OBJECTIVES: Provisions of the 2016 21st Century Cures Act include use of real-world evidence (RWE) to accelerate access to therapies in areas of high unmet need, such as rare disease. This review evaluates published RWE frameworks to assess common elements, including rare disease considerations, across regulatory and health technology assessment (HTA) agencies.

METHODS: Websites for HTA and regulatory agencies in the US (ICER, FDA), UK (NICE, MHRA), and Canada (CADTH, Health Canada) were searched to identify real-world data (RWD) and RWE frameworks. Inclusion criteria included: final framework version, English-language, and published 1-Jan-2018 to 14-December-2023. Each report was assessed (1=yes, 0=no) using 4 framework elements: RWE definition, data specifications/fit-for-use, analysis techniques/study designs, and rare disease considerations. Summary scores were compared by type of agency.

RESULTS: The review identified 13 reports, with a majority (69%, 9/13) published by US agencies (7 FDA, 2 ICER). HTA agencies comprised 4 out of the 13 reports. Four ex-US reports were identified (2 MHRA, 1 NICE, and 1 joint CADTH/Health Canada). Two reports (NICE’s RWE- framework, FDA’s RWE program) addressed all 4 framework elements; MHRA guidance on RWD did not cover any criteria (0/4). ‘RWE definition’ and ‘data specification/fit-for-use’ details appeared in most reports (11/13, 10/13, respectively) followed by ‘analysis techniques/study designs’ (8/13). Details related to ‘rare disease considerations’ (3/13) were covered by the FDA, ICER, and NICE. Across HTA agencies, ICER guidance covered 100% (4/4) of framework elements; NICE and the joint CADTH/Health Canada report addressed 75% (3/4). For other regulatory agencies, the FDA covered 100% (4/4), and one element was covered across the two MHRA reports.

CONCLUSIONS: US agencies published the majority of RWE frameworks identified. While regulatory agencies published more reports, HTA agencies covered RWE topics more comprehensively. Few RWE frameworks included rare disease considerations.