This has been a long time coming! Ever since the first approval of isotretinoin (Accutane – by Hoffmann La Roche, Inc. on May 7, 1982), and the associated safety requirements associated with that product’s labeling, the requirements for the safe use of isotretinoin products have become stricter. This type of safety information and requirements for dispensing eventually morphed into a statutory requirement for the development of “Risk Evaluation and Mitigation Strategies” (REMS) by the passage of the Food and Drug Administration Amendments Act of 2007 (FDAAA). This Act created Section 505-1 of the FD&C Act, which establishes FDA’s REMS authority. “A REMS is a required risk management plan that can include one or more elements to ensure that the benefits of a drug outweigh its risks.”

With that bit of history in mind, the changes from a single REMS for Accutane to a shared REMS with other marketers of isotretinoin and the requirements for use, dispensing, documentation, pregnancy tests, and training became more onerous over time. Recently, FDA sent out a REMS MODIFICATION NOTIFICATION (here) for isotretinoin products which outlined changes that holders of approved NDAs and ANDAs are required to make to ease the burden on practitioners, patients, and pharmacies involved with the prescribing, use, and dispensing of isotretinoin that are outlined in the current REMS. FDA informs the holders of approved applications that:

Your approved REMS must be modified as follows:

  • Remove the requirement that pregnancy tests must be performed in a CLIA-certified laboratory; however, all pregnancy testing before isotretinoin treatment initiation must be completed in a medical setting (e.g., prescriber’s office, clinic, laboratory).
  • Allow prescribers the option of using home pregnancy testing for their patients during and after isotretinoin treatment in conjunction with measures to minimize falsification of pregnancy tests.
  • Remove the waiting period requirement (also referred to as the “19-day lockout”) for patients if they do not obtain isotretinoin within the first 7-day prescription window. Before isotretinoin treatment initiation, a repeat confirmatory test must be completed in a medical setting (as described above) without any required waiting period.
  • Revise the registry requirement to remove the objective to document the outcome (and associated data collection) for each pregnancy.
  • Revise the requirement for prescribers to document patient counseling in patients who cannot become pregnant from monthly to only at enrollment. Before dispensing each prescription, the authorization to dispense must verify patient enrollment and prescriber certification.

The Agency goes on to say, “[B]ecause we [the FDA] have determined that a REMS modification as described above is necessary to minimize the burden on the health care delivery system of complying with the REMS, you must submit a proposed REMS modification within 180-days of the date of this letter.” The Agency further reminds applicants that “[T]he Isotretinoin Product Manufacturer Group (IPMG) [the group that handles the shared REMS system] should submit the proposed modified REMS to DMF 032462.” And to “[S]ubmit your cross-reference submission as a Prior Approval Supplement (PAS) to your NDA.” The same would apply to the holders of approved ANDAs if the modifications are in line with the recommendations for changes described by FDA and the IPMG DMF is the basis for their modified REMS submission.

Following the requirements outlined in the letter will permit the application holders to avoid submitting a rationale for the changes to the REMS. However, if there are differences in the required changes outlined in the letter, then a rationale for deviation would be required.

The proposed modification in the REMS, guided by the Agency’s almost 42-year experience with the issues associated with the safe use of isotretinoin, will remove some of the well-documented pain points experienced by practitioners and patients and will result in significant relief and reduce the burden experienced by all involved with the modified REMS without compromising the safe use of the product.