On July 9, 2019, FDA finalized the Guidance for Industry titled, Risk Evaluation and Mitigation Strategies: Modifications and Revisions. The current Guidance updates the previous Guidance with the same name that was issued on April 7, 2015. The update is more of a finalization; the portion of the draft that sets forth the submission procedures for REMS revisions and modifications.
Section V of the Guidance confirms what could now be a REMS revision and what is considered a modification. Revisions of REMS are related to minor issues and do not require FDA review. But the modifications need to be submitted to the Agency in the form of supplemental applications. The Guidance provides examples of the revisions that can be addressed in annual reports and modifications, which are more serious, and call for a CBE-30 Supplement or a Prior Approval Supplement (PAS). For example, changes to an ETASU (Elements to Assure Safe Use), which need to modify the verification process of drug dispensing to patients may be a PAS, while the addition of a new, recently approved drug to a class of drugs already mentioned in the REMS documents as having the potential to cause drug-drug interactions could be construed as a CBE-30.
FDA has also confirmed the timelines for their response. FDA will work on the minor submissions within 60 calendar days, though in absence of any comments from FDA, the sponsor may implement the changes within 30 days. However, an improper classification of the REMS (e.g., CBE-30 in lieu of a PAS), or inadequate information to support the changes could lead the agency to contact the sponsor within 14 days. When additional information or a change in reporting category is requested, the Agency will expect information from the sponsors within 10 calendar days of their request or issue a Complete Response Letter (CRL). Changes should not be implemented for a CBE-30 submissions, if FDA has come back on the 14th day to ask more questions.
Any major changes in the REMS will require a review clock of 180 days. When a submission has several changes, it is the most significant change that will determine the review time. This is not surprising: the most significant change is always the rate-limiting step. FDA will publish the updated REMS with revisions within 14 days of receiving them, and the ones with modifications within 3 days of receiving them.
When the finalized Guidance is compared to the draft of April 2015, the changes are not dramatic but are more definitive. It is good to see this important guidance finalized as the REMS has become an important tool to monitor safety of new drugs as well as generics. The final Guidance can be found here.