FOOD AND DRUG ADMINISTRATION







                           ADVISORY COMMITTEE

                       IN JOINT SESSION WITH THE




                           ADVISORY COMMITTEE




                       Friday, February 27, 2004


                               8:00 a.m.




                          Hilton Gaithersburg

                           620 Perry Parkway

                         Gaithersburg, Maryland





      Peter Gross, M.D., Chair

      Kimberly Topper, M.S., Executive Secretary




                Wilma F. Bergfeld, M.D.

                Michael E. Bigby, M.D.

                Margaret Honein, Ph.D.

                Arthur H. Kibbe, Ph.D.

                Sarah Sellers, Pharm.D.

                Amarilys Vega, M.D., Ph.D.

                Jurgen Venitz, M.D., Ph.D.




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

                Stephanie Y. Crawford, Ph.D., MPH

                Ruth S. Day, Ph.D.

                Jacqueline S. Gardner, Ph.D., MPH

                Arthur A. Levin, MPH (Consumer


                Robyn S. Shapiro, J.D.

                Brian L. Strom, M.D., MPH





                Roselyn E. Epps, M.D.

                Robert Katz, M.D.

                Paula Knudson (Consumer Representative)

                Sharon S. Raimer, M.D.

                Eileen W. Ringel, M.D.

                Kathleen Y. Sawada, M.D.

                Jimmy D. Schmidt, M.D.

                Elizabeth S. Whitmore, M.D.

                Michael G. Wilkerson, M.D.




                Jonca Bull, M.D.

                John Jenkins, M.D.

                Sandra Kweder, M.D.

                Paul Seligman, M.D., MPH

                Anne Trontell, M.D., MPH

                Jonathan Wilkin, M.D.



                            C O N T E N T S




      Call to Order

                Peter Gross, M.D.                                4


      Conflict of Interest Statement:

                Kimberly Topper, M.S.                            4


           Effectiveness of the Isotretinoin Risk Management

            Program for the Prevention of Fetal Exposure to

                  Accutane and its Generic Equivalents


                Consideration of Whether Changes to this

             Isotretinoin Risk Management Program would be



      Open Public Hearing

                Representative Bart Stupak                       8

                Gordon Day                                      21

                LaDonna Williams                                25

                Boni Elewski, M.D.                              29

                Paul L. Smith                                   35

                Debbie Banner                                   40

                Carter Crosland                                 46

                Lisa Crosland                                   51

                Jeffrey Federman                                57


      Responses from Slone Epidemiology Center

                Allen A. Mitchell, M.D.                         66


      Introduction of Questions:

                Paul Seligman, M.D., MPH                       101


      Committee Discussion                                     106


      FDA Presentation:

                Kathleen Uhl, M.D.                             183

                Carl Kraus, M.D.                               192

                Anne Trontell, M.D., MPH                       205


      Hoffmann-La Roche Presentation:

                Martin H. Huber, M.D.                          208


      Committee Discussion                                     243




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


  2                          Call to Order


  3             DR. GROSS:  We would like to begin by


  4   reading the Conflict of Interest Statement


  5                  Conflict of Interest Statement


  6             MS. TOPPER:  The following announcement


  7   addresses the issue of conflict of interest with


  8   respect to this meeting and is made a part of the


  9   record to preclude even the appearance of such at


 10   this meeting.


 11             The topics to be discussed at today's


 12   meeting are matters of broad applicability.  Unlike


 13   issues before a committee in which a particular


 14   sponsor's product is discussed, issues of broad


 15   applicability involve many sponsors and their


 16   products.


 17             All FDA participants have been screened


 18   for their financial interests as they may apply to


 19   the products and companies that could be affected


 20   by the committee's decisions.  Based on this


 21   review, it has been determined that there is no


 22   potential for an actual or apparent conflict of




  1   interest at this meeting with the following


  2   exception:


  3             In accordance with 18 U.S.C. 208(b)(3),


  4   Dr. Ruth Day has been granted a waiver that permits


  5   her to participate fully.


  6             A copy of the waiver statement may be


  7   obtained by submitting a written request to the


  8   Food and Drug Administration's Office of Management


  9   Programs, Division of Freedom of Information HFI-35


 10   at 5600 Fishers Lane in Rockville, Maryland 20857.


 11             Because issues of broad applicability


 12   involve many sponsors and their products, it is not


 13   prudent to recite all potential conflicts of


 14   interest as they apply to each member, consultant,


 15   and guest speaker.


 16             There will be no industry representative


 17   at today's meeting.  As you are aware, the Food and


 18   Drug Administration has appointed industry


 19   representatives who currently serve on each of


 20   these committees, but Annette Stemhagen, the


 21   industry rep from the Drug Safety and Risk


 22   Management Committee, and Peter Kresel, the




  1   industry rep from Dermatologic and Ophthalmic Drugs


  2   Advisory Committee, work with sponsors that are


  3   directly impacted by the matter before the


  4   committee.


  5             FDA has contacted three other industry


  6   representatives from other Center for Drug


  7   Evaluation and Research Committees that have


  8   experience in risk management and with the FDA


  9   Advisory Committee process, however, none were


 10   available to participate in this meeting.


 11             Dr. Stemhagen and Mr. Kresel are present


 12   in the audience and attending as interested


 13   observers.  Further, we would like to note that Dr.


 14   Lou Morris, a member of the Drug Safety and Risk


 15   Management Advisory Committee, has been recused


 16   from participating in today's meeting.  Dr. Morris


 17   is also present in the audience and attending as an


 18   interested observer.


 19             We would like to remind the FDA


 20   participants not to discuss issues at hand outside


 21   the advisory committee meeting.


 22             In the event that the discussions involve




  1   any other products or firms not currently on the


  2   agenda for which FDA participants have a financial


  3   interest, the participants involvement and


  4   exclusion will be noted for the record.


  5             With respect to all other meeting


  6   participants, we ask in the interest of fairness


  7   that they address any current or previous financial


  8   involvement with any firm whose product they may


  9   wish to comment upon.


 10             Thank you.


 11                       Open Public Hearing


 12             DR. GROSS:  We will begin with the open


 13   public hearing.


 14             Both the Food and Drug Administration and


 15   the public believe in a transparent process for


 16   information gathering and decisionmaking.  To


 17   ensure such transparency at the open public hearing


 18   session of the Advisory Committee meeting, FDA


 19   believes that it is important to understand the


 20   context of an individual's presentation.


 21             For this reason, FDA encourages you, the


 22   open public hearing speaker, at the beginning of




  1   your written or oral statement to advise the


  2   committee of any financial relationship that you


  3   may have with the sponsors of any products in the


  4   pharmaceutical category under discussion at today's


  5   meeting.  For example, this financial information


  6   may include the sponsor's payment of your travel,


  7   lodging, or other expenses in connection with your


  8   attendance at the meeting.


  9             Likewise, FDA encourages you at the


 10   beginning of your statement to advise the committee


 11   if you do not have any such financial


 12   relationships.  If you choose not to address this


 13   issue of financial relationships at the beginning


 14   of your statement, it will not preclude you from


 15   speaking.


 16             The first speaker in the hearing will be


 17   Representative Bart Stupak.


 18             MR. STUPAK:  Good morning.  I do not have


 19   any financial interests with anyone,


 20   pharmaceuticals or any of the sponsors here today.


 21             Thank you for the opportunity to allow me


 22   to address this Accutane Advisory Committee.  I




  1   have submitted a written statement, so let me


  2   highlight some parts of it.


  3             The FDA has documented 366 pregnancy


  4   exposures since the inception of the S.M.A.R.T.


  5   program.  Because the reporting of the pregnancy


  6   exposures to isotretinoin is voluntary, there is no


  7   way of knowing how many pregnancies have actually


  8   occurred.  In fact, Dr. Graham of the FDA has


  9   actually estimated the yearly exposure rate may be


 10   as high as 2,000, and that has recently been


 11   revised, may be as high as 3,500 per year.  This,


 12   of course, does not include abortions.


 13             It seems clear that the only way to


 14   dramatically reduce the rate of pregnancy exposures


 15   in Accutane patients is to regulate like the FDA


 16   regulates Thalidomide.


 17             A toothless, voluntary registry does not


 18   work, and we all know it.  The registry should be


 19   mandatory for all female and male patients, for all


 20   prescribers and dispensers of Accutane.  There


 21   should be real consequences for refusal to


 22   participate in a program.  I plan to introduce that




  1   legislation in the coming weeks.


  2             For 22 years, we have seen the harm


  3   Accutane can do to pregnant women and to our


  4   children.  How many more babies have to be born


  5   with serious birth defects, how many more women


  6   need to have miscarriages, and how many more


  7   children have to die before the FDA implements


  8   meaningful protections and restrictions on the use


  9   of Accutane?


 10             The risk of severe birth defects caused by


 11   Accutane is undisputed.  Let's take a look at the


 12   history of this drug a little bit, because I don't


 13   think anyone has ever focused on the full history


 14   of this drug.


 15             Go back to the Advisory Committee hearings


 16   of 1988, 1989, and 1990.  Roche had assured


 17   Advisory Committees that Accutane would be


 18   prescribed only to women with severe recalcitrant


 19   cystic acne and pregnancy exposure rates would


 20   dramatically decrease because the average


 21   dermatologist would only see less than one female


 22   per year that would require Accutane therapy.




  1             Therefore, they concluded it would be


  2   limited to 5,000 new patients per year, and Roche's


  3   advertising would focus, not on Accutane usage, but


  4   future ads would, quote, "dramatically" focus on


  5   "contraindication and proper use of pregnancy


  6   prevention."


  7             With those assurances, even the 1988


  8   Advisory Committee, by consensus, considered


  9   limiting the use, prescription and distribution in


 10   four ways, but this consensus was never acted upon


 11   and the committee concerns were largely forgotten


 12   as Roche went on to make Accutane their second


 13   highest selling drug.


 14             Ten years later, the FDA and Roche


 15   implemented the Pregnancy Prevention Program after


 16   continued pregnancy exposures.  In this program,


 17   pharmacists, patients, and physicians were to work


 18   together to decrease the pregnancy exposures to


 19   Accutane.


 20             Despite the PPP, the red stickers, the


 21   voluntary consent form, and the NO pregnancy symbol


 22   with the red line through it, Accutane pregnancy




  1   exposures continued at unacceptable levels.  In


  2   fact, many patients, when they saw that pregnancy


  3   with the line through it, the women actually


  4   thought that Accutane was a form of birth control.


  5             Not only did the number of female patients


  6   receiving Accutane dramatically increase, so did


  7   the off-label use of Accutane.  It is estimated


  8   that 90 percent of Accutane use is for off label,


  9   and the FDA is of the opinion that many of the


 10   prescribing physicians do not understand the


 11   teratogenic effects of Accutane.


 12             At the end of the September 2000 Advisory


 13   Committee hearing, the Advisory Committee


 14   recommended five conditions, and I am sure you are


 15   all familiar with them.


 16             The FDA agreed with the Advisory Committee


 17   recommendations.  FDA and Roche then began their


 18   discussions on how to implement these


 19   recommendations.


 20             While the focus of these negotiations


 21   centered on a pregnancy risk management program,


 22   the U.S. House of Representatives became involved




  1   after the death of my son.  In October of 2000, my


  2   family and I went public with our concerns that


  3   Accutane was associated with suicides in some


  4   patients.  Back then, Roche and the FDA claimed


  5   there were 37 suicides.  I believe there were at


  6   least 54 associated with Accutane use.


  7             Congressional hearings were held in


  8   December of 2000 and again on December 11, 2002.


  9   The December 2002 congressional Oversight and


 10   Investigation Subcommittee hearing was attended by


 11   12 members of the Energy and Commerce Committee.


 12             The answers we sought were to the numerous


 13   issues relating to Accutane, but included the


 14   continued pregnancy exposure and the psychiatric


 15   effects of Accutane.  Committee members were


 16   appalled when they learned that the FDA had


 17   reversed its position and decided it was not


 18   necessary to implement the September 2000 Advisory


 19   Committee recommendations.


 20             The FDA excuses of privacy and HIPAA


 21   concerns for not implementing these recommendations


 22   rang hollow with congressional committee members.




  1             In the meantime, Roche continued to


  2   aggressively market Accutane, growing to 1.51


  3   million prescriptions in 2001.


  4             The FDA negotiations with Roche produced


  5   an agreement called the S.M.A.R.T. program.


  6   S.M.A.R.T. did not fulfill the recommendations made


  7   by the Advisory Committee.  The S.M.A.R.T. program


  8   began five months before the December 11, 2002


  9   hearing.


 10             Witnesses from the March of Dimes and the


 11   Organization of Teratology Information Services,


 12   OTIS, as we call them, testified that the


 13   S.M.A.R.T. program would not achieve its


 14   objectives, and the S.M.A.R.T. program did not go


 15   far enough.


 16             The OTIS representative further testified


 17   that a partial review of their organization had


 18   already revealed 17 cases of pregnancy exposure to


 19   Accutane and that there was a lot of slippage in


 20   the system.


 21             At the hearing, the Chairman of our


 22   committee asked the FDA, "What is your fallback




  1   position if the S.M.A.R.T. program doesn't improve


  2   things with the pregnancy exposures?"


  3             Dr. Woodcock answered that for a variety


  4   of reasons, FDA would evoke its authority under the


  5   Food, Drug, and Cosmetic Act only as a last resort.


  6             Members of the committee also learned


  7   firsthand the FDA was dragging its feet.  The FDA


  8   failed to provide relevant documentation until the


  9   day of the hearing, when they dropped off a number


 10   of boxes filled with information requested by the


 11   committee.


 12             The FDA had evidence of the failings of


 13   the S.M.A.R.T. program from its inception.  Doctors


 14   were pre-dating yellow stickers that signify the


 15   female patient had received a negative pregnancy


 16   test.  Medical clinics were pre-dating


 17   prescriptions so the patient could fill more than


 18   one prescription within the seven-day limit of the


 19   negative pregnancy test.


 20             At least one patient was purchasing


 21   Accutane with no pregnancy test, no prescriptions,


 22   no consent forms.  Some health care plans, who




  1   electronically dispense their prescriptions, were


  2   not using the yellow negative pregnancy sticker.


  3             Pharmacies were not giving out the Med


  4   Guides for Accutane, and that compliance with these


  5   toothless regulations were not working.  In fact,


  6   approximately 50 percent of the doctors were not


  7   using the informed consent forms because it's


  8   voluntary.


  9             The FDA withheld this information from our


 10   committee at the December 11th hearing.


 11             Now, Roche said they will support a


 12   mandatory registry and submit a proposal.  Please


 13   understand my and a number of committee members


 14   skepticism after going through the numerous


 15   Advisory Committee hearings.  I still do not


 16   believe the FDA and Roche will ever institute a


 17   registry and certification program similar to that


 18   of S.T.E.P.S. for Thalidomide.


 19             Equivalent effects call for equivalent


 20   restrictions.  There must be a mandatory


 21   isotretinoin registry for patients, doctors, and


 22   pharmacists.  Pregnancies will continue to occur if




  1   any element is left out of the registry.  There


  2   must be consequences for failure to comply with any


  3   part of the program.


  4             FDA complains that if we do this, we will


  5   send this drug to a black market.  Since 1999,


  6   myself and other members of Congress have tried to


  7   address this issue on the Internet.  We have asked


  8   for the FDA to comment on our legislation, where


  9   can we improve upon it.  To date, FDA has not


 10   answered.


 11             The manufacturer of Accutane, Hoffmann-La


 12   Roche, is just as culpable as the FDA in allowing


 13   Internet and mail order of Accutane in the country.


 14   Roche hides behind the FDA's inaction to complain


 15   of Internet sales.  Yet, their product coding


 16   allows them to determine the exact location of


 17   where products are shipped, to whom, and when.


 18             We can cut down on these illegal sales, it


 19   can be done.  In fact, our committee has convinced


 20   Purdue Pharma to stop shipping oxycotin to Mexico


 21   as it is being brought back across the U.S. border.


 22   Yet, when we pointed this out, what we have been




  1   able to do in Mexico, and that Mexico does not have


  2   the same regulatory scheme for Accutane as we have


  3   in this country, Roche has refused to stop the


  4   shipment of Accutane to Mexico.


  5             Answers as to why Roche isn't really


  6   serious about entering into a mandatory registry


  7   for Accutane for patients is very clear.  Roche did


  8   all it could to defeat the registry for Accutane as


  9   recommended by the September 2000 Advisory Panel.


 10             In fact, the recommendations or the defeat


 11   of those recommendations was a cause to celebrate


 12   because, as Roche says, there is no psychiatric


 13   registry.


 14             Not only did Roche view the defeat of the


 15   registry as a cause to celebrate, and they


 16   protected their $450 million sales in Accutane,


 17   Roche does not want any form of registry that would


 18   provide insight into the psychiatric effects on


 19   patients.


 20             Roche is so fearful that a registry may


 21   provide evidence of Accutane causing psychiatric


 22   injury to young, developing brains that it will




  1   stop at nothing to prevent the registry.


  2             If you go back and take a look at the


  3   history of this drug, Roche, in its initial


  4   application to the FDA, they forgot to submit a


  5   study, a study which was uncovered, which shows


  6   that Accutane does adversely affect the central


  7   nervous system in mice.


  8             The committee has uncovered three more


  9   studies, subsequent studies, that also suggest


 10   Accutane does have some effect on the central


 11   nervous system.  Even the FDA, which has been


 12   working with the National Institute of Mental


 13   Health and the National Institute of Health has


 14   kept from the Advisory Committee and the American


 15   people their preliminary studies which do suggest a


 16   causation between Accutane and psychiatric


 17   injuries.  Both the FDA and Roche have misled and


 18   failed to protect the American people, unborn


 19   children, and young adults from the devastating


 20   effect of this drug.


 21             I hope this time the FDA does not allow


 22   the manufacturers of Accutane and its generics to




  1   come in and water down the recommendations that may


  2   be made by this Advisory Committee.


  3             I am not sure Congress is willing to let


  4   them do that anymore.  As I said earlier, I will be


  5   introducing legislation to establish a mandatory


  6   registry of patients, doctors, and pharmacists,


  7   similar to that of the Thalidomide registry.


  8             Within the documents provided by the FDA,


  9   there is a statement provided by an exasperated FDA


 10   investigator who cries out, how could the FDA grant


 11   a patent extension on Accutane for use in young


 12   patients with the devastation this drug has caused?


 13   One begins to ask, what special powers or charm


 14   does Roche have over the FDA?


 15             It is time to put restrictions on the


 16   users, prescribers, dispensers and marketers of


 17   Accutane and its generics.


 18             Thank you and if there is any questions, I


 19   will be pleased to answer them.


 20             DR. GROSS:  Thank you very much,


 21   Representative Stupak.


 22             The second speaker is Gordon Day, who is




  1   President-Elect of the Society of Dermatology


  2   Physician Assistants.


  3             MR. DAY:  Good morning, Advisory Members.


  4             My name is Gordon Day, and I am a


  5   certified physician assistant, and I practice


  6   dermatology in Sandy, Utah, a suburb of Salt Lake


  7   City.


  8             I am the President-Elect of the Society of


  9   Dermatology Physician Assistants.  The SDPA is a


 10   national medical association of 900 members whose


 11   mission is to improve patient care by providing


 12   additional education and training for our members.


 13             Physician assistants are but one group of


 14   physician providers that prescribe isotretinoin.


 15   We are an integral component of the medical team.


 16   The collegial and dependent relationship we have


 17   with dermatologists  contributes directly to the


 18   quality  of diagnostic and therapeutic care


 19   furnished to our patients.


 20             The uniqueness of our position allows us


 21   to spend more time with patients, providing


 22   education on the therapeutic options for acne




  1   treatment including the risks and benefits of


  2   isotretinoin therapy.  This also includes


  3   contraceptive counseling.


  4             Our Society firmly believes it is


  5   necessary to assure the public that our members who


  6   prescribe medications such as isotretinoin are


  7   qualified to do so.  Continuing medical education


  8   and other life-long learning opportunities offered


  9   by our Society include compliance with the


 10   manufacturer-developed and FDA-approved risk


 11   management program for fetal exposure.


 12             It is also essential that medical


 13   providers using isotretinoin be proactive in ways


 14   that guarantee the continued availability of this


 15   drug for qualified patients, and that is why I am


 16   here today.


 17             There are few other therapeutic options


 18   available to us to effectively treat nodulocystic


 19   acne.  Additionally, it is important to the


 20   dermatology health care team that patients be


 21   compliant in all aspects of isotretinoin therapy,


 22   including adherence to contraceptive practices




  1   which are in place to minimize the likelihood of


  2   adverse outcomes.


  3             The importance of isotretinoin cannot be


  4   emphasized strongly enough for our patients with


  5   severe acne, who can avoid scarring and


  6   disfigurement by use of this medication.


  7             As a physician assistant in dermatology, I


  8   see older patients on a daily basis who would have


  9   benefited from isotretinoin, but whose bouts of


 10   this severe acne occurred before this wonder drug


 11   was approved for sale in the United States.  They


 12   will be scarred forever.


 13             I have observed firsthand how patients


 14   with severe cystic acne may be so concerned with


 15   their appearance that it affects their daily


 16   living, self-concept and quality of life.  There


 17   are patients I care for who will not go swimming


 18   because of the severe cystic acne lesions and


 19   scarring on their backs and shoulders.


 20             I have female patients that have limited


 21   outings socially because of their severe cystic


 22   acne, and I have those patients who suffer from low




  1   self-esteem and required psychiatric treatment


  2   because of their severe acne.  Isotretinoin is an


  3   important tool for helping these patients when all


  4   other options fail to improve their condition.


  5             In the dermatology practice where I


  6   provide care, in an attempt to avoid adverse


  7   outcomes, I not only employ the S.M.A.R.T. program,


  8   but also have developed a protocol that I and my


  9   supervising physician, and other members of our


 10   health care team use to make sure that all the


 11   necessary risk management program components are


 12   documented when using isotretinoin.


 13             This enhanced protocol encompasses review


 14   of side effect profiles, pregnancy testing,


 15   contraceptive counseling, the completion of


 16   time-specific laboratory testing, a thorough review


 17   of the patient's own responsibilities,


 18   participation in the survey, and completion of the


 19   informed consent process.


 20             It is an unfortunate fact that a small


 21   number of fetal exposures still occur in female


 22   isotretinoin patients, relative to the overall




  1   number of female patients taking this drug.


  2             Therefore, the Society of Dermatology


  3   Physician Assistants would like to collaborate with


  4   the American Academy of Dermatology Association and


  5   the FDA on improving the effectiveness of the


  6   current risk management program in ways that lead


  7   to fewer adverse outcomes and safeguard patient


  8   confidentiality and rights in the health care


  9   system.


 10             This process, once completed, should serve


 11   as an educational tool for the patients, the


 12   prescribers, and the pharmacists.


 13             Thank you.


 14             DR. GROSS:  Thank you, Mr. Day.


 15             The third speaker is LaDonna Williams,


 16   Executive Director, Inflammatory Skin Disease


 17   Institute.


 18             MS. WILLIAMS:  Good morning.  I am LaDonna


 19   Williams, and I am the Executive Director of the


 20   Inflammatory Skin Disease Institute, a patient


 21   advocacy group that provides education, public


 22   awareness, and support to those patients with




  1   inflammatory skin disease and their families.


  2              Inflammatory skin disease is a broad


  3   category of conditions ranging in severity.  As you


  4   can imagine, these diseases are very distressing to


  5   those who have them, causing great discomfort and


  6   real emotional distress.


  7             You can learn more about inflammatory skin


  8   disease by visiting our web site


  9   www.isdi.online.org.


 10             I feel it is important to be here today on


 11   behalf of the patients who suffer from the


 12   inflammatory skin disease acne.  Severe acne is


 13   characterized by papules, pustules and inflamed


 14   nodules.  Acne is a common skin disease and can be


 15   a very serious medical condition.


 16             For many Americans it is more than a


 17   temporary cosmetic problem that can be treated by


 18   over-the-counter lotions and creams.


 19             For many Americans it is more than a


 20   condition that can be treated by antibiotics, oral


 21   contraceptives, or steroids.  Indeed, for thousands


 22   of unfortunate Americans, acne can be a




  1   life-altering and a socially terminal medical


  2   condition for which isotretinoin is the only


  3   effective method of treatment.


  4             I am representing hundreds of acne


  5   patients who cannot be here today.  These patients


  6   are both male and female, teenagers and adults who


  7   have contacted me to express their strong support


  8   for continued access to isotretinoin.  This drug


  9   literally worked wonders for them and they want to


 10   make certain that it remains available for other


 11   severe acne sufferers.


 12             You have already reviewed reams of


 13   briefing material and listened to hours of


 14   testimony about the current risk management effort


 15   to reduce fetal exposure to isotretinoin.


 16             The Inflammatory Skin Disease Institute


 17   agrees it is necessary to provide and improve a


 18   program and reduce the number of pregnancies


 19   associated with this drug keeping in mind I have


 20   received numerous letters from teenagers and adults


 21   stating how isotretinoin saved their skin and their


 22   self-esteem.




  1             Many parents have written to me on behalf


  2   of their children.  One grateful mother told me how


  3   isotretinoin improved her daughter's skin, and not


  4   only made positive changes in her teenager's life,


  5   but made positive changes in the whole family


  6   because they could go out in public and do social


  7   things together again.


  8             I have received calls in my office from


  9   patients and their parents explaining how academics


 10   in high school has improved dramatically because


 11   attendance became 100 percent after isotretinoin


 12   cleared up their student's acne.


 13             One patient had to consider to leave her


 14   job that she loved very much because her acne was


 15   so severe that her face was in a constant state of


 16   being red, swollen, and painful, with disfiguring


 17   pustules.  Children were afraid of her, which in


 18   turn made her withdrawn and depressed.  She took


 19   isotretinoin and she feels it saved her job, her


 20   relationships, and her life.


 21             I could go on and on with personal


 22   accounts from patients for whom isotretinoin made a




  1   positive difference in their lives.  It is on their


  2   behalf that I speak with you today.


  3             I thank you for your time and your


  4   attention in listening to these stories, and I hope


  5   you will keep these testimonies in mind as you


  6   debate the future direction of the isotretinoin


  7   risk management program.


  8             If I may close with somewhat of a cliche -


  9   the effectiveness of isotretinoin goes beyond skin


 10   deep.  I hope that I have impressed upon this


 11   committee how absolutely essential it is for this


 12   drug treatment for acne to remain on the market,


 13   and I hope I have impressed upon you how essential


 14   it is for the qualified patients


 15             Thank you.


 16             DR. GROSS:  Thank you.


 17             The next speaker is Dr. Boni Elewski,


 18   President of the American Academy of Dermatology,


 19   the fourth speaker.


 20             DR. ELEWSKI:  Good morning, everyone.


 21             My name is Dr. Boni Elewski.  I am a


 22   practicing dermatologist and Professor of




  1   Dermatology in the Department of Dermatology at the


  2   University of Alabama in Birmingham.


  3             In addition to my medical duties, I am


  4   also President of the American Academy of


  5   Dermatology Association.  On behalf of the 14,000


  6   members of the Association, and our hundreds of


  7   thousands of acne patients, I thank you for the


  8   chance to speak with you about the current


  9   pregnancy risk management program for isotretinoin.


 10             The health, safety, and welfare of our


 11   patients is of paramount importance to


 12   dermatologists, as is the integrity of the


 13   doctor-patient relationship.  Indeed, because of


 14   these concerns, our organization is committed to


 15   optimizing the safety of our patients taking this


 16   drug, as well as ensuring continued access to


 17   isotretinoin for all qualified prescribers.


 18             Education and communication with our


 19   members and their patients about isotretinoin


 20   compliance is essential to the safe use of this


 21   drug.


 22             The current risk management program has




  1   been promoted in numerous education and


  2   communication efforts, such as CME activities,


  3   Member Alerts, articles on our web site, in our


  4   official publication Dermatology World, and will be


  5   augmented by new initiatives.


  6             In addition, the Association hosted a


  7   scientific consensus conference on the safe and


  8   optimal use of isotretinoin to which key


  9   decisionmakers in the FDA and the scientific


 10   community were invited.  The proceedings will be


 11   published next month.


 12             Recently, the Association sent a letter to


 13   the FDA Commissioner with a list of web sites that


 14   sell isotretinoin on line.  We hope this


 15   information will assist the agency with addressing


 16   the problem of illicit sales of this powerful drug.


 17             You have just heard a number of compelling


 18   stories about the benefits of isotretinoin therapy.


 19   I myself have treated hundreds of patients whose


 20   quality of life has improved tremendously because


 21   of this drug.


 22             This is because acne is not simply a




  1   cosmetic problem.  In 1948, renowned dermatologist


  2   Dr. Marion Sulzberger said, and I quote, "There is


  3   no single disease which causes more psychic trauma,


  4   more maladjustment between parents and children,


  5   and general insecurity and feelings of inferiority


  6   and greater sums of psychic suffering than does


  7   acne."  More than a half century later, his


  8   observation still rings true.


  9             When all other treatment options fail,


 10   isotretinoin is the miracle drug that clears away


 11   the redness, painful swelling, and lesions of


 12   severe, nodulocystic acne, which may lead to


 13   painful and disfiguring scars.


 14             Unfortunately, a small number of women are


 15   pregnant or become pregnant while taking this drug.


 16   As always, our goal is to ensure both patient


 17   safety and continued access to isotretinoin for all


 18   qualified patients. For this reason, we would like


 19   to offer the following recommendations for


 20   improving the current risk management program.


 21             First, the survey of female patients


 22   should be mandatory, not voluntary.  We propose




  1   that isotretinoin therapy be prescribed for


  2   qualified female patients only if they participate


  3   in the survey.  Data generated by this mandatory


  4   survey would be more complete.  Of course, it is


  5   the ultimate responsibility of the female patient


  6   to comply with the birth control requirements of


  7   the program and to avoid pregnancy.


  8             Second, a single questionnaire and vendor


  9   for the female patient survey should be designated.


 10   The present situation with the generic


 11   manufacturers using one questionnaire and vendor,


 12   and Hoffmann-La Roche using another questionnaire


 13   and vendor, is confusing to prescribers and


 14   patients alike.


 15             Furthermore, differences in the surveys


 16   make it difficult to compare data.  A single


 17   questionnaire and vendor would minimize this


 18   confusion, improve data gathering, and promote


 19   patient safety and education, and ultimately


 20   improve the health, safety, and welfare of our


 21   patients taking this drug.


 22             Third, the survey questionnaire should be




  1   re-evaluated and simplified to obtain the pertinent


  2   information to assess the risk management program.


  3   Ultimately, this will improve the health, safety,


  4   and welfare of our patients taking isotretinoin.


  5             Fourth, the current risk management


  6   program must be clarified and simplified to address


  7   ongoing issues of concern for doctors and patients


  8   alike.


  9             And finally, it is crucial that program


 10   materials warn patients to avoid Internet sales,


 11   avoid re-use, or sharing of isotretinoin.


 12             Let me close by saying, the preservation


 13   of the doctor-patient relationship is crucial, and


 14   may I add, an integral component to the risk


 15   management system.  As we strive to improve the


 16   current risk management program for isotretinoin,


 17   the American Academy of Dermatology Association's


 18   guiding principle has always been, and will


 19   continue to be, the health, safety and welfare of


 20   our patients.


 21             Thank you.


 22             DR. GROSS:  Thank you, Dr. Elewski.




  1             The next speaker, the fifth speaker, is


  2   attorney Paul Smith.


  3             MR. SMITH:  Good morning.  My name is Paul


  4   Smith and I am an attorney practicing law in


  5   Austin, Texas.


  6             My practice relates exclusively to


  7   pharmaceutical litigation and for the past two


  8   years I have worked nearly full time on behalf of


  9   families and individuals who have experienced


 10   devastating and catastrophic side effects from


 11   Accutane.


 12             In connection with this privilege, I have


 13   personally seen and known dozens of individuals and


 14   families whose lives have been horribly altered as


 15   a result of this powerful and dangerous drug.


 16             The tragedy of a parent who has lost their


 17   child to suicide and the tragedy of these parents


 18   and babies who have to live with serious and


 19   permanent birth defects is beyond description.


 20             I understand that as my role, I am charged


 21   with the responsibility to seek redress for these


 22   people in the court system.  However, today, I am




  1   stepping out of my role as a legal advocate, today,


  2   I come before you as a member of the public who has


  3   talked to and seen many who have been harmed by


  4   Accutane.


  5             Today, I am asking you to take a serious


  6   and deliberate look at risk presented by this drug,


  7   which has not, in my opinion, been fairly and


  8   accurately examined.


  9             You are fortunate to have the ability to


 10   suggest and ensure that the tragedies that I have


 11   seen in connection with this drug are substantially


 12   reduced.


 13             For over 20 years now, the FDA has made an


 14   effort to regulate this product by adding warnings


 15   and warnings in connection with this drug.  This is


 16   a laudable goal to try to ensure some safe use of


 17   this product, however, as has been well established


 18   and is beyond dispute today, the various programs


 19   that have been instituted have failed miserably.


 20             The admission and concession by Roche that


 21   a registry is needed is too late for many.  If


 22   there is a registry, however, there are two




  1   components which must be incorporated.


  2             The first involves paternal exposure, that


  3   is, where the father takes Accutane when the mother


  4   conceives the fetus.  This is limited to treatment


  5   of the father with Accutane.


  6             The second is the incredible failure of


  7   Roche to consider the known psychiatric component


  8   of the drug to impair complete compliance with any


  9   rational program aimed at preventing fetal


 10   exposures.


 11             The dangers and risk of paternal exposure


 12   is something that must be better studied and


 13   understood.  I point you to the Thalidomide


 14   warnings which strongly advised male patients


 15   taking Thalidomide to use contraceptive measures.


 16   This is in dramatic contrast to the Accutane,


 17   which suggests that there is no risk to the fetus


 18   as the result of paternal exposure.


 19             I have with me recently released documents


 20   that indicates that Roche's own internal experts


 21   has, in reviewing 13 potential paternal exposures,


 22   found that in 5 of those cases, a possible




  1   relationship could not be excluded.


  2             This is a document that Roche fought hard


  3   to keep from the public.  I have it here with me.


  4   It is sitting here for your review.  I would


  5   welcome and request that you get a copy of this and


  6   review it thoroughly.


  7             Carter Crosland, who is here with his


  8   mother and father, is, in fact, one of the five


  9   whose medical records were examined by the Roche's


 10   internal geneticist.  The Roche consultant


 11   concluded that Carter's difficulties could very


 12   well be related to Accutane embryopathy.


 13             Roche's response to this phenomena and the


 14   risk associated with paternal exposure is


 15   inadequate.  The public should be aware the


 16   potential exposure does exist, and there should be


 17   warnings specifically advising that there is


 18   problem with paternal exposure.


 19             We would strongly urge a registry that


 20   includes males using Accutane that specifically


 21   tracks their sexual activities.


 22             The second issue for your consideration is




  1   the inability of certain patients to comply with


  2   warning and instructions as a direct result of


  3   known psychiatric side effects presented by this


  4   drug.


  5             Only Roche disputes that Accutane may


  6   cause depression and behavioral changes.  It seems


  7   to be well accepted within the rest of the


  8   scientific community that there is a strong


  9   relationship between Accutane and psychiatric


 10   adverse events and depression.


 11             I have seen nothing publicly which


 12   suggests that Roche has even considered this


 13   foreseeable and predictable phenomenon of pregnancy


 14   secondary to impaired capacity as a result of


 15   depression.


 16              Debbie Banner is here to explain to you


 17   how she got depressed and was unable to comply with


 18   the program in effect at the time to prevent her


 19   pregnancy.


 20             I thank you for your attention and your


 21   kind consideration and again the paternal exposure


 22   study itself that was submitted to the FDA is here




  1   for your review.


  2             Thank you very much.


  3             DR. GROSS:  Thank you, Mr. Smith.


  4             The sixth speaker is Debbie Banner.


  5             MS. BANNER:  Good morning.  My name is


  6   Debbie Banner.  I am here with my husband Kevin.  I


  7   have known my husband since I was 17, and we have


  8   been married for seven years.  I appreciate this


  9   opportunity to share with the members of this


 10   honorable committee my horrifying experience with


 11   the drug Accutane.


 12             Starting today, we will offer one of the


 13   answers to this question, why are girls continuing


 14   to become pregnant while on Accutane despite the


 15   warnings that Accutane causes birth defects?


 16             I am afraid that one of the answers I will


 17   propose today is one that neither the FDA, this


 18   committee, or Hoffmann-La Roche has adequately


 19   studied or considered.


 20             I am also here to describe the nightmare


 21   of having a child who has been born with Accutane


 22   birth defects.




  1             I became pregnant while on Accutane.  I


  2   survived this nightmare by the grace of God, strong


  3   faith, a loving husband, and an overwhelming


  4   commitment to my son.


  5             I was devastated that I played a role in


  6   causing my own child to be deformed.  So, I vowed


  7   to sacrifice everything to give him the best life I


  8   could possibly give.  Because I accepted my fate


  9   humbly, I believe that is why God finally revealed


 10   the other side of the story to me, the missing


 11   piece of the puzzle.


 12             On October 4th, 1996, my son Deven was


 13   born.  There is no medical doubt that his birth


 14   defects are due to the effect of Accutane on him as


 15   a developing fetus.  He has been seen by the best


 16   physicians and was diagnosed with Accutane


 17   embryopathy.


 18             Deven was diagnosed with an underdeveloped


 19   cerebellum resulting in cerebral palsy and


 20   hypotonia.  At the age of 7, he is fed through a


 21   feeding tube that is surgically inserted into his


 22   stomach, he suffers from seizures.




  1             After four eye surgeries, he has visual


  2   perceptual problems.  He has sensory integration


  3   problems which manifest as autistic-like behaviors.


  4   He has verbal expressive disorder, speech problems,


  5   and requires physical therapy, occupational


  6   therapy, and speech therapy.


  7             He has a chronic history of pneumonia.  He


  8   requires special education services in school and


  9   special accommodations.  Along with these and other


 10   medical problems, as well as fine motor and gross


 11   motor impairments, it is likely that he will be


 12   unable to take care of himself as an adult.


 13             I was on Accutane in 1995 when I was 24


 14   years old. I was an aerobics instructor and


 15   attending school.  I was working two jobs.  I was


 16   of healthy mind, body, and spirit, so when I first


 17   visited the dermatologist, I was a happy person


 18   although I had an acne problem.


 19             Days after ingesting Accutane, I began to


 20   react as if I were poisoned.  I developed severe


 21   headaches and sharp, piercing head pains.  I was


 22   nauseous day and night.  I was weak, dizzy,




  1   confused, forgetful, suffering from hypersomnia and


  2   severe crying spells.


  3             Eventually, I developed suicidal thoughts.


  4   I just wanted to sleep and never wake up again.  I


  5   was too sick when I was awake.


  6             At the initiation of treatment, I had


  7   chosen abstinence as my method of birth control.  I


  8   chose this for religious reasons and did not plan


  9   to be sexually active again until I was married.


 10             However, once in a state of severe


 11   depression, I became mentally incapable of making


 12   appropriate decisions. My thoughts were filled with


 13   thoughts of suicide and death, which eventually


 14   required psychiatric intervention.


 15             At the time of conception, I was no longer


 16   a patient that was reliable and capable of


 17   complying with mandatory pregnancy prevention


 18   procedures and reliable in carrying out


 19   instructions.


 20             The missing piece of the puzzle was given


 21   to me when I learned that the psychiatric problems


 22   that led to my pregnancy were a side effect of




  1   Accutane.


  2             Through my research, I have now met other


  3   mothers who became pregnant on Accutane.  I have


  4   learned that depression was a factor in their


  5   inability to comply with the warnings that, like


  6   me, led to a nightmare of birth defects.


  7             I have spoken to one mother who actually


  8   attempted suicide while on Accutane and became


  9   pregnant weeks later. To this day, there is no


 10   instruction, education, or warning on how


 11   psychiatric side effects of this drug may prevent


 12   you, despite the best intentions, from complying


 13   with the pregnancy prevention program.


 14             It seems fundamental to me now, but how


 15   can you educate someone that may not be able to


 16   protect themselves. How can anyone including the


 17   doctors who prescribe it believe that the drug


 18   could do this when Roche refuses to admit that


 19   there is a psychiatric component to the drug?


 20             I am here to tell you from my own


 21   experience, and experience told to me by other


 22   mothers admitted in a cloud of shame and stigma




  1   that depression can and does interfere with


  2   pregnancy prevention even when patients have chosen


  3   other forms of birth control.


  4             Because women and girls are continuing to


  5   become pregnant, I plead with this committee to


  6   require that females of childbearing potential


  7   receive an initial psychiatric evaluation and are


  8   then monitored by a psychiatrist throughout


  9   treatment.


 10             To leave this decision to patients who may


 11   be in denial and cannot protect themselves is to


 12   guarantee more birth defects and abortions.


 13   Because Accutane is such a powerful drug, it is


 14   worth the extra effort and expense to save children


 15   from a lifetime of deformity and pain and to


 16   finally bring an end to the outrageous number of


 17   Accutane abortions.


 18             Warning is simply not enough when


 19   psychiatric side effects are involved.


 20             In conclusion, I want to express my


 21   sympathy for people suffering from acne, but even


 22   in the very worst cases of acne, their suffering




  1   cannot compare to the suffering endured daily by


  2   children born with Accutane birth defects.


  3             Thank you.


  4             DR. GROSS:  Thank you, Debbie, and Kevin


  5   Banner.


  6             The seventh speaker is Carter Crosland.


  7             MR. CROSLAND:  Good morning.  My name is


  8   Carter Crosland.


  9             Today, you will hear my story.  Not only


 10   do I speak for myself, but also for the hundreds,


 11   perhaps thousands of children whose voices will


 12   never be heard. Those dreams and hopes will never


 13   be realized.  Today, I am their voice.


 14             I was born January 22, 1985, in a small


 15   rural town in central Utah, the first child of my


 16   parents.  As a young boy, I was told that I was a


 17   miracle and that I had something important to share


 18   with the world.  I have been blessed with the


 19   health, strength, and mental faculties to speak


 20   before you today.  Perhaps that is my purpose.


 21             As a young boy, I dreamed of being a


 22   wrestler.  I loved sports and had an unusual talent




  1   for learning statistics.  I played T ball with my


  2   friends and they ran the bases for me while I


  3   stopped the ball with my wheelchair tires.


  4             And then the boys moved on to minors and


  5   majors and I stayed behind.  I became the batboy


  6   and then the base ump.  Then the coach, manager, or


  7   anything else just to stay involved.  The same was


  8   true with football and wrestling.  As I matured, I


  9   realized I would be left behind again.  Not only in


 10   sports, but in every single aspect of my life.


 11             My parents sacrificed to get me where I


 12   am, and because they worked hard, we didn't qualify


 13   for disability funding from the government.  I was


 14   too smart.  I passed all the cognitive tests,


 15   despite missing a third of my brain to a cyst.


 16             I passed all the skills and vocabulary


 17   tests.  I could even pick up the blocks with my


 18   mouth and put them in the holes quickly.


 19   Therefore, by their standards, I wasn't disabled,


 20   and I was at the end of the waiting list without


 21   assistance.


 22             I had generous people who helped me get




  1   arms as a young boy, but we couldn't keep up with


  2   the constant re-fitting and trips to the city.  My


  3   mom worked full time to keep insurance for me, but


  4   she couldn't keep leaving work for sick kids and


  5   trips to the prosthetic specialist, so I gave up on


  6   the arms.  They were too costly.


  7             When I entered first grade, my mom quit


  8   work, so that I could go on field trips, birthday


  9   parties, and to the library with my friends.  Where


 10   I went, my chair went, and also my parents and my


 11   van went.  That made our financial situation even


 12   worse, but I appreciated having my mom around.


 13             I took drivers ed at 15 and passed with


 14   flying colors, well, all except for the driving


 15   test.  You see, I can't afford the car for me to


 16   drive and the school district can't provide it.  I


 17   completed high school and graduated with my class.


 18   I was voted most preferred senior probably because


 19   I had the gift of gab and I like to visit with


 20   everyone.


 21             My school built a ramp so that I could


 22   participate in pomp and circumstance with my peers.




  1   I now attend college and I am studying


  2   communications.  I hope to be a sports broadcaster


  3   or work for some firm as a public relations guy.


  4             My voice is the only asset I have that


  5   puts me on the same playing field as those around


  6   me.  It is literally the only thing I can do on my


  7   own.  This is what I have accomplished so far in my


  8   life against all odds.  Now I would like to tell


  9   you what I cannot do.


 10             I room with a friend at college.  I pay


 11   him to help me bathe, get dressed, cook my meals,


 12   charge my wheelchair, get my books, help me on


 13   dates, drive my car, and anything else I want to


 14   do.  My friends lift me up the stairs to their


 15   place or to any other place that is not accessible.


 16             I have to plan for bathroom breaks because


 17   I need help.  My friend will get married soon, and


 18   I will find another person and then another, and


 19   another.  My parents travel to bring me home and


 20   back on weekends because I cannot afford a car that


 21   I can drive on my own.  My buddies take me shopping


 22   and help prepare and eat my meals.  They clean up




  1   for me and do my wash.


  2             Because I have all my mental faculties, my


  3   dreams are the same as every other young man my age


  4   - a car, a job, a girlfriend, and someday a wife


  5   and family.  I hope for these things, but I take it


  6   one day at a time, and I don't know what the future


  7   holds for me.


  8             I keep being determined to make the best


  9   of it and to find happiness in every small thing


 10   around me.  Some of these dreams I can realize now


 11   if I could afford it.  Money is a tremendous


 12   limitation, nearly as limiting as my disability.


 13   Please do not make money a factor in your decision


 14   to research and regulate this drug.


 15             They say that I don't fit into any


 16   category or syndrome because of my intelligence.  I


 17   feel that my mental abilities are a gift from God


 18   and are for a purpose.  Today, I hope that purpose


 19   is to bring this matter before you to your


 20   attention.


 21             I hope that you will look deep into your


 22   heart and do everything you can to study, research,




  1   and take every step possible to prevent this from


  2   happening to one more child.  Most are not as


  3   fortunate as I am.  Their voices will never be


  4   heard.  Please hear mine.


  5             I thank you for your time.


  6             DR. GROSS:  Thank you, Mr. Crosland.


  7             The eighth speaker will be Lisa Crosland.


  8             MRS. CROSLAND:  Ladies and gentlemen, good


  9   morning.  I am Lisa Crosland, and I am here with my


 10   husband Russell and my son.


 11             A first pregnancy is supposed to be a


 12   happy time filled with anticipation and excitement,


 13   but mine was neither.  For me, I was a 19-year-old


 14   in college, in love. We had big plans, big plans


 15   and dreams that included marriage and children, but


 16   things changed when Russell began using Accutane.


 17             Our relationship became a disaster filled


 18   with unkept promises and unpredictable behavior.


 19   An engagement was broken and so was my heart, and


 20   then I found out I was pregnant and alone.


 21             Things went from bad to worse.  I had


 22   recurring nightmares that the baby inside me was




  1   not right.  I didn't grow enough, the baby banged


  2   back and forth.  An ultrasound at almost six months


  3   confirmed my worst nightmare.


  4             We were told that our baby had no arms and


  5   legs, no sex organs.  The child had a third of its


  6   brain covered with fluid that was increasing.  They


  7   felt his eyes were too big and his head too large.


  8   A large growing hernia and funny-shaped mouth was


  9   also evident.


 10             Most doctors felt the child would abort


 11   itself. Others said that if it lived, it would be


 12   on life support, unable to suck, and


 13   institutionalized.  I was devastated and so was


 14   Russell.  We prayed for a miracle that our child


 15   would not suffer.


 16             Our miracle was not what we expected, our


 17   child lived, and today we are telling his story.


 18   As parents, our first concern was why did this


 19   happen, what did I do.  Parents need to know why


 20   this has happened to them.


 21             I had lived what I thought was a clean and


 22   healthy life.  I did not smoke, I did not drink or




  1   use drugs.  Every effort was made to determine what


  2   I could have done to prevent this as a mother.


  3   Yet, we turned up empty-handed.


  4             The first time I heard the word Accutane


  5   embryopathy was from a genetics counselor at the


  6   University Hospital in Salt Lake City.  Carter was


  7   almost three months old and had just had his second


  8   surgery.  The doctor felt Carter's symptoms were


  9   too similar to maternal Accutane exposure to


 10   ignore.


 11             I told her that I had never used the drug,


 12   but his father had before, during, and after I


 13   became pregnant.  Carter has been worked up by the


 14   best doctors and the best facilities.  Everyone


 15   wanted to know whether Russell or I carried some


 16   odd genetic code that would cause this in the


 17   future.


 18             We looked everywhere, but there was


 19   nothing else but Accutane.  We reported an adverse


 20   reaction to Hoffmann-La Roche, who responded that


 21   this could not be the cause of our child's


 22   deformities.  A few years later I spoke directly to




  1   a doctor at Hoffmann-La Roche who told me that


  2   there were a few other reports of paternal


  3   exposure, but all could be attributed to another


  4   cause.


  5             I even asked for and received films and


  6   study materials from Roche.  You see, as we have


  7   now learned from Roche's internal documents made


  8   public only after Roche fought and lost the battle


  9   to keep it private.  Carter has all the clinical


 10   signs of Accutane embryopathy.


 11             Roche initially agreed that paternal


 12   exposure to Accutane could not be ruled out.  Why


 13   then hasn't this been researched?  Are kids like


 14   Carter not worth it?


 15             Since this time, I have seen warning


 16   labels and adverse reports increase, more children


 17   aborted and affected.  I have studied and found


 18   more and more similarities to things Carter was


 19   experiencing in his life that other children whose


 20   mothers were exposed were experiencing.


 21             His mouth, his dental problems, his


 22   problems with temperature regulation are just a few




  1   of the less visible problems.  Some children whose


  2   only link is a mental I.Q. of under 85 have been


  3   attributed to Accutane.  I find it impossible not


  4   to include Carter in this category simply because


  5   his father was the user and he is normal in


  6   intelligence.


  7             Of course, it may very well be that women


  8   who become pregnant from a father who has taken


  9   Accutane may never put the issue together.  The


 10   possibilities of hundreds and thousands of


 11   abortions simply attributed to poor development or


 12   unwanted pregnancy may have occurred, with the


 13   public being kept in the dark of these risks.


 14             The fact that there has not been more


 15   reporting of this issue does not mean that there is


 16   not a serious risk and danger.  It only means that


 17   Roche has been successful in keeping this from the


 18   public.


 19             This drug Accutane has devastated my


 20   family emotionally, physically, and financially.


 21   It has been carelessly over-prescribed and


 22   under-regulated.  It has destroyed our dreams and




  1   shattered our lives, yet we stand before you today


  2   united in our efforts to demand a change.


  3             We want adequate research and funding into


  4   the possibility of paternal exposure of retinoids.


  5   We want the prescription of this drug for


  6   dermatological reasons restricted to dermatologists


  7   who are forced to prescribe it only as a last


  8   resort for both men and women.


  9             We want those greedy individuals who


 10   facilitate unprescribed Internet sales of this drug


 11   stopped and prosecuted.


 12             Most of all, we want answers, not only for


 13   ourselves, but for the hundreds of babies aborted


 14   who may very well be exactly like Carter, but


 15   discarded.


 16             I cannot stand before you today and tell


 17   you exactly how Accutane is responsible for my


 18   son's disabilities, only that we know that it is.


 19   Our family and many others have suffered long


 20   enough at the hands of Hoffmann-La Roche.  We urge


 21   you to take a stand and ensure the safety of this


 22   drug.




  1             Thank you for your time.


  2             DR. GROSS:  Thank you, Mrs. Crosland.


  3             Is there anyone from the public who wants


  4   to speak at this point?


  5             [No response.]


  6             DR. GROSS:  Hearing none, we will declare


  7   a recess at this point, and we will reconvene at


  8   9:15.


  9             [Break.]


 10             DR. GROSS:  While we had closed our public


 11   hearing, we are going to reopen it briefly.  The


 12   tenth speaker from earlier today, Jeffrey Federman


 13   will speak.


 14             MR. FEDERMAN:  Good morning.  My name is


 15   Jeff Federman, and I am President of Paragon Rex, a


 16   company that provides services to the


 17   pharmaceutical industry.


 18             For purposes of disclosure, we are not


 19   engaged with the manufacturers involved in today's


 20   meeting.  In addition, my colleagues and I authored


 21   a book about pharmaceutical risk management.


 22             Let me begin my proposing that today's




  1   proceedings provide two insights about what can


  2   reasonably be expected about the design and


  3   improvement of risk management programs.


  4             The first focus is on the expectations of


  5   rigor and precision.  We are all associated with a


  6   pharmaceutical industry that is famous for the


  7   rigor and precision of its well-controlled clinical


  8   trials.  We expect to be able to determine drug


  9   efficacy using scientific and statistical methods,


 10   and would hope to bring a similar level of rigor to


 11   pharmaceutical risk management.


 12             Our colleagues in other risk-intensive


 13   industries, such as nuclear energy and aerospace,


 14   have much to teach us about applying a similar


 15   degree of rigor to risk assessment and program


 16   design.  Validated well-established methodologies


 17   exist to guide the design of risk management


 18   programs in these industries.


 19             Research of these practices, as well as


 20   the disease management and adult learning


 21   disciplines, suggest that effective drug risk


 22   management may have several key elements.




  1             1.  Evidence-based assessment and design


  2   process, perhaps such as failure mode and effects


  3   analysis, or FMEA, that targets interventions to


  4   address specific process-related causes of failure.


  5             2.  Redundancies that back up the


  6   inevitable human failures.


  7             3.  Collaborative design with practicing


  8   physicians to help program elements fit seamlessly


  9   into their day-to-day practice of medicine.


 10             4.  Predictive modeling or pre-testing to


 11   determine the likely effectiveness of any proposed


 12   program and anticipate where program weaknesses may


 13   exist.


 14             5.  Innovative implementation approaches,


 15   perhaps such as scenario-based learning, that build


 16   on the way clinicians and patients learn.


 17             Finally, ongoing monitoring and


 18   measurement with the anticipation that initial


 19   programs change over time.


 20             Certainly, rigorous design is achievable,


 21   yet, in the world of every-day clinical practice,


 22   where care is delivered based on the judgments and




  1   knowledge and motivations of well-meaning men and


  2   women, high precision in terms of predicting


  3   program compliance and use may be an unrealistic


  4   expectation at the time of program introduction.


  5             This key difference between the controlled


  6   clinical trial environment to which we are


  7   accustomed and the realities of clinical practice


  8   lead to a second expectation.


  9             I suggest that expecting a definitive


 10   precise or final design at the time of risk


 11   management program introduction may not be


 12   reasonable.  Quality improvement standards in other


 13   industries are built on the foundation of


 14   continuous quality improvement, or CQI.


 15             The concept of intervening with an initial


 16   program, then, monitoring and measuring for early


 17   opportunities to improve the program may be a more


 18   achievable expectation.


 19             The approach of showing continuous


 20   movement towards a goal may require a frequency of


 21   analysis and potential redesign occurring in


 22   intervals of months, not years.




  1             Today's discussions are another step in


  2   the ongoing improvement of Roche's pioneering PPP


  3   and enhanced S.M.A.R.T. programs.  We support these


  4   FDA initiatives and believe these hearings today


  5   will help lead to the next generation of effective


  6   pharmaceutical risk management programs that


  7   incorporate both rigorous evidence-based program


  8   design, as well as continuous quality improvement


  9   to provide the degree of product we are all seeking


 10   to achieve.


 11             Thank you.


 12             DR. GROSS:  Thank you, Mr. Federman.


 13             At this point, we will close the open


 14   public hearing again, and we will move on to some


 15   other orders of business.


 16             Allen Mitchell, Director, Slone


 17   Epidemiology Center, Boston University, will have a


 18   few minutes to comment on some questions that were


 19   raised yesterday.


 20             DR. MITCHELL:  Thank you very much, Dr.


 21   Gross, and committee, I really appreciate your


 22   offer of a few minutes to respond to some of the




  1   concerns raised in the FDA review.


  2             Yesterday, I mentioned that I was not here


  3   on behalf or speaking for the FDA, and then this


  4   morning's remarks, I just want to point out that


  5   not only is that the case for these remarks, but I


  6   am not speaking on behalf of the generic sponsors


  7   or Hoffmann-La Roche.  I guess that leaves me


  8   speaking on behalf of the Slone Epidemiology


  9   Center, which I think they will allow me to do.


 10             This presentation has not been shared with


 11   anyone other than our own group.


 12             [Pause.]


 13             DR. GROSS:  We have a few questions from


 14   yesterday.  I would like to start with Dr. Day.


 15             DR. DAY:  Thank you.  I did have questions


 16   yesterday, however, I would like to defer that


 17   comment and use it for an additional comment on the


 18   questions today.


 19             Would that be all right, Dr. Gross?


 20             DR. GROSS:  That's fine.


 21             Dr. Bigby.


 22             DR. BIGBY:  I have a couple of questions. 




  1   The first is to Hoffmann-La Roche.


  2             The question was asked I think yesterday


  3   about annual sales, and you found the number, but


  4   didn't say what it was, the number of 450 million


  5   came out today.


  6             What are the annual sales of Accutane?


  7             MS. REILLY:  What year, sir?


  8             DR. BIGBY:  Last year.


  9             MS. REILLY:  In 2003, our U.S. net sales


 10   were $144 million.


 11             DR. BIGBY:  Do you have any idea sort of


 12   what you have spent in terms of legal fees and


 13   lawsuits around the issue of teratogenicity?


 14             MS. REILLY:  No, sir, I do not.


 15             DR. BIGBY:  Is that an obtainable figure?


 16             MS. REILLY:  I would defer to our counsel.


 17             DR. GROSS:  Dr. Cohen, Michael, did you


 18   have a question from yesterday?


 19             DR. COHEN:  No, I will hold it until a


 20   discussion later.


 21             DR. GROSS:  Dr. Katz.


 22             DR. KATZ:  I wanted to ask Dr. Huber, on




  1   the people who enroll, what percentage of those,


  2   how soon do they get a notice that they have


  3   enrolled do they get a questionnaire, and what


  4   percentage of the people that enroll fill out those


  5   questionnaires, the two or three questionnaires


  6   they get?


  7             On the enrollment form, it says you will


  8   get two or three questionnaires through the


  9   treatment.  So, what percentage of the people that


 10   enroll get the questionnaires and answer them, and


 11   how quickly do they get them?


 12             DR. HUBER:  I will refer to Dr. Blesch who


 13   will answer your question.


 14             DR. BLESCH:  The Accutane survey is


 15   divided into two sections.  Eighty percent of the


 16   patients who enroll, 80 percent get questionnaires


 17   immediately upon enrollment.  The other 20 percent


 18   get a questionnaire approximately six months after


 19   they enroll, and then a final questionnaire six


 20   months after they finish treatment.


 21             All Accutane-surveyed patients are


 22   followed, continue to receive questionnaires until




  1   six months after their treatment has stopped.


  2             DR. KATZ:  What percentage of patients who


  3   you send that questionnaire to fill out the


  4   questionnaire?


  5             DR. BLESCH:  I don't have that exact


  6   number, but I believe it is about 80 percent.


  7             DR. KATZ:  Thank you.


  8             DR. GROSS:  Then, the last question from


  9   yesterday was from Mr. Levin.


 10             MR. LEVIN:  I will defer questions until


 11   later, but I do have one.


 12             I am just curious what the sales for


 13   Accutane for Roche were in 2002, prior to generic


 14   entry into the market.


 15             MS. REILLY:  In 2002, that year to date


 16   figure was 380 million.


 17             DR. GROSS:  Thank you.


 18             Before proceeding, I would like to read a


 19   comment that Dr. Jackie Gardner suggested I read,


 20   and I concur.


 21             We would like to publicly thank the people


 22   who came forward during the open public hearing




  1   with their personal stories and acknowledge how


  2   difficult that was.


  3             Thank you.


  4             Allen Mitchell.


  5             Responses from Slone Epidemiology Center


  6             DR. MITCHELL:  Thank you.  I think we have


  7   things working.


  8             [Slide.]


  9             If I can follow up on Dr. Katz's question


 10   from our survey, which is a similar design, the


 11   response rate to the during and after treatment


 12   questionnaires, the questionnaires that are sent to


 13   women at the onset of therapy and the midst of


 14   therapy is about 97 percent in our survey.  It is


 15   extremely high.  That is both with mail and


 16   telephone responses included.


 17             I wanted to speak about the limitations of


 18   the voluntary isotretinoin survey and perhaps some


 19   of the non-limitations because it seems to us that


 20   this is a critical issue in interpreting the data.


 21             [Slide.]


 22             Quickly, to review some of the questions,




  1   and these are questions that we have posed as


  2   potential limitations to this or any other survey


  3   since 1988 when we first designed it, what is


  4   success.  The committee is struggling with this.


  5             Of course, there were no pre- and


  6   post-comparisons possible, and here we are talking


  7   about the data up until the onset of S.M.A.R.T.


  8   These are the 14 years of data preceding S.M.A.R.T.


  9             What are the critical events that one


 10   judges success by, is it pregnancies, live born


 11   infants, infants with birth defects?  Is the


 12   critical outcome a rate of pregnancy, or is it an


 13   absolute number?


 14             One could imagine different scenarios with


 15   very different responses to that final question.


 16             [Slide.]


 17             Two other limitations that we have


 18   identified is that survey participation may provide


 19   an unintended intervention and also that recall of


 20   risk management may be biased among women who


 21   become pregnant.


 22             We were well aware of those two concerns




  1   going into it, and to deal with those concerns, the


  2   design, which is admittedly complicated, includes


  3   two arms, the AT arm, which is the after therapy


  4   only interview, if you will, and the DAT arm, which


  5   is the during and after therapy interview with a


  6   number of contacts with patients throughout the


  7   course of therapy.


  8             Those have varying degrees of patient


  9   contact, and information in those arms is collected


 10   either prospectively or retrospectively with


 11   respect to some of these behaviors. So, we think


 12   that we have been able to deal with those issues.


 13             [Slide.]


 14             There is another point about whether the


 15   reporting of pregnancies among survey participants


 16   is credible.  We are, of course, concerned about


 17   that.  If women are avoiding pregnancy during


 18   treatment, one would expect a rebound in pregnancy


 19   rates following treatment.  That seemed to us to be


 20   an indirect measure of whether reports may be


 21   accurate.


 22             [Slide.]




  1             We have lifted this figure from our 1995


  2   New England Journal paper, which summarized the


  3   survey experience to date at that point, to


  4   describe the pregnancy rates and outcomes during


  5   and after isotretinoin therapy.


  6             I think it becomes fairly clear that


  7   during treatment now, which is lumped together, the


  8   pregnancy rate is somewhere approximately 9 per


  9   1,000 person years.  We are using person years


 10   here.


 11             And as you can also see, elective


 12   termination represents about 70 percent roughly of


 13   those pregnancies.  In the one month after


 14   treatment, where the risk of malformation is


 15   considerably reduced, and in our data doesn't show


 16   much increase at all, but in that one month of


 17   therapy, you begin to see the pregnancy rates


 18   increase, and in the two months, three months, and


 19   four months after therapy--and we only go out to


 20   four months--what you find is a considerable


 21   rebound in the pregnancy rates, which is what one


 22   would expect if women are trying to avoid pregnancy




  1   during the course of therapy.


  2             But it is also interesting to point out


  3   that by the time you get to the fourth month, the


  4   proportion of pregnancies that result in elective


  5   termination approximates what we see for the U.S.


  6   population.


  7             So, this provides some indirect assurance


  8   that reporting is not terribly inaccurate.


  9             [Slide.]


 10             But what I want to focus on is the issue


 11   of whether voluntary enrollment may compromise


 12   representativeness, and, of course, one always


 13   worries about that.


 14             The response to that concern is to


 15   maximize enrollment.  We all know that, that is


 16   basic epidemiology.


 17             [Slide.]


 18             The second approach is to compare the


 19   survey population to the target population, and to


 20   do that, using demographic characteristics, on the


 21   one hand, and ideally, the risk factors in the two


 22   groups, on the other hand.




  1             [Slide.]


  2             I think we should make the point and


  3   understand clearly that enrolling 60 percent or


  4   more of the target population does not, in itself,


  5   assure that that population is representative.


  6             Conversely, enrolling less than 60 percent


  7   of the target population does not assure that the


  8   sample is unrepresentative, and I think that there


  9   has been a fair amount of assumption that because


 10   the enrollment rates are below 60 percent,


 11   therefore, the sample population is


 12   unrepresentative.


 13             [Slide.]


 14             It is very difficult to make direct


 15   comparisons in trying to respond to the question


 16   about is the survey population a biased sample, and


 17   we could spend days, as we have, we have spent


 18   months over the past 14 years struggling with how


 19   to evaluate this, the best we can do, and this is


 20   based, not only in our own considerations, but


 21   suggestions from FDA and from advisory committees


 22   and our own advisory committee that we have, is to




  1   do some indirect comparisons.


  2             These are necessarily limited and


  3   imperfect, and I wish to make that very clear.


  4             [Slide.]


  5             Two parts of data that I want to present


  6   were alluded to in the FDA review document.  One


  7   was a comparison we did using United Health Care


  8   data, which is a large plan that had I think 14


  9   different prescription plans under one umbrella.


 10             What we were able to do through a


 11   complicated process was to compare women who had


 12   received a prescription for Accutane through that


 13   plan, and look at those who enrolled in our survey


 14   and those who didn't enroll.


 15             [Slide.]


 16             There were very few variables that we


 17   could identify for comparison, but one of them was


 18   age, and what we found was that the age among the


 19   Accutane participants was somewhat younger by about


 20   two years than it was in the population that didn't


 21   enroll in the survey.  This was actually compatible


 22   with some anecdotal reports which we frankly didn't




  1   believe from one of our colleagues at Roche at the


  2   time.


  3             This was back in the beginning of the


  4   survey, in the '90s, who had said that in his


  5   conversations with providers, he was finding a


  6   number of them reporting to him that they tried to


  7   have women participate in the survey if they felt


  8   that woman was at increased risk, that they felt


  9   that the survey would provide some additional


 10   intervention or a component that would help


 11   encourage compliance.  It might do that indirectly,


 12   but it certainly isn't the purpose of the survey.


 13             [Slide.]


 14             So, this was compatible in that one would


 15   expect that women who are older would be at less


 16   risk for pregnancy, and, indeed, when you stratify


 17   these findings according to age, and now we are


 18   looking at this time the participation rate in the


 19   survey was estimated to be about 40 percent, what


 20   we found was that that 40 percent rate was fairly


 21   consistent across the three youngest age strata.


 22   Where the participation rates were lowest were in




  1   the oldest group of women, and, in fact, among the


  2   women 50 to 59 years old, only 14 percent


  3   participated, which would be compatible with the


  4   either subselection or doctor's selection of women


  5   at low risk saying don't both participating in the


  6   survey, you are not at risk for pregnancy.


  7             [Slide.]


  8             The other data alluded to in the FDA


  9   review, and that we have cited, and these are again


 10   previously presented data, is a consumer survey


 11   that was conducted by Roche identifying a number of


 12   women who had been prescribed Accutane, and asking


 13   them whether they enrolled in the survey or not,


 14   and interestingly enough, the age difference was


 15   again about two years, that the enrolled women


 16   tended to be about two years younger than those who


 17   didn't enroll in the survey.


 18             Median education wasn't terribly


 19   different, the source of their prescription wasn't


 20   terribly different, indeed, the women in the


 21   survey, 10 percent more than the women who weren't


 22   in the survey reported being sexually active, and




  1   not surprisingly, along with that, higher rates of


  2   contraception use.


  3             Now, one of the things cited in the FDA


  4   report was that, well, gee whiz, if you look at


  5   this population, use of the birth control pill was


  6   reported by 40 percent of the women enrolled in the


  7   Slone survey, but only 16 percent among the women


  8   who did not enroll.


  9             On the face of it, there is no question


 10   there is a difference there.  It is not accounted


 11   for by condom use or other barrier methods, but it


 12   is striking that the surgical sterilization rates


 13   were compensatorily different among the enrolled


 14   and unenrolled women, and if you add up the highly


 15   effective contraceptive methods as a percent, what


 16   you find is that they are virtually identical in


 17   terms of highly effective contraception use among


 18   the women in the survey and the women who chose not


 19   to participate in the survey.


 20             [Slide.]


 21             But again, even within this analysis,


 22   there is about three times as many women--two and a




  1   half times as many women on the pill in the survey,


  2   suggesting that again, if anything, the survey


  3   population may be at higher risk for pregnancy


  4   since surgical sterilization is a highly effective


  5   and more effective method than the pill.


  6             [Slide.]


  7             Finally, bringing us to the most recent


  8   data, we compared the survey data, as did FDA,


  9   versus isotretinoin users according to age--and


 10   this is in the one year before S.M.A.R.T., and we


 11   used the FDA data presented for advanced PCS as


 12   representing the base population, the target


 13   population, and we have provided the survey age


 14   distributions on the left.


 15             I think most observers would say that this


 16   is actually, until you get to the older age groups


 17   for sure, pretty representative, and while there is


 18   a decrease in the proportion of participants who


 19   are 15 years of age or under, that decrease is


 20   relatively small, where again we see a deficit of


 21   participation that is fairly consistent is again in


 22   the older women who are less at risk for pregnancy




  1   by and large.


  2             [Slide.]


  3             And, indeed, when you compare the


  4   pregnancies-- this is again in the year


  5   pre-S.M.A.R.T.--reported by our survey, and the


  6   total reported by FDA including the spontaneous


  7   reports, we see striking similarities in the


  8   distributions.


  9             [Slide.]


 10             So, in answer to the question is the


 11   survey population a biased sample, to us, the


 12   evidence does not suggest that the survey


 13   population is biased towards women at low risk of


 14   pregnancy.


 15             Indeed, the indirect evidence, and I


 16   stress it is indirect, suggests that, if anything,


 17   the survey disproportionately includes women at


 18   relatively high risk of pregnancy, and this pattern


 19   has been observed consistently at various points in


 20   the survey's history.


 21             [Slide.]


 22             That brings us back to this figure that we




  1   showed in our presentation yesterday, where we


  2   observed, again in the pre-S.M.A.R.T. era, 14 years


  3   experience, a decrease in the pregnancy rate from


  4   roughly 4-fold to a little bit over 1-fold, a


  5   rather striking and consistent decrease over time.


  6             [Slide.]


  7             Well, if the survey has any value, we need


  8   to consider what this means, and we think this


  9   trend is unlikely to be explained by enrollment


 10   biases, which would have to have changed over the


 11   14-year period.


 12             We have done all sorts of models as to how


 13   one might account for this trend through biases,


 14   and it is very difficult to come up with one.


 15             [Slide.]


 16             Rather, we think it may reflect continuing


 17   improvements in the implementation of the risk


 18   management program via its incorporation into


 19   routine practice and I might add residency training


 20   programs and the dermatology programs, so that our


 21   summary view is that without respect to S.M.A.R.T.


 22   specifically, we do think that the 14 years




  1   experience preceding S.M.A.R.T. does reflect


  2   incorporation of risk management elements to the


  3   point where they have actually appeared to result


  4   in a fairly substantial decrease in the pregnancy


  5   rates.


  6             I will be happy to take questions, and


  7   thank you for your consideration.


  8             DR. GROSS:  Are there any questions?  Yes.


  9             DR. KIBBE:  My question deals with the


 10   characteristics of the individuals in the two


 11   groups, those that undergo therapy and don't get


 12   pregnant, and those that undergo therapy and end up


 13   having either been pregnant when they start or end


 14   up getting pregnant during the time frame.


 15             I guess we could say that 99 percent of


 16   the women who enroll in therapy are successful in


 17   not having a pregnancy occur during that, and 1 or


 18   2 percent do, but what characterizes the


 19   differences between those two groups, because if we


 20   want to improve what we do, we don't have to change


 21   it for the 98 percent who go through the process


 22   effectively, but if we could find some handle that




  1   would help our clinicians identify individuals that


  2   needed an additional activity or procedure, it


  3   would help us a lot.


  4             DR. MITCHELL:  Actually, it is obviously a


  5   relevant question.  First of all, from these data


  6   in the most recent years preceding S.M.A.R.T., the


  7   pregnancy rate would be 99.9 percent, it's roughly


  8   1 in 1,000.  I don't mean to quibble, but it is


  9   useful to keep that in mind.


 10             What we would call the analysis you are


 11   describing is a risk factor analysis.  What one of


 12   the public speakers called it was a failure mode


 13   and effects analysis.


 14             We are in the midst at the present time


 15   frankly in doing a detailed analysis of exactly


 16   that consideration.  We have certainly identified


 17   crudely that there are no gross characteristics


 18   that appear to predict an increased risk of


 19   pregnancy.


 20             As one might expect, we have seen the


 21   chosen method of birth control is directly related


 22   to the risk of pregnancy.  We have seen that the




  1   typically effective methods are effective and the


  2   typically ineffective methods are ineffective.


  3             We have also seen and published in this


  4   paper in 1995, our experience which indicates that


  5   for any given mode of contraception, we provide


  6   data to suggest considerably higher efficacy than


  7   the generally published data on efficacy, and that


  8   is because we think the motivation of this


  9   population is unusually high.


 10             What we are doing now is looking at all


 11   the elements in the Pregnancy Prevention Program,


 12   the pre-S.M.A.R.T. Pregnancy Prevention Program, to


 13   see if we can identify any elements that do exactly


 14   what you are describing, that characterize the


 15   women who become pregnant and distinguish those


 16   women from the women who did not become pregnant,


 17   so that interventions could be targeted to that


 18   population, and we are hoping to have that


 19   completed--Dr. Trussel, James Trussel is going to


 20   be joining us in that analysis as he has in the


 21   past--and we hope to have completed in the next few


 22   months.




  1             DR. KIBBE:  A second question has to do


  2   with my interest in the international experiences,


  3   if you will, with this medication.  Roche has said


  4   that they have never had a country ask them to take


  5   it off the market, but I can't imagine that there


  6   aren't countries that are interested in eliminating


  7   the risks.


  8             Do you have any access to any data that


  9   would help us understand how their interventions


 10   differ from ours and how their risk ratios might


 11   differ from ours, and how that might impact our


 12   decisionmaking?


 13             DR. MITCHELL:  The short answer is no, we


 14   don't have any data and we have certainly tried to


 15   find such data. One of the concerns that we have is


 16   that the way drugs are managed philosophically in


 17   some other countries, and particularly one


 18   scandinavian country with which I am aware, is very


 19   different culturally from the U.S.


 20             In one country, the attitude was that we


 21   do what we do and after that it is not our concern,


 22   and they don't track the outcomes of exposures, not




  1   pregnancy exposures, but even pregnancy rates.


  2             I think the U.S. is frankly, uniquely


  3   providing information that has a denominator.


  4   Other countries have not, to our knowledge, taken


  5   this concern nearly as seriously as it has been


  6   taken in the U.S., and the result is that there is


  7   very little data.


  8             DR. GROSS:  Thank you, Dr. Kibbe, for your


  9   questions.


 10             The next question comes from Dr. Honein.


 11             DR. HONEIN:  Yes.  Dr. Mitchell, you


 12   mentioned 38 to 45 percent survey enrollment based


 13   on the United Health Care survey for 1990 to 1996.


 14   Yesterday, the FDA presented data suggesting a 19


 15   percent survey enrollment for the year prior to


 16   S.M.A.R.T.


 17             Was there that much decline in enrollment


 18   in the survey over that time period, or is this a


 19   different methodology for calculating the estimated


 20   survey participation?


 21             DR. MITCHELL:  The methodologies by which


 22   you calculate participation requires that you know




  1   what the denominator is, and the denominator is the


  2   number of unique women taking the drug.


  3             The difficulty in establishing that


  4   denominator, the difficulties are considerable, and


  5   we have had a lot of debates over the years about


  6   what is an appropriate denominator.


  7             I mean if you simply divide the total


  8   number of female scripts by 3.7, as the FDA used


  9   the figure from one experience in the Seattle area,


 10   you come up with one estimate of a denominator.  If


 11   you divide that by 4 prescriptions or 2


 12   prescriptions, you get very different denominators.


 13   The Kaiser data I think were closer to what we use.


 14             But the fact is that we do suspect, based


 15   on indirect evidence, that participation rates


 16   declined over time, and it was really because of


 17   our concern that we focused a lot of attention on


 18   does the decline also reflect some differences in


 19   the way women are enrolling.


 20             What we think, although we can't prove, is


 21   that the $10 incentive, which we identified at the


 22   outset of the survey back in '89 as an incentive to




  1   get women to participate in the survey through the


  2   medication package which we came up with the idea


  3   of putting the enrollment form in the medication


  4   package to bypass the physicians who may not want


  5   women to participate or may not encourage them.


  6             So, we said, you know, make it like a


  7   toaster rebate coupon and encourage women who might


  8   be noncompliant to participate.  But that was a $10


  9   incentive back in 1989, and one of the reasons for


 10   increasing the incentive in the most recent efforts


 11   was to adjust, if you will, for inflation that $10


 12   incentive.  So, we do think that there has been a


 13   decline.


 14             DR. GROSS:  The next question is from Dr.


 15   Wilkerson.


 16             DR. WILKERSON:  Considering best practices


 17   once again, considering the women that we have, the


 18   ages, the methods of birth control that they have


 19   employed and reasonable rates of success of those


 20   programs, what would be your calculated rate of


 21   pregnancies per 1,000 cases if everybody did


 22   exactly what they were supposed to do and they used




  1   the methods which are they using, what would this


  2   rate actually look like?  Instead of being 1 per


  3   1,000 courses of therapy, how much would it go down


  4   to?


  5             DR. MITCHELL:  Can I turn your question a


  6   little bit?


  7             DR. WILKERSON:  It depends.


  8             DR. MITCHELL:  I can't give you the


  9   answer.  Okay, I can't give you the answer, but I


 10   want to understand the question, so we could give


 11   you the answer.


 12             DR. WILKERSON:  In other words, if you


 13   take the current women and their methods of birth


 14   control that they are currently using, use


 15   optimally as real, everyday life people use them,


 16   what would be the predicted rate of pregnancy per


 17   1,000 courses or however you want to express this.


 18   We know that methods fail, we know that.


 19             That zero is not obtainable in this


 20   process short of females not taking this drug right


 21   now, but I mean best practices in normal settings,


 22   what would be the predicted rate of pregnancy in




  1   this setting.


  2             DR. MITCHELL:  I think I can parse that


  3   question, to use an old term.  One question is in


  4   efficacy in the normal use of the method, and, in


  5   fact, what our data suggests is that efficacy is


  6   better than normal data would suggest.  We can


  7   spend a lot of time on defining on how best


  8   efficacy was defined some years ago.


  9             In the population we have observed, what


 10   we see is roughly 1, 1.2 per 1,000.  If all women


 11   were on the pill, I could actually get you some of


 12   those estimates, it's in the paper, but I think the


 13   real question is what is the efficacy if women are


 14   on two methods of contraception, which is what is


 15   specified in the risk management program.


 16             The difficulty in assessing that is trying


 17   to find out whether women who report two methods


 18   were reporting two simultaneous methods.  Those


 19   kinds of questions become extremely, not only


 20   invasive, but they become extremely difficult to


 21   ask, because you essentially have to understand if


 22   a woman is on the pill, did she take a pill every




  1   day, if she was using the pill and the condom, did


  2   she use the condom with every act of sexual


  3   intercourse with the male partner.


  4             One of the concerns is that women may be


  5   interpreting the two methods, may be using two


  6   methods, but forgetting the simultaneous.  It is


  7   conceivable, this is sort of the law of unintended


  8   consequences that Dr. Trontell mentioned yesterday.


  9   A concern we have, although we don't have data to


 10   support it, is there going to be a fraction of


 11   women who say, okay, I have got to use two methods,


 12   I will use the pill a couple days a month and I


 13   will use the condom when I think of it.


 14             I don't mean to dodge your question.  We


 15   can give you contraceptive efficacy rates for any


 16   single method that was reported, and it's in the


 17   paper, in the New England Journal paper from '95,


 18   but we can't answer the question any more directly


 19   than that.


 20             DR. GROSS:  Dr. Kweder, do you want to


 21   comment on that?


 22             DR. KWEDER:  Yes, basically, it is similar




  1   to what Allen had to say.  We have some slides that


  2   display contraceptive method effectiveness rates as


  3   generally understood, but there really are not data


  4   that help us with the two methods simultaneously


  5   used, and Allen's point is exactly what we have


  6   struggled with, as well, does it mean, you know,


  7   how many women actually interpret use of two


  8   methods as simultaneous all the time.  That, we


  9   don't know.


 10             DR. GROSS:  The next question is from


 11   Sarah Sellers.


 12             DR. SELLERS:  I am wondering if you have a


 13   regional distribution of the study participants.


 14             DR. MITCHELL:  We do, and it is compatible


 15   with the sales.  I could get the slide out, I would


 16   be happy to provide you.  It will take me a couple


 17   minutes to find it, but it is similar.


 18             DR. SELLERS:  Just one more follow-up, and


 19   we may have addressed this yesterday, but has the


 20   survey been validated at all with any medical


 21   records or exam data?


 22             DR. MITCHELL:  Specifically, how would




  1   you--


  2             DR. SELLERS:  To confirm in particular any


  3   way to validate voluntary reporting on pregnancies.


  4   Primarily, that would be the only thing that we


  5   could look at.


  6             DR. MITCHELL:  I think the concern is


  7   false negatives, in other words, women who fail to


  8   report pregnancies, and we have not done that.


  9   That raises some privacy issues that are a little


 10   tricky to get around.


 11             Pregnancies that are reported are followed


 12   up, and any pregnancy that is identified with any


 13   suggestions of malformations, the records are


 14   obtained if the woman will allow us to.


 15             DR. TRONTELL:  I would like to try and


 16   address Dr. Sellers' question.  I just wanted to


 17   point one challenge in assessing pregnancy.  Many


 18   health plans do not cover termination of pregnancy,


 19   so individuals who self-diagnose pregnancy and


 20   elect to terminate outside their usual medical care


 21   system will never be captured or ascertained.


 22             DR. MITCHELL:  Which is one of the reasons




  1   that we rely on voluntary reporting from


  2   participants.


  3             DR. GROSS:  Thank you, Dr. Trontell.


  4             Dr. Strom.


  5             DR. STROM:  I wanted to follow up on Dr.


  6   Kibbe's question with a comment and then a question


  7   to the company in follow-up.  You were asking about


  8   the international experience in particular.


  9             Anecdotally, my colleagues in other


 10   countries tell me that Accutane is seen as a


 11   uniquely American problem, but that is not because


 12   we are the only ones looking, but because we are


 13   the only ones using it so widely, that other


 14   countries don't use it anywhere nearly as widely as


 15   we use it, so use is much less.


 16             What I wonder about from the company is


 17   whether you could give us sales data by population


 18   for some selected countries, so, for example, to


 19   try to nail down whether that anecdotal experience


 20   is correct, in other words, what is the rate of use


 21   in the U.S. population, how does that compare to


 22   perhaps the English population or the Swedish




  1   population or otherwise.


  2             DR. HUBER:  We do not have the data on


  3   sales broken down by country here.  That would take


  4   us a little time to compile and we don't keep those


  5   here in the U.S., so it would take us some time.


  6             DR. STROM:  But I think that is why you


  7   are not seeing the sensitivity from other


  8   countries.


  9             DR. KIBBE:  I think there is an underlying


 10   social issue, too, and that general acceptability


 11   of birth control methods in Sweden and some other


 12   countries in Europe are going to be quite a bit


 13   different than the United States.  I am trying to


 14   figure out what factors are out of the direct


 15   control of the system that we have are impacting


 16   it, that's all.


 17             DR. GROSS:  Thank you, Dr. Kibbe.


 18             Dr. Whitmore has the last question.


 19             DR. WHITMORE:  Can you clarify, you had a


 20   graph up there talking about the number of


 21   pregnancies during Accutane and then for the


 22   subsequent months after therapy, and I thought it




  1   was 10 per 1,000 person years, is that correct?


  2             DR. MITCHELL:  It was about 9 during


  3   therapy, 9 per 1,000 during the course of therapy


  4   at that time.


  5             DR. WHITMORE:  So, just to clarify, that


  6   would be 1 in 100 essentially as opposed to 1 in


  7   1,000.


  8             DR. MITCHELL:  Well, yes, but I am sorry,


  9   I accept your correction.  I am confusing


 10   different--our usual rate estimators per course,


 11   per 1,000 courses, correct.


 12             DR. WHITMORE:  And that was person years,


 13   and therapy can range anywhere from 24 to 48 weeks


 14   depending how dosing is done essentially.  I think


 15   that is a point that need to be re-emphasized as


 16   opposed to if birth control pills and a second form


 17   of contraception were used effectively, maybe more


 18   like 1 in 1,000 rate of pregnancy.  I mean those


 19   numbers are not correct, but I think just to give


 20   us a ballpark idea.


 21             One more question about your survey.


 22   There is incentive to fill out the survey.  For




  1   teenagers, their parents probably make them fill it


  2   out.  For adults, there is a monetary reward for


  3   doing it, and also there are probably some adults


  4   who think oh, if I don't fill this out, something


  5   bad is going to happen, or think that it is part of


  6   all the program or something they need to do


  7   particularly with all the PR about Accutane and


  8   everything else.


  9             So, I would say that a lot of people would


 10   probably fill out the survey, fill it out because


 11   of incentive reasons of some sort, and then I would


 12   ask you, these women are signing a form that says I


 13   will be abstinent or I will use two forms of


 14   contraception throughout therapy.


 15             What makes you think that a non-anonymous


 16   survey is going to capture any information about


 17   people actually not doing these things, they have


 18   signed on a document saying they are going to do?


 19             Also, reports about abortions, what makes


 20   you think that these women who have signed this


 21   document, if they do get an abortion, if they are


 22   not going to tell their doctor, what makes you




  1   think they are going to report it to you?


  2             DR. MITCHELL:  Probably the fact that we


  3   are dealing with human beings would be a large part


  4   of that answer.  We were similarly skeptical going


  5   in, and remain somewhat skeptical, but less so.


  6             What is very interesting is how often we


  7   find women telling us things they have not told


  8   their doctor.  In fact, we did--and, Dr. Katz, you


  9   had asked the question yesterday and I couldn't


 10   remember what it was when we bumped into each


 11   other, but it comes to mind now--and that question


 12   is really how accurately do the data reflect what


 13   the physician is doing.


 14             We identified back in I think it was the


 15   early '90s, a group of women who reported to us


 16   that they had not had pregnancy testing prior to


 17   the prescription of Accutane. From their enrollment


 18   forms, we were able to identify the physicians who


 19   were in that loop.


 20             We called those physicians' offices to ask


 21   sort of an anonymous survey question about we are


 22   just calling from Boston University, we are




  1   querying physicians about their practices with


  2   respect to Accutane, and typically, very often the


  3   person responding would be an office manager or the


  4   office nurse rather than the physician.


  5             We asked whether they routinely did, in


  6   fact, do pregnancy testing as one of a number of


  7   questions, and a surprising number--not a


  8   surprising number--a large number of physicians


  9   indicated that they routinely do pregnancy--I mean


 10   the office nurse said oh, we always do pregnancy


 11   testing, but a number of offices said to us we


 12   don't.


 13             Now, would you expect a physician's office


 14   to tell a survey that they don't do pregnancy


 15   testing?  The converse is also the case, that when


 16   we identify a woman who reports that she is


 17   sexually active and does not use contraception, we


 18   consider that woman at such great risk for


 19   pregnancy that the design of the survey calls for


 20   us to call that woman.


 21             We call it reading the riot act.  We call


 22   that woman and say to her that the behaviors you




  1   reported to us put you at high risk for pregnancy,


  2   and we urge you to immediately call your physician,


  3   stop taking the drug. Incidentally, would you also


  4   be willing to allow us to talk to your doctor.


  5             When the woman gives us permission to call


  6   her doctor, you would assume that the doctor would


  7   give you some response that would be compatible


  8   with what the woman is reporting, and, in fact, I


  9   can't give you the quantitative response, but there


 10   were a disturbing number of times where the


 11   physician would get on the phone with us, once the


 12   woman gave us permission, and would go to the


 13   medical record and read us from the medical record


 14   that the woman said she was actively--so here was a


 15   woman inviting us to find out, and what she was


 16   doing was telling the survey--this is a long answer


 17   to your question, but I think it deserves that--she


 18   was telling us something that she wouldn't tell the


 19   doctor.


 20             So, the survey is actually in a position


 21   to find out things that a woman wouldn't tell the


 22   doctor.




  1             DR. WHITMORE:  I had no idea that you


  2   called patients.  I think that is absolutely


  3   fantastic.


  4             DR. GROSS:  Dr. Mitchell, thank you very


  5   much for your presentation.


  6             DR. MITCHELL:  Thank you.


  7             DR. GROSS:  Dr. Katz.


  8             DR. KATZ:  I want to clarify.  You call


  9   the doctor's office, and you said some said they


 10   didn't do any pregnancy testing, but you talked to


 11   the office manager and most doctors' offices--I


 12   happen to draw blood in the office, but most don't


 13   draw blood in the office--so, the office manager


 14   says no, we don't do pregnancy testing.  They send


 15   them to the laboratory, but they don't do it.


 16             DR. MITCHELL:  First of all, let me


 17   explain this was a very biased sample.  This was a


 18   sample of women, a small sample of women who had


 19   told us they had not gone through a compliant


 20   process, so we are already dealing with a subset


 21   that is hopefully small.


 22             When we called--Dr. Katz, I can't remember




  1   the specific questions, but we can get them for


  2   you--we asked a series of questions of someone who


  3   would be familiar with the offices practices, it


  4   often was the nurse, but it represents only a very


  5   small fraction, and we did incidentally try to


  6   reach those doctors subsequently and get them


  7   informed of what the appropriate practices were.  I


  8   don't mean to suggest that was a widespread


  9   phenomena.


 10             DR. GROSS:  Thank you again, Dr. Mitchell.


 11             We will now move on to Dr. Trontell, who


 12   had some information to present to us that will be


 13   helpful in our consideration of the questions.


 14             DR. TRONTELL:  There were some questions


 15   yesterday about the specifics of the clozapine


 16   program and also of the S.T.E.P.S. program.  I am


 17   thankful to the representative from Celgene who


 18   came and provided information, which I will repeat,


 19   and I will also invite that individual to come to


 20   the microphone to supplement it.


 21             But relative to the registration of


 22   patients in the S.T.E.P.S. program, patients are




  1   registered by their Social Security number.  In the


  2   event that that number is not unique, a second


  3   unique number is assigned to those individuals.


  4   So, the provision of patient anonymity in


  5   S.T.E.P.S. it isn't truthfully there.  If you have


  6   their Social Security number, that can be readily


  7   linked to an individual's name.


  8             The other question that was asked was


  9   about clozapine and the mechanism that led to its


 10   institution.  In fact, information provided to me


 11   by one of the members of the Division of


 12   Neuropharmacologic Drug Products told me, in fact,


 13   that some of the experience that I cited with


 14   agranulocytosis related to post-marketing


 15   experience abroad where the product was marketed


 16   with recommended monitoring for white counts and


 17   prevention for agranulocytosis.


 18             That rate was on the order of 1 to 2


 19   percent, and that had been described in the era of


 20   the clozapine national registry in practice with


 21   mandatory monitoring of white count to be less than


 22   1 percent, specifically 0.38 percent.




  1             If there are additional questions, I would


  2   invite the individuals who know each of those


  3   registries to come to the microphone to address


  4   them.


  5             DR. GROSS:  Hearing none, we will move on


  6   now to Dr. Paul Seligman, Director of the Office of


  7   Pharmacoepidemiology and Statistical Science at the


  8   FDA, who will introduce the questions to us.


  9                    Introduction of Questions


 10             DR. SELIGMAN:  Good morning.  I have been


 11   asked to present the issues and questions for


 12   consideration by the committee this morning and


 13   this afternoon.


 14             Please note that these questions are part


 15   of the agenda that was distributed for the meeting


 16   and can be found after the agenda.


 17             Before I begin, I just want to take a


 18   brief moment on behalf of myself and my colleagues


 19   at the FDA to also thank the members of the public


 20   this morning who were here to share their testimony


 21   and their personal experiences.


 22             The issues and questions fall into the




  1   following sort of broad categories.  We are asking


  2   the committee today to evaluate the performance of


  3   the current program and the data that have been


  4   presented both yesterday and today, to consider


  5   options for improvement of this current risk


  6   management program, to consider how best to monitor


  7   any recommended changes, and to consider benchmarks


  8   for success as noted yesterday morning.


  9             I think it was the first question out of


 10   the gate by Dr. Bigby, as well as others this


 11   morning, who have focused on how best to determine


 12   whether subsequent changes or any program that


 13   comes out of these deliberations should be


 14   determined to be successful.


 15             [Slide.]


 16             The first issue that we ask the committee


 17   to consider this morning is that based on the


 18   reports and patient surveys, there does not appear


 19   to be a meaningful decrease in the number of


 20   pregnancies reported in women taking a course of


 21   isotretinoin since implementation of the current


 22   risk management program.




  1             We would ask you then to discuss the


  2   measurement and implementation factors that may


  3   have contributed to these findings.


  4             [Slide.]


  5             The second issue is based on prescription


  6   audits and patient surveys, use of the


  7   qualification sticker is high.  Patient surveys


  8   suggest an inconsistent link between monthly


  9   pregnancy testing and use of the stickers.


 10   Reported pregnancies and patient surveys indicate


 11   incomplete or inadequate birth control measures


 12   among females.


 13             Again, we ask you to please comment on


 14   measurement and implementation aspects of the


 15   current program that may have contributed to these


 16   findings.


 17             [Slide.]


 18             Question 3.  FDA's goals for the


 19   Isotretinoin Pregnancy Prevention Risk Management


 20   Program are that:  no woman who is already pregnant


 21   be prescribed and dispensed isotretinoin, and that


 22   no pregnancies should occur while on this therapy,




  1   and that effective pregnancy prevention occur


  2   throughout the course of treatment.


  3             [Slide.]


  4             In recommending any changes to the risk


  5   management program, we ask the committee to


  6   consider the potential tools and strategies in


  7   light of the likelihood of effectiveness in further


  8   reducing fetal exposure, the practical impact on


  9   health care providers who prescribe and dispense


 10   the product, and the impact on patients who must


 11   navigate any such program.


 12             [Slide.]


 13             Given these factors, we are asking the


 14   committee to consider the following options:


 15             (a) Continue the current risk management


 16   program without additional tools, and if this is


 17   the recommendation, if so, what approaches do you


 18   recommend to improve adherence with the program by


 19   patients, physicians, pharmacists and others, such


 20   as health educators?


 21             [Slide.]


 22             (b) Or to consider modification of the




  1   current program with additional risk management


  2   tools to reduce fetal exposure.


  3             We list a number of them here, such as


  4   programs to enhance education and interaction with


  5   patients to identify and minimize high risk


  6   behaviors; to tighten the linkage of prescriptions


  7   dispensed by pharmacists with required check of


  8   pregnancy test results; the registration of


  9   patients, pharmacists, physicians and/or others


 10   such as health educators; limiting the access or


 11   distribution of the drug, or other tools.  In


 12   recommending the other tools, we would ask you to


 13   describe them.


 14             I should note that in the course of our


 15   discussions and deliberations, other tools have


 16   also been mentioned, but not listed here.


 17             [Slide.]


 18             Question 4.  In order to adequately


 19   monitor the risk management program, we ask the


 20   following:


 21             (a) Would it improve monitoring of risk


 22   management program performance to register




  1   patients, pharmacists, physicians, and other


  2   relevant participants?


  3             (b) If participants in such a risk


  4   management program are registered, how can this be


  5   more effectively done in a multi-source


  6   environment, so that individuals are not registered


  7   multiple times or double-counted?


  8             [Slide.]


  9             Finally, we are asking the committee to


 10   identify critical benchmarks for determining the


 11   success or failure of the  pregnancy risk


 12   management program, and suggest, for example, such


 13   as reducing to zero the number of women who are


 14   pregnant at the initiation of isotretinoin


 15   treatment, and others.


 16             I am happy to answer any questions about


 17   these issues and provide any clarification as need


 18   be.


 19             DR. GROSS:  Thank you, Dr. Seligman.


 20                       Committee Discussion


 21             As Chair, I am going to make a suggestion


 22   that we consider Question 3 last because that is




  1   the recommendation of the committees on what the


  2   program should be in the future.


  3             Question 4, I suggest be considered before


  4   3 because it talks about whether or not registers


  5   would be helpful, and that may be part of the


  6   ultimate plan that we come up with in Question 3,


  7   and assessing success and failure is something that


  8   we can also consider beforehand.


  9             Is that okay with the committee if we do


 10   it in that order, Question 1, 2, 4, 5, then 3?


 11   Does anybody have any objections to that?  Okay.


 12             Why don't we begin with Question No. 1.


 13   Based on the reports and patient surveys, there


 14   does not appear to be a meaningful decrease in the


 15   number of pregnancies reported in women taking a


 16   course of isotretinoin since implementation of the


 17   current risk management program.


 18             Data has been presented on that.  Please


 19   discuss measurement and implementation factors that


 20   may have contributed to these findings.  If I may


 21   be so bold as to say that insufficient data has


 22   been presented to answer that part of the question,




  1   but let's hear what committee members think on


  2   those issues.


  3             Dr. Gardner.


  4             DR. GARDNER:  As a non-clinician, it would


  5   help me greatly to understand what happens in the


  6   clinician's office in terms of the implementation


  7   of these processes both from the standpoint of


  8   physician and patient burden, and also the


  9   logistics we heard yesterday, a scenario of trying


 10   to get a pregnancy test, is it the result or a new


 11   request, and so on.


 12             Could the clinicians comment on how these


 13   processes are implemented in practice for example?


 14             DR. GROSS:  Any dermatologist want to--Dr.


 15   Katz.


 16             DR. KATZ:  We will walk you through it


 17   from the beginning.  First of all, the patient has


 18   been seen multiple times previously, on every other


 19   treatment we know, different antibiotics starting


 20   with the least risk of inducing and most used for


 21   decades, and then antibiotics with a high risk


 22   profile.




  1             Then, the patient is evaluated, and if it


  2   is a minor, the parent is in the office initially,


  3   a complete discussion of all side effects are done,


  4   and then the female patient, one can't portray in


  5   this meeting the doctor-patient contact and the


  6   validity of patient response, reliability of


  7   patient, we can't project that here, but the


  8   physician assesses that, as well.


  9             Then, you give the patient a choice of


 10   having a parent leave the room, so you can discuss


 11   the contraception end.  We ask them if they are


 12   using contraceptives, and it is burdensome going


 13   through this entire thing, then, of all the side


 14   effects involved.


 15             All risks are mentioned and if it is


 16   decided to go ahead with the Accutane, in female


 17   patients, baseline bloodwork is done, CBC, hepatic


 18   profile, lipids, and HCG pregnancy test, and they


 19   are told to come back at the time of the next


 20   period for another pregnancy test, or they can get


 21   that done, since they are not coming, that might be


 22   in 10 days, they wouldn't have to come back to the




  1   office, they can go to the lab and get the


  2   laboratory test. They will often fax it, and then


  3   they can come by and get a prescription with the


  4   yellow stickers.


  5             They are told to come back in two weeks


  6   and then every four weeks through the course of


  7   treatment.  Bloodwork is obtained each time, and


  8   then they are given a prescription again.  They are


  9   reminded each time about the necessity of two means


 10   of pregnancy.


 11             They are asked about the side effects, how


 12   they are feeling as far as generally, and once


 13   again you can't project everything.  You are


 14   looking at their face to see how they are doing.


 15   With all this said and done, you remind the patient


 16   each time about the necessity of two means of


 17   contraception.


 18             A lot of times people say yes, it happened


 19   to me, to bear on this question further, how can


 20   these adverse effects be reduced, it can't be to


 21   zero because a patient says that she is not


 22   sexually active, and each time she remarks a little




  1   bit, she said I told you that last time, and each


  2   time I remind her, she reminds me that, doctor, I


  3   told you I am not sexually active, and then two


  4   weeks later she calls me and says she missed her


  5   period.  This happens. So, how do you eliminate


  6   that?


  7             Now, it so happens, then, we got a


  8   pregnancy test, she wasn't pregnant, she had just


  9   missed a period.  But she was concerned because


 10   obviously, she wasn't sexually inactive.  So, these


 11   are the problems that face us, and that is why this


 12   is going to happen anyway.


 13             Does that answer your question?


 14             DR. GARDNER:  Thank you.


 15             DR. GROSS:  Dr. Crawford has a question.


 16             DR. CRAWFORD:  A follow-up either to Dr.


 17   Katz or any other member of the committee.  Other


 18   than actual pregnancy testing, what would be


 19   different with the male patient prescribed


 20   isotretinoin?


 21             DR. KATZ:  No, except that contraception


 22   isn't discussed, which might bring up some points




  1   that came up with the male patients, but, no, that


  2   is not discussed.


  3             DR. GROSS:  That is an issue we will need


  4   to consider later on, whether male contraception


  5   should be recommended.


  6             At this point, I would like to encourage


  7   the committees to specifically stick to the


  8   question.


  9             The first part of the Question 1, does


 10   anybody disagree with the statement, the statement


 11   being there does not appear to be a meaningful


 12   decrease in the number of pregnancies?  Does


 13   anybody disagree with that?  Yes.


 14             DR. BERGFELD:  I would like to speak to


 15   that.  This was a new program, the S.M.A.R.T.


 16   program for the dermatologists, and when they were


 17   asked to participate, the American Academy of


 18   Dermatology put in place very intensive teaching


 19   courses at all of their meetings to inform the


 20   dermatologists of their behaviors.


 21             We were also visited by the company in our


 22   offices in which the S.M.A.R.T. programs were




  1   introduced to us.  We then had didactic sessions to


  2   go through what our responsibilities were to be in


  3   this program, and we were requested, and it was


  4   inferred, that unless we signed up, we would not be


  5   prescribing this drug and that we would be out of


  6   order to prescribe this drug.


  7             So, in my practice at the Cleveland


  8   Clinic, we did abide by what we felt was the best


  9   thing for our patients, we became informed, we


 10   abided by the sticker qualifications, and we did


 11   somewhat what you did, Dr. Katz.  We used the forms


 12   that are given to us to go over with the patients.


 13             But what I would like to say about this is


 14   that what happened was that the compliance of the


 15   dermatologists went up with informed consent and


 16   education of the patient.


 17             I think that is reflected by the fact that


 18   you have decreased numbers of prescriptions being


 19   written overall, but a constant number of


 20   pregnancies, and I think there has just been an


 21   increased reporting that has gone on because of the


 22   educational program.




  1             I think when you open or begin a new


  2   program, this is what you would expect, and I would


  3   think that what we here do today would be to


  4   enhance this program to make it more efficient and


  5   improve it, so the reporting continues and the


  6   education continues, with the ultimate objective to


  7   reduce the pregnancies to zero if possible.


  8             DR. GROSS:  Okay.  I am still trying to


  9   answer Question No. 1.  Let me take the prerogative


 10   of the Chair and say there does not appear to be a


 11   meaningful decrease in the number of pregnancies.


 12             Would anybody disagree with that?  Dr.


 13   Whitmore.


 14             DR. WHITMORE:  The one thing that you


 15   asked was are there contributing factors.


 16             DR. GROSS:  That is the second part of the


 17   question.  Let's do the first part first.


 18   Otherwise, we are never going to get through the


 19   day.


 20             Does anybody disagree?  Dr. Ringel.


 21             DR. RINGEL:  I think the real honest


 22   answer is that we really don't know.  We don't know




  1   if Dr. Bergfeld's comment about the number being


  2   artificially high because of increased reporting is


  3   true.


  4             On the other hand, if that number really


  5   reflects the actual rate, that is problematic


  6   because the rate should have decreased, in fact,


  7   because there were decreased numbers of


  8   prescriptions written.


  9             I think the only thing that this shows is


 10   we don't have the answer to that, and we really


 11   need a registry.


 12             DR. GROSS:  So, we have one dissenter.


 13   Does anybody else dissent on the statement there


 14   does not appear to be a meaningful decrease in the


 15   number of pregnancies?  Dr. Bigby.


 16             DR. BIGBY:  The suggestion has been raised


 17   should we consider as an objective, the rate or the


 18   absolute number, so if, in fact, you could show,


 19   and you could probably do this, that the rate had


 20   actually decreased and the absolute numbers in the


 21   hundreds, is that a success. That is the point I


 22   think we should think about, so maybe rate isn't




  1   what we should be looking at.


  2             DR. GROSS:  Could I see a show of hands on


  3   the question there does not appear to be a


  4   meaningful decrease in the number of pregnancies?


  5   We are never going to get through the program.  We


  6   are going to be stuck on Question 1 until 5:00 p.m.


  7   To me, the answer seems obvious.  Yes.


  8             DR. SCHMIDT:  Yesterday, on page 70 in


  9   this Pregnancy Rate and Accutane Survey, this, I


 10   thought was meaningful that it decreased, that


 11   there was almost like a 2- to 4-fold decrease in


 12   some of the slides that were shown in the decrease


 13   in pregnancy rate.


 14             I want to add one other thing to back up


 15   Wilma.  You know, people are very, very anal about


 16   doing these different things in the offices.


 17             At least in Houston, I mean we really bend


 18   over backwards to do everything and cross out t's


 19   and dot our i's on these, and from a clinical


 20   experience, I took a straw vote at one of our major


 21   meetings, our Thursday morning conference, and


 22   since this S.M.A.R.T. program started, I could only




  1   identify in this group one pregnancy that had


  2   occurred at least in our group, which probably


  3   includes a lot of people doing a lot of Accutane.


  4             DR. STROM:  To bring it to resolution, I


  5   think the problem is an issue of terminology and


  6   people are confusing numbers and rates.  The


  7   question is there does not appear to be a


  8   meaningful decrease in the number of pregnancies


  9   reported.  I think it is very clear that is the


 10   case.  That is based on spontaneous reports, the


 11   numbers are roughly even.


 12             All of the issues everybody is raising are


 13   correct in terms of issues of reporting that maybe


 14   that the rates have gone down despite the fact that


 15   the numbers haven't, and I think those are the two


 16   things that people have confused.


 17             But the question says not a meaningful


 18   decrease in the numbers, and those numbers are


 19   based on spontaneous reports, that is clearly the


 20   case.  The numbers are roughly the same.


 21             MR. LEVIN:  I just want to add to Brian's


 22   comment that I think what people are responding to




  1   is the second part.  I mean the issue of whether we


  2   are seeing better reporting, more accurate


  3   reporting or actually that things are remaining the


  4   same is a question of measurement, and that is in


  5   the second part of the question.


  6             DR. GROSS:  So, a show of hands on the


  7   first part of the question.


  8             DR. DAY:  Excuse me.  Could I ask a


  9   clarification? I know these questions have been set


 10   for some time, but is there a way for us to ever


 11   modify it, so that we could have a second part that


 12   we could vote that the number has not decreased,


 13   but that we do not have sufficient evidence about


 14   the rate or the rate has or has not?  Can we


 15   address number and rate in this question?


 16   Otherwise, some of us will be uncomfortable in


 17   voting quickly one way or another to get it off our


 18   agenda.


 19             DR. GROSS:  Sure, there is no reason.  I


 20   think we should answer the question, then, if you


 21   want to put another statement, there is no reason


 22   we can't do that.




  1             DR. TRONTELL:  May I offer some


  2   clarification from the Agency?  We do our best to


  3   express the questions clearly, but our intent in


  4   this question was, in fact, to engage the committee


  5   is some discussion on the issue of ascertainment of


  6   pregnancy, some of which have already been raised


  7   in some of the remarks around the table.


  8             We would appreciate some discussion or


  9   closure around it, not so much an issue of debating


 10   whether or not the numbers have changed.  We can


 11   make our assessment of that, but the issue of


 12   ascertainment, as well as implementation are what


 13   we would like the committee to address.


 14             DR. GROSS:  So, ascertainment really


 15   relates to the second part of the question.


 16             A show of hands on the number of


 17   pregnancies.  Do all people think the number of


 18   pregnancies appear not to have decreased


 19   meaningfully?  A show of hands that they agree that


 20   is the case.


 21             [Show of hands.]


 22             DR. GROSS:  Those who disagree?




  1             DR. KIBBE:  Abstentions?  I think the data


  2   is inconclusive and I will not vote one way or the


  3   other when the date is unreliable.


  4             DR. GROSS:  Fine.  So, the majority agree


  5   and there is one abstention.


  6             DR. KWEDER:  Dr. Gross, if there is a


  7   vote, we would appreciate it if you could record it


  8   for the record in the instances when you do vote.


  9   Thank you.


 10             DR. GROSS:  For the record, the group


 11   agrees there does not appear to be a meaningful


 12   decrease.


 13             Do you want to go around the room, is that


 14   what you mean by record?


 15             MS. TOPPER:  For the record, we are


 16   required to go around the room individually and


 17   have each person record their vote.  If you will


 18   say your name and you agree or disagree, we will


 19   need to have that.  Thank you.


 20             DR. GROSS:   Art, do you want to start?


 21             MR. LEVIN:  Arthur Levin.  I agree.


 22             DR. SAWADA:  Kathy Sawada.  I agree.




  1             DR. VENITZ:  Jurgen Venitz.  I agree.


  2             DR. STROM:  Brian Strom.  I agree.


  3             DR. BERGFELD:  Wilma Bergfeld.  I agree


  4   with the number, but I do not agree with the rate.


  5   I believe the rate has gone down.


  6             DR. GROSS:  You believe the rate has gone


  7   up?


  8             DR. BERGFELD:  Down.


  9             DR. RAIMER:  Sharon Raimer.  I am going to


 10   abstain.  I don't think we have good enough data.


 11             DR. GROSS:  So, that is an abstention?


 12             DR. RAIMER:  Abstention.


 13             MS. KNUDSON:  Paula Knudson.  I agree.


 14             DR. BIGBY:  Michael Bigby.  I agree with


 15   the statement that there hasn't been a meaningful


 16   decrease in the number of pregnancies reported.  I


 17   do think that there is information that the actual


 18   rate has decreased.


 19             DR. HONEIN:  Peggy Honein.  I agree.


 20             DR. COHEN:  Michael Cohen.  I agree.


 21             DR. WHITMORE:  Beth Whitmore.  I agree


 22   there has not been a meaningful decrease.




  1             MS. SHAPIRO:  Robyn Shapiro.  I agree and


  2   also observe that by asking for numbers as opposed


  3   to rates, there seems to be an implied goal about


  4   what we should be looking for, whether intended or


  5   not.


  6             DR. EPPS:  Roselyn Epps.  I agree.


  7             DR. SCHMIDT:  Jimmy Schmidt.  I agree.


  8             DR. CRAWFORD:  Stephanie Crawford.  I


  9   agree there has not been a meaningful decrease in


 10   the absolute number.


 11             DR. GROSS:  Peter Gross.  I agree.


 12             DR. WILKERSON:  Michael Wilkerson.  I


 13   agree with the question.


 14             DR. RINGEL:  Eileen Ringel.  I agree also.


 15             DR. VEGA:  Amarilys Vega.  I think that we


 16   don't have sufficient data.


 17             DR. GROSS:  So, that is an abstention?


 18             DR. VEGA:  Yes, sir.


 19             DR. DAY:  Ruth Day.  I agree with the


 20   decrease in number reported and make no claims


 21   about anything else, numbers that may have


 22   occurred, as well as changes in rate.




  1             DR. KIBBE:  Arthur Kibbe.  I abstain on


  2   the basis that the data is not conclusive, nor is


  3   this an appropriate question.


  4             DR. GARDNER:  Jackie Gardner.  I agree.


  5             DR. KATZ:  Robert Katz.  I agree.


  6             DR. SELLERS:  Sarah Sellers.  I agree.


  7             DR. GROSS:  Thank you all.


  8             Now, for the more difficult part--that was


  9   easy, believe it or not--please discuss measurement


 10   and implementation factors.  This is really where


 11   the expertise of the committee could be enormously


 12   helpful.


 13             Any suggestions, comments?


 14             Robyn Shapiro.


 15             MS. SHAPIRO:  I agree with your earlier


 16   comment that there is insufficient data to weigh in


 17   on that.


 18             DR. GROSS:  Anyone else?  Art.


 19             MR. LEVIN:  I guess I am just confused by


 20   what the rate, when talking about rates, where we


 21   are.  If I look at P70 of the Roche presentation,


 22   which is sourced at Slone and tracks the number of




  1   pregnancies per 1,000 Accutane treatment courses


  2   and the number of pregnancies per 1,000 patients


  3   per year, there does seem to be a decrease, but


  4   where we get down to is around the number 3, and we


  5   have just heard from 4 to 3.  Over the period of


  6   1989 to the year 2002, and if we sort of track


  7   into, you know, sort of approximate on this graph


  8   where the first prevention program came into effect


  9   and then where S.M.A.R.T. came into effect, which


 10   is probably not on this graph actually.  You know,


 11   we see recent history.


 12             But we just heard of a rate of 1, I think,


 13   in the presentation from Slone.  So, I am just


 14   personally somewhat confused as to the different


 15   presentations of what the rate issue is, whether it


 16   is in the course of treatment or per patient year


 17   what we are discussing here.


 18             DR. GROSS:  Sarah.


 19             DR. SELLERS:  I would just like to remind


 20   everyone that we are talking about a reporting


 21   rate, we are not talking about an incidence rate,


 22   and the primary objective of the risk management




  1   program is to decrease the number of pregnancies,


  2   not to decrease the reporting rate.


  3             These are reported pregnancies and the


  4   number of reported cases are small in comparison to


  5   what we believe are the overall number of


  6   pregnancies that may be occurring and exposures


  7   during pregnancy.


  8             So, a meaningful decrease in a reporting


  9   rate, in my opinion, has very little validity in


 10   the discussion of decreasing pregnancy exposures.


 11             DR. GROSS:  Thank you.


 12             So far we have been talking about


 13   measurement on this question.  How about


 14   implementation factors, implementation factors that


 15   may have contributed to a lack of a decrease in the


 16   number of pregnancies?  Dr. Katz.


 17             DR. KATZ:  Just to take one second to


 18   reiterate an anecdote--I won't reiterate it--but to


 19   remind you we don't have part of not being able to


 20   improve on it although we have to keep trying and


 21   use every effort is the human fallibility and that


 22   was my only point in mentioning that little




  1   anecdote.  You can't completely control human


  2   behavior, nor can we unfortunately 100 percent


  3   control physician behavior and how much time


  4   somebody is spending with a patient, and so forth.


  5             So, some of it, we are not going to be


  6   able to reduce it to zero.


  7             DR. GROSS:  A point well taken.


  8             DR. KATZ:  It was also pointed out


  9   yesterday, with all the stringent requirements that


 10   one might consider adding, that still doesn't


 11   eliminate pregnancies.  It will capture the numbers


 12   better and it may be a reminder, an education


 13   reminder, but if somebody is going to tell the


 14   doctor that they are sexually inactive, you can't


 15   force them to take birth control pills.  There is a


 16   certain limit to what we can do.


 17             DR. GROSS:  Exactly.  There is going to be<