February 2, 2004





Dear Advisory Committee Members and Guests:;


Thank you for agreeing to participate in the upcoming joint meeting of the Drug Safety and Risk Management and the Dermatologic and Ophthalmic Drug Advisory Committees on February 26 and& 27, 2004.  Your discussion at the meeting is important to FDA, as it will focus on the critical public health issueinterface of minimizing isotretinoin exposure in and risk of pregnancy. Overall, tThe purpose of the meeting is to fully discuss data available for existing isotretinoin fetal exposure risk management programs, determine what elements have worked, and identify needs and regulatory options for further improvement. 


Accutane (isotretinoin) was approved in 1982 for the indication of the treatment of severe recalcitrant nodular acne. IsotretinoinIt remains the only approved entityproduct for this indication and has been the subject of numerous advisory committee meetings since approval, most of which have focused onspecifically due its teratogenicity and continuing efforts to minimize fetal exposure during therapy.


Most recently, in September 2000, the Dermatologic and Ophthalmic Drugs Advisory Committee convened to review the adequacy of of Hoffman-LaRoche, Incorporated’s Pharmaceuticals’  Pregnancy Prevention Program (PPP) for Accutane.  At that time, FDA had determined that there were an unacceptable number of reports of pregnancy occurring at the time of initiating and during Accutane treatment.  The Committee agreed and recommended that additional program improvements, including options of a patient and prescriber registry, be developed.  In October 2000, based on the Committee’s discussion, a letter to the company from Janet Woodcock, M.D., Director, Center of Drug Evaluation & Research, articulated FDA’s goals for improving Accutane’s risk management.  A copy of that letter is included in your background packet.


Over the course of the next year, a revised program, the System for Minimizing Accutane Risk of Teratogenicity (SMART), was developed by Hoffman-La  Roche, in discussion and negotiation with the FDA.  The program attempted to meet the goals outlined by the Advisory Committee and FDA, but in a manner that was manageable for a product that had been the standard of clinical practice in treating severe acne for two decades.  For example, the program did not incorporate a mandatory patient or prescriber registry, but it did add significant risk management elements designed to minimize the possibility of drug being dispensed to pregnant women.  Specifically, it improved strategies to educate prescribers and patients and, most importantly, required use of a yellow sticker on all prescriptions in order for a pharmacist to dispense the product.  The sticker was the vehicle through which the prescriber would attest to having counseled the patient, obtained written informed consent and documented a negative pregnancy test in all female patients of childbearing potential.  Further, prescriptions could not be filled for more than a 30- day supply, and no automatic refills were to be allowed.  The SMART program was approved by FDA in October 2001, along with expected performance metrics by which the effectiveness of the program in leading to meaningful reductions in fetal exposure could be assessed periodically by the Agency.  SMART was implemented in April, 2002.  At the upcoming meeting the findings from these metrics and FDA’s assessment will be presented.  This background package includes a written assessment of the metrics.  In the sponsor’s background packages for this meeting, you will receive

 one or more proposals for more constrained distribution of isotretinoin.  The Agency has encouraged sponsors of the drug, innovator or generic firms, to work together to devise such a plan that could unify all current, independent risk management programs for isotretinoin.  Due to the close proximity in time of submission of the proposal(s) and the February meeting, a review of the plan by FDA is not included in this packet.  However, we plan to address it at the meeting.


Since implementation of the SMART program, generic manufacturers of isotretinoin have entered the market.  Each company is required to have an equivalent risk management program to SMART as a condition of marketing.  Therefore, you will also be asked to consider early data from these programs, which are not in the background package, but will be presented.. 


Based on our review of all of risk management programthe data, we have asked the manufacturers to work together in preparing for this meeting.  Specifically, we have requested that they jointly address the adequacy of the current revised program and provide the committee with a proposal for discussion of possible changes.


  In light of the complexity attendant to this deliberation, other risks issues associated with the use of isotretinoin will not be addressed in detail at the meeting. 


In reading through the background materials (see attached content guide on next page) provided by the sponsors of isotretinoin and by FDA, pleaseyou may wish to keep in mind the following general areas that we may request that the Committee discuss:


1.  Whether the SMART and equivalent generic programs have demonstrated: 

·        Low potential for program misuse by patients, pharmacists and prescribers

·        An acceptable risk reduction profile for fetal exposures, based on prior prescription marketing experience of the Roche Pregnancy Prevention Program (PPP)


2.  Whether, based on the data presented, the manufacturers’ proposal (s):

·        Adequately address deficiencies of the current risk management program

·        The benefits of the proposed changes outweigh the risks of change


3.      Whether the proposed program can reasonably be implemented based on the realities of clinical practice (e.g., office based healthcare)


4.      What Mmodifications to the current or proposed programthat would further ensure safe use and better meet program goals?


Again, thank you for your willingness to participate in the meeting.  If you have any questions or need for clarification regarding the meeting content or logistics, please contact Mary Gross ______________ at 301-827-3216______________.  We are looking forward to seeing you at 8:00 AM on February 26, 2004.







                                                Jonca Bull, M.D.


                                                Office of Drug Evaluation V

                                                Office of New Drugs

                                                Center for Drug Evaluation and Research






                                                Anne Trontell, M.D., MPH

                                                Deputy Director

                                                Office of Drug Safety

                                                Office of Pharmacoepidemiology and

                                                           Statistical Science

                                                Center for Drug Evaluation and Research


Attachment; Jonca and Anne





Contents of Package




Office of Drug Evaluation V

Division of Dermatologic and Dental Drug Products

Tab A

·        Isotretinoin Historical Summary

·        Letter, Dr. Janet Woodcock, dated October 6, 2000, subject:  Need for registry, linkage of pregnancy status with drug dispensing

      (Note to Committee:  registry not implemented per innovator due to HIPAA and

      other constraints, so SMART program evolved over 1 year prior to


·        Letter, Dr. Jonathan Wilkin, dated October 30, 2001, subject:  Approval Letter, NDA 18-662/S-044

            Enclosure to Letter - Final printed labeling (FPL) – 108 pages      



Office of Pharmaceutical Science

Office of Generic Drugs

Tab B

·        Letter, Dr. Janet Woodcock, dated November 8, 2002, subject:  Citizen Petition Response – Procedures and Standards; Abbreviated New Drug Applications



Office of Pharmacoepidemiology and Statistical Science

Office of Drug Safety

Executive Overview - Office of Drug Safety

Combined Review -  Division of Drug Risk Evaluation and Surveillance, Research, and Communications Support, Office of Drug Safety

Tab C

·        Overview of the 1st of the Isotretinoin Risk Management Program

·        Overview of the First Year Evaluation of the Isotretinoin Risk Management Program

·        PID D030417, Drug: Isotretinoin, Topic: Pregnancy Exposures

·        PID D030471, Drug: Isotretinoin, Topic: Isotretinoin Utilization

·        PID D030471, Drug: Isotretinoin, Topic: Prescription Compliance Survey to Measure Compliance with Isotretinoin Qualification Stickers

·        PID D030471, Drug: Isotretinoin, Topic: Review of Isotretinoin Patient Survey Materials and Data with Interest in Compliance During the First Year of the System to Manage Accutane Related Teratology (SMART) Program

·        Synopsis of  the elements of the System for Thalidomide Education and Prescribing Safety™ (S.T.E.P.S.)


The regulatory history of isotretinoin is described in materials from Jill Lindstrom of the Division of Dermatologic and Dental Products. 


The regulatory history is also summarized in the background to the ODS consult. 


Primary documents pertaining to the regulatory history appear _________ and include:

Woodcock letter describing need for registry, linkage of pregnancy status with drug dispensing: Note to committee that registry not implemented per innovator due to HIPAA and other constraints, so SMART program evolved over 1 year prior to implementation

Supplement approval letter fall 2001

Essential elements memo used for generics



Features of the current isotretinoin risk management program are described in the ODS consult (section  ) and Dr. Lindstrom’s materials. 


The ODS consult contains:

An executive overview from the Office of Drug Safety

A combined review from components within the Office of Drug Safety Describing

Reported pregnancy exposures during the enhanced risk management program for isotretinoin

Analysis of the prescription compliance survey to assess whether stickers are being used and if they are being completed correctly

Analysis of the patient survey data bearing upon the extent of pregnancy testing during isotretinoin exposure, correlation of reported pregnancy testing with the use of prescription stickers, and questions on components of the enhanced risk management program such as counseling, contraceptive behaviors, and signing of informed consent.