Presentation (CTI)

OBJECTIVES: From January 2025, the mandatory Joint Clinical Assessment (JCA) for comparative clinical review across EU Member States came into force. In June 2026, tovorafenib, developed for relapsed/refractory paediatric low-grade glioma harbouring a BRAF fusion, rearrangement, or V600 mutation, became the first completed JCA. Here, we analyse this JCA to understand remaining unaddressed areas for future submissions with different evidence bases.
METHODS: We conducted a structured review of the JCA for tovorafenib, examining the PICO framework, primary evidence base, systematic literature review (SLR), and statistical methods against JCA guidance requirements, with a focus on highlighting remaining areas of uncertainty.
RESULTS: Eight PICOs were defined across three populations. Evidence came from FIREFLY-1, a single-arm, open-label, multicentre study. Limited comparator evidence was identified; the HTD submitted indirect evidence for only 2/8 PICOs (5 and 7): an unanchored matching-adjusted indirect comparison versus dabrafenib+trametinib (PICO 5) and versus trametinib (PICO7). PICO7 was excluded from the report entirely given insufficiently-reported comparator data. Remaining areas of uncertainty included: how PICOs were consolidated; database acceptability and search requirements for the SLR; likelihood of acceptance of different analytical approaches given data availability constraints; how instances where evidence exists but the HTD considers a PICO inappropriate will be handled; the rationale for descriptive versus quantitative outcome reporting; inconsistency in endpoint specification; and how broad PICOS criteria will be handled in the context of a potentially large body of evidence in non-rare indications.
CONCLUSIONS: The tovorafenib JCA established the first precedent for how assessors apply JCA methodology in a rare paediatric oncology indication with a single-arm trial; however, key areas of uncertainty remain unanswered. Most critically, this single, highly specific precedent may generalize poorly: given vague guidance, future assessors may take substantially different approaches. Future appraisals will provide additional precedence for both assessors and HTDs navigating JCA submissions.