February 2, 2004
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.
Sincerely,
Jonca
Bull, M.D.
Director
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
implementation)
·
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.)