OBJECTIVES: Real-world evidence (RWE) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This study aimed to evaluate the use of RWE generated for RD therapies to support regulatory application packages to the US Food and Drug Administration (FDA).

METHODS: New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened and manually reviewed using RWE related keywords. The qualitative synthesis was focused on key categories of output to determine the role of RWE outcomes in the overall drug approval process, including reviewer’s feedback on its strengths and key challenges.

RESULTS: A total of 868 NDAs and BLAs were screened for non-oncologic RDs, and 151 were subsequently reviewed for the real-world data (RWD) used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications of non-oncologic products with orphan designation were included in the review. Most (18; 90%) applications used only retrospective RWD, while two applications (10%) collected RWD both retrospectively and prospectively. RWD studies included RD registries (2; 10%), natural history/historical controls (12; 60%), medical chart-reviews (4; 20%), and external controls from other studies (2; 10%). The FDA critiqued applications due to differences in patients’ baseline characteristics, subjective evaluations of disease severity, non-standardized primary endpoints, incomplete information on genotypes/concomitant medication/diet management, and statistical issues (e.g., censoring imbalances, matching imprecision, covariate measurement errors, and unmet model-assumptions).

CONCLUSIONS: This review demonstrated how appropriately conducted RWE studies in RD can strengthen the clinical evidence for contextualization or efficacy comparison, to support product approval efforts. However, the quality and completeness of RWD as well as other critiques towards its comparability with trial data are noted to serve as learnings to advance future science and regulatory approvals.