SP04J - Longitudinal Evaluation of U.S. REMS Program Modifications (2008–2020)

Background: U.S. Risk Evaluation and Mitigation Strategies (REMS) programs are complex healthcare interventions mandated by FDA to protect public health. The dynamic nature of these programs has not been well described.

Objectives: To evaluate the natural history of REMS programs with Elements to Assure Safe Use (ETASUs) and characterize the frequency and characteristics of program modifications.

Methods: A retrospective cohort analysis of REMS programs with ETASUs (N=63) approved since 2008 was conducted using data from REMS@FDA Reports & Data Files (accessed: 2020.07.01). Dates and program characteristics were abstracted using Atlas.ti. Mean follow-up was 6.4 yrs/program (sd=3.3 yrs). Changes were classified and categorized into major, minor modifications or revisions using definitions from FDA’s Guidance to Industry. Cox regression estimated relative hazards of program modification by program characteristics using SAS (SAS V. 9.4 Cary, NC).

Results: REMS authorization coincided with product approval for most programs (N=38); the remainder emerged post-approval (either converted from previous risk management requirements (N=16) or following post-marketing experience (N=9). Drug safety public health goals varied across programs: primary (N=37), secondary (N=29), and tertiary (N=8) prevention; or only ensuring informed benefit-risk decision-making available (N=14). Median time-to-first-modification was 21.5 mos (95%:16.2-30.4 mos). Major modifications were common: 76% of programs (N=48); 172 modifications (median=3/program, IQR:1-5; range:1-16). Major modifications affected: REMS goals (N=6); drug administration/testing (N=21); removal/addition of REMS elements (N=35); substantial modification of REMS elements (N=46); substantial change of REMS tools (N=51). Nine modifications released REMS requirements; eight institutionalized them by creating a shared system REMS. Time-to-first-major-modification was 8 mos sooner for REMS programs enacted at product approval vs. programs enacted post-marketing (HR=1.39, 95% CI:0.81-2.40).

Conclusions: REMS programs represent a dynamic cohort within a learning healthcare system. Findings underscore the importance of rigorous implementation surveillance and program assessment as feedback for evaluating the need for, and effectiveness of, modifications.