FDA Revises Draft Guidance On Substantial Evidence Of Effectiveness To Clarify Confirmatory Evidence Requirements For A Single Clinical Investigation

On June 25, 2026, the U.S. Food and Drug Administration (FDA) announced the availability of revised draft guidance titled “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.” The original draft guidance was issued in December 2019. When finalized, the revised draft guidance will replace the FDA’s 1998 guidance titled “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.”

The revised draft guidance provides recommendations to applicants seeking to meet the substantial evidence of effectiveness standard in support of new drug applications, biologics license applications, and related supplements. According to the Federal Register notice, FDA revised the draft guidance in response to public comments on the 2019 draft guidance, as well as advances in the understanding of biological processes and the increasing availability of high-quality data. The revised draft guidance emphasizes the circumstances in which a single adequate and well-controlled clinical investigation, together with confirmatory evidence, may satisfy the substantial evidence of effectiveness standard.

Changes from the 2019 draft guidance include: (1) streamlining the history of the standard to focus on current requirements; (2) clarifying the need for confirmatory evidence when relying on a single clinical investigation to meet the standard; and (3) expanding the discussion of how a single clinical investigation together with confirmatory evidence may satisfy the standard across a range of drug development programs.

The deadline to submit comments on the revised draft guidance is September 22, 2026.

The revised draft guidance is complemented by the FDA’s 2023 draft guidance titled “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence,” which focuses specifically on the use of a single adequate and well-controlled clinical investigation together with confirmatory evidence. The FDA notes that comments submitted on the 2026 revised draft guidance may inform future action on the 2023 draft guidance, which also remains open for comment.