The regulator issued guidance on changes to approved risk evaluation and mitigation strategies (REMS), distinguishing “modifications” from “revisions,” and explaining how these should be submitted and how the FDA will review and act on them.
As noted in the FDA’s guidance, certain drugs require a risk management plan that uses measures beyond the PI to make certain that benefits outweigh risks. As reported by Law360, this document — which provides guidance on the submission of changes to these plans — was prompted by the 2012 user fee law that contained provisions meant to streamline amendments to REMS. The FDA committed to REMS reforms under the user fee law, and in September put out a report updating its progress on the matter and promising specific actions in several areas, including patient comprehension, physician education, REMS standardization and access to REMS policies.
In its guidance, the FDA says REMS changes will be categorized by the degree of their possible impact on the risk message and other REMS requirements, and that they will fall into one of two categories: “revisions” or “modifications.” The FDA specified that a risk message is potentially affected when a change increases, reduces or modifies its focus or addresses a new serious risk, while a REMS requirement can be affected when a change increases, minimizes or changes the plan’s goals, elements and tools, and/or actions required for compliance.
Revisions are limited to editorial changes, corrections of typographical errors or application holder name or address changes — all of which don’t have any effect on the risk message and other REMS requirements. The FDA also noted that amendments to the REMS document and/or appended material don’t have an impact on the risk message or requirements of the REMS. Included in the guidance document is a list of changes that will be deemed revisions, with the FDA specifying that any change not included in the list will be considered a modification. Revisions should be submitted as “REMS Revisions” and documented in the next annual report.
Modifications are split into two categories: minor and major. Minor modifications may nominally impact the risk message or REMS requirements and should be submitted as a CBE-30 supplement, while major modifications can significantly affect the risk message or REMS requirements and should be submitted as a PAS. The document lists examples of minor and major modifications, with the FDA clarifying that the examples are only representative. Examples of minor modifications include nominal amendments to REMS requirements or associated processes, such as the expansion of the enrollment process, or changes that nominally affect the risk message, such as changes in graphics. Examples of major modifications include any amendment relating to a REMS goal; changes to an element of the plans, such as the removal of the Medication Guide; amendments to a REMS tool, such as the removal of a prescriber educational tool; or changes due to safety labeling modifications.
The guidance document also covers procedures related to REMS changes. The FDA goes over general considerations, detailing information that should be included in submissions, recommended formats and methods of submissions. Submission procedures for each type of change are also covered.