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P203: Evaluating Regulatory Assessment of Risk Management Strategies by the EMA and US FDA

Poster Presenter

      Ana Macarenco

      • Risk Management, Div of Mitigation Assessment & Medical Error Surveillance, OSE
      • FDA
        United States


Comparison of the rationale supporting the regulatory assessment of, and resulting risk mitigation approaches for four medicinal products approved in the U.S. and the European market.


Review European public assessment reports (EPAR) and the FDA approval packages for brodalumab, tolvaptan, pegvaliase, and afamelanotide and compare the risk mitigation approaches communicated in the U.S. package insert, the European summary of product characteristics, aRMM, and REMS.


Conceptually, the assessment of a product’s risk management should be consistent around the globe, given the harmonization of key guidelines which support the definition of important risks. Practically, however, the likely medication use system in which the product is being evaluated, including the location, the healthcare delivery system of that region, socioeconomic factors and each regulators’ interpretation of the data may lead to risk management strategies varying for the same product. Out of the four products evaluated, two (tolvaptan and pegvaliase) demonstrated alignment between U.S. FDA and EMA RM strategies. Both have mitigation plans with similar elements which include but are not limited to restricted access to the drug and additional patient monitoring. For brodalumab, driven by fatal cases observed during clinical trials, the FDA implemented a more restrictive risk mitigation strategy to minimize the risk of suicidal ideation and behavior (SIB) compared to EMA. Although causality was unclear, the FDA concluded to require a REMS to mitigate the risk of SIB based on input from several committees; it’s heavily an informational program. Conversely, no aRMM was implemented in Europe for this risk. For afamelanotide, EMA implemented more restrictive risk minimization for the risk of skin cancer than the FDA. The European agency was the first to approve this medication assessing clinical trial safety data which did not include the long-term safety data for this risk. The subsequent FDA analysis was based on data from clinical trials on top of the European post-marketing monitoring data, which includes up to 10 years of afamelanotide use; therefore, a broader amount of real-world information was available to FDA which resulted in no REMS for afamelanotide.


As risk management continues to rapidly evolve, the comparison of evaluation processes can identify points of improvement and streamline the process for a more integrated global approach.