OBJECTIVES: To characterize regulatory applications with RWE in the pre-approval setting by design, approach, and other parameters in the U.S. and Europe.

METHODS: RWE regulatory use cases were identified through systematic review and screening of publications (January 2016-June 2022) from PubMed, Embase, Web of Science, and from FDA/EMA regulatory review documents. Data was extracted and synthesized from eligible publications, and unique features such as RWD sources, study design, and endpoints used to support regulatory decision-making were characterized. Further, we conducted a detailed review and data extraction from FDA/EMA approval packages to provide additional information.

RESULTS: After screening, the systematic review identified 85 regulatory applications with RWE. Of these cases, 31 were in the oncology and 54 were in the non-oncology therapeutic area. Most were for indications in adults only (N=42, 49.4%), while 13 were in pediatrics only (15.3%) and 30 were in both (35.3%). In terms of regulatory use, 59 cases (69.4%) were approved through an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) for label modification. Most also received special regulatory designations (e.g., orphan indication, accelerated approval, breakthrough therapy, fast track, and conditional). A variety of data sources were utilized including electronic health records (18.8%), claims (2.4%), registries (24.7%), prior clinical trials (14.1%), literature (29.4%), and site-based chart data (18.8%). The common endpoints in oncology use cases were overall survival, progression-free-survival, and objective response while a wide range of endpoints were used in non-oncology use cases. In 13 use cases, RWE was not considered supportive/definitive in the regulatory decision-making due to design issues such as small sample size, selection bias, and missing data.

CONCLUSIONS: This review suggests that RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide a range of approaches and data sources.