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P206: Comparison of US FDA and EMA Risk Minimization Strategies for Products with Eliminated REMS with ETASU and EU aRMMs

Poster Presenter

Tiffany Dominic

Risk Management Fellow
Pfizer
United States

Objectives

Compare U.S. Food & Drug Administration (FDA) and European Medicines Agency (EMA) required risk minimization strategies for products with an eliminated Risk Evaluation and Mitigation Strategies (REMS) with elements to assure safe use (ETASU) and additional risk minimization measures in the EU.

Method

The REMS Public Dashboard (RPD) identified products once requiring REMS with ETASU that are now eliminated. Rationale was collected from Drugs@FDA, Drug Safety Communications, and the RPD. The EMA European Public Assessment Report (EPAR) was utilized for aRMMs and rationale.

Results

44 products were identified. After eliminating duplicates, products part of shared systems and those never licensed by EMA centralised procedure, 7 remained: emtricitabine/tenofovir disoproxil fumarate (DF), epoetin alfa, eltrombopag, darbepoetin alfa, romiplostim, rosiglitazone and dofetilide. Rosiglitazone and dofetilide were excluded as they never simultaneously required aRMMs and REMS. Of the remaining 5 products, 2 (epoetin alfa and darbepoetin alfa) were not included as the REMS and aRMMs addressed differing risks. Emtricitabine/tenofovir DF’s aRMMs and REMS consisted of educational materials. The REMS was eliminated as FDA determined non-REMS materials and clinical guidelines provide awareness and knowledge regarding the risk. The aRMMs are ongoing in the EU. The REMS was implemented for 83.5 months; the aRMMs have been implemented for 87.9 months. Eltrombopag’s REMS required stakeholders to certify and enroll while the aRMMs consisted of educational materials. Both the REMS and aRMMs were eliminated/discontinued, but due to different reasons. The aRMMs were discontinued as the educational materials are now part of standard care and the safety profile is currently reflected in the product information. Rationale for the REMS elimination is outlined later in the abstract. The REMS was implemented for 67.9 months, the aRMMs for 86.2 months. Romiplostim’s REMS was also restrictive and required HCPs and institutions to certify. The aRMMs consisted of educational materials. The aRMM educational materials were later revised to only address a risk not addressed by the REMS. The REMS was implemented for 149.2 months; the aRMMs to address the same risk was 105.2 months. The REMS for romiplostim and eltrombopag were modified to eliminate the ETASU as FDA decided long-term safety data would be best collected through ongoing studies. The modified REMS required a one-time distribution communication plan for both products. Both REMS ultimately were eliminated.

Conclusion

While there have been >100 products requiring REMS or aRMMs since introduction of the requirements, differences in regulatory conclusions resulted in 3 products having REMS with ETASU and aRMMs for the same or similar risks, allowing evaluation of programmatic structure, rationale for elimination, and length of duration. Eltrombopag had its aRMMs and REMS discontinued/eliminated based on different rationale from each regulator, despite addressing the same safety concern. Emtricitabine/tenofovir DF’s aRMMs remain ongoing as the EMA determined the safety concern is still present, despite the FDA eliminating the REMS requirement. Romiplostim’s aRMMs and REMS previously addressed the same safety concerns, but no longer requires REMS or aRMMs to addresses the risks. In the aggregate, a common rationale by the FDA for eliminating a REMS was HCP awareness of the risk. No trends for rationale of aRMM discontinuation were observed. There have been numerous discussions regarding evaluation of risk minimization strategies. A study by Huynh et al., concluded multiple implementation frameworks such as RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) and others can be utilized for REMS assessments and evaluation. Additionally, the Prescription Drug User Fee Act Goals for 2023-2027 includes updating or creating new policies to assess if a REMS is still necessary. On a similar note, the draft for GVP Module XVI Revision 3 discusses risk awareness forms and calls for regular evaluation to assess if an aRMM has been integrated into clinical practice and can be discontinued. Therefore, there is no surprise that the current landscape from both regulatory bodies includes goals through the upcoming years to enhance the assessment of aRMMs and REMS through the evaluation of risk awareness and clinical practice integration and potential remains for a more efficacious way to evaluating these safety strategies and allow elimination, when possible.