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FDA Announces Enhancement to Isotretinoin Risk Management Program

The Food and Drug Administration (FDA) today announced the strengthening of the risk minimization action plan (RiskMAP) for Accutane (isotretinoin) and its generic equivalents. Isotretinoin is a drug indicated for the treatment of a specific type of severe acne (severe recalcitrant nodular acne) that is not responsive to other therapies. The goal of the strengthened RiskMAP is to reduce the risk of birth defects associated with fetal exposure to isotretinoin.

The strengthened RiskMAP reflects agency and sponsor's consideration of the recommendations from the February 2004 joint Advisory Committee of the Drug Safety and Risk Management and the Dermatologic and Ophthalmic Drug Advisory Committees which examined the current isotretinoin risk management program known as the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) program. SMART was implemented in 2002 in response to agency recommendations at that time to further decrease fetal exposures to isotretinoin.

The February 2004 joint Advisory Committee discussion focused on whether changes were necessary to SMART and its generic equivalents, based on FDA assessments of the program's performance and its ongoing surveillance of pregnancy exposures to isotretinoin.

The committees agreed that changes were called for, especially in light of the fact that the SMART program, operated by Roche Pharmaceuticals, was only one of several similar programs that had been created with the introduction of generic isotretinoin to the market. The multiple programs created confusion and the concern that patients would not receive appropriate counseling and testing to prevent the possibility of birth defects.

Today's changes reflect a joint response by the agency and the sponsors of isotretinoin drug products to the Advisory Committee's recommendations that the sponsors strengthen the isotretinoin RiskMAP. Under the new program, sponsors will obtain registration of not only prescribers, but also pharmacies that dispense and patients who use isotretinoin. The program also includes documentation of a negative pregnancy test before giving isotretinoin to women who are capable of becoming pregnant. Importantly, the registration system will be built to incorporate physician and patient identification codes that will also protect the privacy of patients. The innovator and generic sponsors of isotretinoin have jointly contracted with Covance, Inc., to design, build, implement, and operate a single strengthened isotretinoin riskMAP incorporating these elements.

As stated in 2002, the goal of the agency was to eliminate fetal exposure to isotretinoin by ensuring that no woman start isotretinoin therapy if pregnant and no woman on isotretinoin therapy become pregnant. The agency and the sponsors believe this new program will go a long way to achieving this goal.

While the program development itself is complex, FDA has emphasized the need to make it as unintrusive as possible for healthcare providers and patients. At the same time that FDA has asked industry to be mindful of the need for simplicity and minimal burden on the health care community and patients. Keeping this in mind, the sponsors' new program will include, but will not be limited to, the following:

• Registration of all prescribers, patients and dispensing pharmacies will be registered in a single centralized "clearinghouse".
• Before a registered pharmacy first dispenses the medication for a particular patient, the following will occur:
  
  • Completion of patient education by the prescriber
  • An appropriately timed and documented negative pregnancy test prior to dispensing the medication
  • Completion of the informed consent, education and risk management components by the patient.
  • Electronic or other verification of the above actions.
    
•  For all subsequent prescriptions, the following will occur monthly:
  
  • Ongoing patient education by the prescriber
  • Repeated negative pregnancy test within a specified window prior to dispensing
  • Completion of the education and risk management components by the patient.
  • Electronic or other verification of the above actions.

The isotretinoin sponsors will play a large role in determining compliance and effectiveness of the strengthened RiskMAP. In addition to shipping drug only to authorized distributors, the sponsors have agreed to perform the following tasks:

• Establish and maintain the clearinghouse.
• Monitor for sales of the drug outside of approved distribution channels, including via the Internet.
• Develop procedures to monitor and evaluate each component of the RiskMAP to include clearinghouse compliance with specified responsibilities, prescriber and pharmacy registration and prescribing and dispensing by non-registered prescribers and pharmacies, respectively.
• Evaluate the effectiveness of the program in reducing and limiting pregnancy exposures.

In order to implement the new program, the innovator and generic sponsors of isotretinoin have worked diligently to reach an agreement with Celgene Corporation, which holds patents on a successful program for preventing pregnancy exposures to thalidomide. Because this agreement with Celgene has now been achieved, the program can move forward in full compliance with recommendations of the agency and members of the Drug Safety and Risk Management and the Dermatologic and Ophthalmic Drug Advisory Committees.

The FDA will continue to monitor all adverse events reported with isotretinoin use, to include neuropsychiatric adverse events, in order to protect the public health by ensuring that the risks associated with isotretinoin use are minimized for those patients who need treatment with this drug.

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