                69

 

  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

 

                                                                70

 

  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

 

                                                                71

 

  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

 

                                                                72

 

  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

 

                                                                73

 

  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.

 

                                                                74

 

  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

 

                                                                75

 

  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.

 

                                                                76

 

  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

 

                                                                77

 

  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

 

                                                                78

 

  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

 

                                                                79

 

  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

 

                                                                80

 

  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

 

                                                                81

 

  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

 

                                                                82

 

  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.

 

                                                                83

 

  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. 

 

                                                                84

 

  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

 

                                                                85

 

  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

 

                                                                86

 

  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

 

                                                                87

 

  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

 

                                                                88

 

  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

 

                                                                89

 

  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

 

                                                                90

 

  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

 

                                                                91

 

  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

 

                                                                92

 

  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

 

                                                                93

 

  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

 

                                                                94

 

  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

 

                                                                95

 

  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. 

 

                                                                96

 

  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

 

                                                                97

 

  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

 

                                                                98

 

  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

 

                                                                99

 

  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

 

                                                               100

 

  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.

 

                                                               101

 

  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

 

                                                               102

 

  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

 

                                                               103

 

  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

 

                                                               104

 

  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

 

                                                               105

 

  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

 

                                                               106

 

  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

 

                                                               107

 

  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

 

                                                               108

 

  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.

 

                                                               109

 

  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

 

                                                               110

 

  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.

 

                                                               111

 

  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

 

                                                               112

 

  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

 

                                                               113

 

  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]

 

                                                               114

 

  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

 

                                                               115

 

  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

 

                                                               116

 

  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.

 

                                                               117

 

  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

 

                                                               118

 

  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

 

                                                               119

 

  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

 

                                                               120

 

  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

 

                                                               121

 

  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

 

                                                               122

 

  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

 

                                                               123

 

  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

 

                                                               124

 

  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

 

                                                               125

 

  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

 

                                                               126

 

  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

 

                                                               127

 

  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