OBJECTIVES: Real-world evidence (RWE) has played a growing role in supporting clinical trial designs and has increasing implications in regulatory decision-making for new and expanded indication approvals, coverage decisions, and post-market safety monitoring. In December 2018, the FDA issued a framework for the agency’s RWE program. The agency has since issued several guidance documents on types of RWE and considerations for using RWE to support regulatory decisions and data standards for submitted real-world data (RWD). This review evaluated examples of RWE in regulatory submissions to the FDA following the issuance of the framework to provide a recent understanding of how RWE has been utilized to support new regulatory submissions and the resulting feedback from agency review.

METHODS: A targeted literature review was conducted to evaluate examples of regulatory submissions which used RWE in NDAs and BLAs reviewed and approved by the FDA between 2019 and 2021. Examples of new drug approvals and indication expansions were selected for analysis of RWE type, design, comparison to pivotal clinical trial, and FDA comment to determine whether RWE successfully contributed to the drug approval. The search included drugs from any therapeutic area but excluded examples of medical device approvals.

RESULTS: Fourteen examples of new drug approvals and indication expansions were selected through the literature search. Sources of data were primarily registries, EHR data, and chart reviews. Other RWE sources included external control data from previously conducted clinical trials and natural history studies.

CONCLUSIONS: Different sources such as registries, EHR data, and chart reviews were used within submissions. The primary focus of FDA review was on how RWE was compared to or contextualized with the main clinical trial as well as how the RWD component was selected, designed, and analyzed using statistical methods.