Problem Statement: In the global single-arm ELARA trial, tisagenlecleucel demonstrated efficacy and a favorable safety profile in relapsed/refractory (r/r) follicular lymphoma (FL) after ≥ 2 lines of prior therapy, with a homogeneous treatment effect in high-risk populations. The European Medicines Agency (EMA) emphasized the importance of having an external control arm (ECA) with patient-level data as part of an evidence package to support a submission for a tisagenlecleucel indication in r/r FL.

Description: As part of the strategy to address this need, real-world evidence (RWE) was derived in a target trial which estimated the efficacy of tisagenlecleucel compared with real-world standard of care (SoC). Key ELARA eligibility criteria were applied to the Flatiron Health Research Database (FHRD) to select a cohort of patients with >3 lines of systemic FL therapy, weighting by odds was used to reduce systematic differences in key prognostic variables, and efficacy was estimated by complete response (CR), overall response (OR), overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT). Sensitivity analyses estimated the impact of remaining imbalanced variables and missing data for key prognostic variables. After weighting, among 97 ELARA and 98 FHRD patients, there was a consistent trend towards greater CRR, ORR, TTNT, OS and PFS in favor of tisagenlecleucel vs SoC, and results were consistent for sensitivity analyses. Following a positive EMA opinion on the submitted evidence package, tisagenlecleucel became the first CAR-T cell therapy approved in the EU for adults with r/r FL.

Lessons Learned: Health Authority opinions and recommendations can be leveraged to develop fit-for-purpose RWE to supplement clinical trial data and meet regulatory stakeholder needs. Robust analytic methods to address important shortcomings in real-world data can support development of rigorous RWE to support regulatory approval.

Stakeholder perspective: Industry