Are EU JCA Evidence Requirements Achievable? Insights From a Retrospective Evidence Analysis Study for Rare and Non-Rare EU Treatment Landscapes

OBJECTIVES: Ahead of mandatory EU Joint Clinical Assessment (JCA) for first-indication oncology and rare medicines in 2025 and 2028, respectively, we retrospectively assessed to what extent evidence generated for the EMA regulatory process would have addressed JCA requirements, for PICOs identified for avelumab. We evaluated evidence in an orphan, first-to-market landscape (metastatic Merkel cell carcinoma [mMCC]) and in the densely-populated renal cell carcinoma (RCC; combination with axitinib) landscape, to explore potential challenges for manufacturers.

METHODS: Following a simulated PICO scoping exercise for avelumab in mMCC/RCC (see Abstract #143800), evidence in EMA European Public Assessment Reports for avelumab was assessed against EU JCA evidence requirements guidance, for consolidated PICOs.

RESULTS: PICO scoping identified 22 (7 comparators) and 8 (4 comparators) consolidated PICOs for avelumab in RCC and mMCC, respectively. Considering RCC comparators, evidence requirements were addressed for n=1/7, through a head-to-head trial with patient characteristics/geographies largely representative of PICOs identified. Pre-planned trial stratification was not considered for any identified PICO subpopulations; however, pre-planned subgroup analyses were available (n=4/8 subpopulations).

For mMCC, evidence synthesis included observational studies covering n=4/4 comparators, however, only naïve comparisons of single arm and observational studies were performed. Trial populations were not stratified by PICO subpopulations (n=2) and subgroup analyses were not presented.

CONCLUSIONS: Given close alignment of JCA and EMA timelines, manufacturers will need to generate comparative evidence earlier to fulfill PICO requirements. In crowded therapeutic landscapes particularly, fulfilling requirements for all PICOs will be challenging due to high comparator numbers. As demonstrated, comparative evidence for all PICO comparators is not typically developed for regulatory purposes, so manufacturers will need to consider earlier engagement in landscaping activities and broader comparator inclusion in evidence syntheses. Data for relevant subpopulations identified during PICO simulation were generally insufficient; thus, careful consideration of subpopulations at trial design stage, guided by early clinician/payer discussions, are recommended.