(2) Application of The BRACE Framework for Benefit-Risk Assessment, Communication, and Evaluation of Pexidartinib

Publication Number: 333

Background: Pexidartinib (Turalio®), the first systemic therapy for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), was approved by the FDA in the United States, August 2019, with a mandatory risk evaluation and mitigation strategy (REMS) program to mitigate the risk of serious and potentially fatal liver injury seen in clinical trials.

Objectives: The objective was to evaluate pexidartinib and the REMS program using the Benefit–Risk Assessment, Communication, and Evaluation (BRACE) framework.

Methods: The application of the BRACE framework includes a cycle of five steps: benefit-risk evidence identification, evidence integration and analysis, decision-making, benefit-risk communication and risk minimization, and evaluation. These iterative phases were applied to the pexidartinib life cycle.

Results: In the benefit-risk evidence identification phase, data from the phase III trial showed that pexidartinib was effective in the treatment of TGCT with improved patient functional outcomes and symptomatic relief, although there were reports of hepatic-related adverse events. Hepatotoxicity was identified as an important risk associated with pexidartinib use and was weighed against the potential benefit of the therapy (evidence integration and analysis). Pexidartinib’s benefits outweighed the hepatotoxicity risk in TGCT patients and was approved in the United States with a REMS program, which includes a medication guide, communication plan, and ‘elements to assure safe use’ (ETASU) to mitigate potential hepatotoxicity (decision-making). The Turalio® REMS program focuses on the implementation of the ETASU components by ensuring that providers are educated on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic, and irreversible hepatotoxicity. Additionally, patient education is required. Prescribers and participating pharmacies also complete training for certification and enrollment in the REMS program (benefit-risk communication and risk minimization). The evaluation phase is iterated by the continuous REMS assessments through knowledge attitude and behavior (KAB) surveys and the post-marketing study to evaluate the long-term risk of hepatic failure associated with pexidartinib use.

Conclusions: Through application of the BRACE framework, pexidartinib’s benefit-risk profile is continually monitored, evaluated, communicated, and optimized.