Background: The use of real-world evidence (RWE) in regulatory and health technology assessment (HTA) submissions is growing, reflecting greater reliance on real-world data (RWD) to support marketing authorization applications (MAAs). However, differences in evidentiary standards among regulatory and HTA bodies pose challenges for sponsors developing RWE-based submissions.
Objectives: This study evaluates patterns of RWE acceptance and highlights areas of concordance and divergence among key regulatory authorities — U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada (HC), and U.K. Medicines and Healthcare products Regulatory Agency (MHRA) — and the HTA bodies NICE, G-BA, HAS, AEMPS, CDA, TLV, and SMC.
Methods: A literature review was conducted to identify medicines submitted between January 2021 and the present that incorporated RWE into their MAAs. The therapies spanned multiple therapeutic areas, data sources, and evidence types. Regulatory and HTA reports were used to extract data. RWE was classified as substantial if it served as primary evidence and supportive if it provided supplementary evidence in the MAA. Acceptance was categorized as accepted, partially accepted, not adequate, or not discussed, with key review concerns recorded and analyzed.
Results: Seven case studies were identified which contained RWE that supported approvals: idecabtagene vicleucel (ide-cel), sotorasib, alpelisib, palovarotene, tacrolimus, omburtamab, and omaveloxolone. Among these, FDA demonstrated higher acceptance rates of medicines (86%, 6/7) compared to EMA (50%, 3/6). Among the RWE reviewed, both FDA and EMA cited concerns about residual confounding, cohort comparability, and generalizability although with varying acceptance. HTA bodies exhibited mixed responses to the RWE. Ide-cel’s RWE was not accepted by FDA, accepted by MHRA and EMA, and not discussed by HC; HTA acceptance of RWE for ide-cel varied. Sotorasib’s RWE was accepted by FDA, EMA, and MHRA, although HTA bodies did not discuss the RWE. Alpelisib’s RWE was accepted by FDA but rejected by EMA. Palovarotene’s RWE was accepted by FDA and HC but rejected by EMA. Tacrolimus’s RWE was accepted by FDA although MAAs were not filed elsewhere. Omburtamab’s RWE was rejected by both FDA and EMA and not evaluated by HTAs. Omaveloxolone’s RWE was accepted by both FDA and EMA, while HTA acceptance of the RWE varied.
Conclusions: RWE acceptance varies across agencies, with FDA showing greater acceptance than EMA. Both regulators and HTA bodies expressed concern about the RWE, including confounding, data completeness, and comparability. Addressing such concerns through robust designs and methods can improve RWE acceptance, facilitating approvals and market access.
