A Practical Guide to Implementing Real‐World Evidence as Primary Basis for Approval and Label Expansion

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Abstract
In June 2026, the FDA issued a revised draft guidance describing the circumstances in which one adequate and well‐controlled clinical investigation plus confirmatory evidence may satisfy the statutory substantial evidence standard for establishing efficacy and safety. Confirmatory evidence includes real‐world evidence (RWE). The evolution of the regulatory use of RWE builds on more than two decades of FDA experience with real‐world data (RWD), first for pharmacovigilance and later in effectiveness and risk/benefit determination. RWD/RWE guidances have been released since the 21st Century Cures Act was passed in 2016, but implementation remains operationally and methodologically challenging. This article provides practical guidance for teams considering RWE as part of a registrational program. Key topics include selection of fit‐for‐purpose data, study design, protocol development, study execution and governance, data transformation, analysis and assessment of residual bias, and submission. Recommendations emphasize early FDA alignment, filling gaps in procedural documentation and systems, multidisciplinary collaboration, and anticipating technological demands associated with large real‐world datasets.

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