FDA Issues Substantial REMS Draft Guidance

By William T. Koustas –

FDA recently issued its most extensive guidance for industry regarding Risk Evaluation and Mitigation Strategies (“REMS”) since their enactment of the Food and Drug Administration Amendments Act of 2007 (“FDAAA”).  The “Draft Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications” (“REMS Guidance” or “Guidance”) addresses issues that drug companies may struggle with as they develop REMS.  While some of the information found in the REMS Guidance is not new, it is one of the few times FDA has revealed its thinking on these issues to this extent to the public.  The REMS Guidance mainly addresses three issues: (1) the content of a proposed REMS submission; (2) REMS assessment and modification of proposed REMS; and (3) communicating with FDA about REMS.  The introduction and background sections of the guidance also contain useful information about REMS and their relationship to RiskMAPs.  Interestingly, the REMS Guidance also contains an example of a REMS for a fictitious drug product.  Though much of this information can be gleaned from already approved REMS, it is likely a useful tool for sponsors to examine as they struggle to develop a REMS of their own.

I.  Content of a Proposed REMS Submission to FDA

This section of the REMS Guidance essentially describes what FDA expects a REMS to contain in the “proposed REMS” and “REMS supporting document” sections of the REMS submission.  As described in this guidance, the “proposed REMS” section of this submission should contain information regarding the goals of the REMS as well as the elements the sponsor proposes to implement in order to achieve those goals.  FDA notes that goals should “target the achievement of particular health outcomes or knowledge related to known safety risks and should be stated in a way that aims to achieve maximum risk reduction.”  FDA, Draft Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (Sept. 2009) at 9.  This part of the Guidance also gives generic examples of how a sponsor may phrase a goal as well as objectives.  The “proposed REMS” should also contain one or more of the REMS elements many are familiar with – medication guides or patient package inserts, communication plans, elements to assure safe use, an implementation system and a timetable for submission of assessment – as required by FDA or FDAAA.  Id. at 10-15. 

The “REMS supporting document” section of this Guidance describes the information and format of such a document.  According to the REMS Guidance, the supporting document should include a background section explaining why the sponsor believes a REMS is necessary; a goals section describing the rationale for each goal stated in the “proposed REMS;” supporting information about the proposed elements so that it is clear to FDA how each element will contribute to the goals; and a REMS assessment plan which should permit the sponsor to evaluate how the REMS elements are, or are not, achieving the stated goals and whether these elements or goals should be modified.  Id. at 16-21.

II.  REMS Assessment and Proposed REMS Modification Submission to FDA

The REMS Guidance devotes an entire section to REMS assessments and modifications, which describes what FDA expects sponsors to include in the REMS assessments that must be submitted according to the timetable for submission of assessments included in the “proposed REMS.”  The assessment may propose modifications to approved REMS elements either at the sponsor’s initiative or when FDA determines that new safety information requires the modification of the REMS.  Id. at 22.  Any modifications to approved REMS must be submitted as a new prior-approval supplemental application and each modification should include a new “proposed REMS” as well as an updated “REMS supporting document” that describes the rational for the modifications.  Id.

III. Communicating with FDA Regarding REMS

The REMS Guidance also describes how a sponsor should communicate with FDA regarding REMS submissions.  A proposed REMS may be submitted in the original drug application, as a supplement to an existing application or as an amendment to an original or supplemental application.  Id. at 23.  While submission of a REMS assessment alone is not considered a supplemental application, a REMS assessment with a proposed modification to an approved REMS would be.  Id.  Additionally, a supplemental application for a new indication for a drug with an approved REMS should include a REMS assessment and proposed modifications if necessary.  FDA also identifies how the initial pages of a REMS submission should be formatted such that it is able to quickly identify it.  Id. at 24-26.  FDA notes that sponsors should contact  their regulatory project manager in the division assigned to the drug, while the a sponsor of an ANDA should contact the Director of the Division of Labeling and Program Support in the Office of Generic Drugs with questions.  Id. at 26.