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

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