OBJECTIVES: The 21st Century Cures Act has played a pivotal role in accelerating the use of real-world evidence (RWE) into regulatory decision-making. It has led to significant changes in incorporating RWE into drug development regulation. This research aims to identify cases applying RWE in FDA approvals for New Drug Applications (NDAs) and Biologics License Applications (BLAs) and to understand the contribution of RWE in the US regulatory process.

METHODS: To identify cases applying RWE, we reviewed NDA and BLA approvals from 2021 to 2022 in the Drugs@FDA database. Approvals for new molecular entities (NMEs) with NDA type 1 and type 9 were included based on FDA's classification system. We examined RWE keywords through FDA review documents.

RESULTS: Between 2021 and 2022, the FDA approved 255 NDA and BLA submissions. 92% of 88 NME cases incorporated RWE in their submissions to support the therapeutics context. Among these, 16 cases used RWE to support either effectiveness or safety, with oncology (31.3%) being the most common therapeutics area, followed by neurology (12.5%), dermatology (12.5%), and endocrinology/metabolism/bone (12.5%). Notably, 75% of these cases received at least one of the designations-priority review, orphan drug, breakthrough therapy, and fast track, indicating high unmet needs. The application of fosdenopterin utilized RWE as primary evidence for effectiveness, while others used RWE as supportive evidence. However, 3 cases incorporating RWE to support effectiveness did not provide adequate evidence for decision making.

CONCLUSIONS: In recent FDA’s regulatory decisions for NMEs, RWE have been incorporated into their submissions for diseases with high unmet needs. To support effectiveness, RWE has been applied as an external control arm to compare with single-arm trials or as a description of the disease’s natural history. However, it is crucial to address biases during the analysis to minimize potential harmful effects.