FDA Emphasizes Totality-of-the-evidence Approach In Revised “substantial Evidence” Draft Guidance For Drugs, Biologics

In January 2026, (now former) U.S. Food and Drug Administration (FDA) leaders described a “single trial default” approach in a New England Journal of Medicine (NEJM) article, and in the months since, stakeholders have speculated about the meaning of a new policy announced outside of FDA's guidance process. Last week, a letter from the Acting FDA Commissioner provided additional context, referencing FDA's guidance database—and no other source—as the place where “statements of policy and interpretations of statutes and regulations” were listed. In the same letter, the Commissioner explained that an earlier article by the same authors “did not communicate FDA policy or interpretation of a regulatory issue.”

This development comes shortly after FDA provided greater clarity on evolving evidentiary standards by publishing a revised draft guidance on “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.” The revised guidance builds on FDA's longstanding interpretation of its statutory authority under which FDA may rely on a single adequate and well-controlled trial plus confirmatory evidence to establish substantial evidence of effectiveness. The draft guidance signals emphasis on a totality‑of‑evidence approach that is likely to preserve significant discretion within inpidual review pisions but does not explicitly endorse a single trial default. The revised draft guidance also reframes “regulatory flexibility” as a principle-based tool, increases the focus on safety data requirements, and expands acceptance of alternative statistical approaches and real-world evidence. FDA invites comments through September 22.

Background

Under the federal Food, Drug, and Cosmetic Act, a drug’s effectiveness must be established by “substantial evidence,” which is defined as:

“…adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”

This language was historically interpreted to require two adequate and well-controlled clinical trials, but in 1997, as part of the FDA Modernization Act, Congress amended section 505(d) to explicitly authorize FDA to find “substantial evidence of effectiveness” if it determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness. Thus, for more than 25 years, FDA has had explicit statutory authority to determine that a new drug is effective based on data from a single trial paired with “confirmatory evidence.”

In the months preceding introduction of this new statutory language, FDA had issued draft guidance on “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products” that described the characteristics that might cause a single trial to be sufficient as substantial evidence of effectiveness. This guidance was finalized May 15, 1998, shortly after the statutory provision was passed. The guidance explained that FDA may consider a single adequate and well-controlled study together with other supportive evidence, or, in limited circumstances, rely on a single robust multicenter study demonstrating a highly reliable and statistically strong evidence of clinical benefit (e.g., survival effect). In December 2019, FDA issued draft guidance on “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products,” intended to replace the 1998 guidance when finalized. The 2019 guidance clarified that while “substantial evidence of effectiveness” requires adequate and well-controlled clinical investigations, the standard is flexible and can be met with different types and amounts of evidence—including with a single adequate and well-controlled trial with confirmatory evidence—depending on outcomes. The 2019 draft guidance similarly explained that a single large, multicenter trial may, in some circumstances, provide evidence comparable to multiple trials. It further noted that reliance on a single study is generally most appropriate when the effect is clinically meaningful and statistically persuasive, particularly where conducting a second trial would be impracticable or unethical.

In September 2023, FDA supplemented its 2019 guidance with draft guidance on “Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence,” which explains in more detail how sponsors of drugs and biologics can rely on a single adequate and well-controlled clinical investigation and confirmatory evidence to support a finding of “substantial evidence” of effectiveness (SEE). This guidance continued FDA’s trend toward signaling an openness to accepting evidence from a single trial, together with confirmatory evidence, in drug and biologic approval reviews.

In February 2026, FDA’s then-Commissioner Marty Makary and then-Director of CBER Vinay Prasad published an NEJM article announcing the agency would shift to a default drug approval standard of a single robust pivotal trial, instead of the previous standard of two pivotal trials. Later that month, FDA published draft guidance formalizing a “plausible mechanism” approval framework for inpidualized therapies, clarifying areas where the agency may exercise greater “regulatory flexibility” in assessing evidence of effectiveness for certain inpidualized therapies, essentially an interpretation of the single trial plus confirmatory evidence standard.

The format of the single-trial default announcement and the subsequent departure of its authors left open questions about whether and how the announced default would be implemented. Now, FDA has published a revised draft guidance clarifying the agency’s current thinking on how sponsors can demonstrate “substantial evidence of effectiveness” in new drug applications (NDAs), biologics license applications (BLAs), and supplements. The guidance does not go so far as to establish a new default evidentiary standard, although the Department of Health and Human Services has characterized the draft guidance as “clarifying that, in many cases, one high-quality late-stage clinical trial with confirmatory evidence will generally be sufficient to provide substantial evidence of effectiveness in support of a drug approval.”

The guidance was published as part of “Operation TrialBlazer,” a coordinated initiative to promote early-stage clinical research in the U.S., which we summarized online here.

Changes to the guidance and implications for sponsors

Compared to the 1998 and 2019 guidance documents, the revision focuses on how sponsors can rely on “one scientifically rigorous adequate and well-controlled clinical investigation with confirmatory evidence” to satisfy the statutory “substantial evidence of effectiveness” standard. Instead of centering the guidance around the number of trials, the 2026 version focuses on a totality-of-evidence assessment, highlighting advances in FDA’s understanding of biological processes and data quality. This represents a more holistic decision model, aligning with recent FDA practice as described above.

Most significantly, in the 2026 version of the guidance, the “single trial plus confirmatory evidence” pathway is promoted as a routine pathway to satisfying the SEE standard, rather than an exception. The revision further splits the “single trial” pathway into two sub-pathways: a) a single trial plus strong external confirmatory evidence; and b) a “highly persuasive” single trial plus early-phase confirmatory evidence. The revision defines “highly persuasive” as:

• Clinically meaningful endpoints (e.g., survival)
• Strong statistical evidence (e.g., stringent significance levels)
• Robust subgroup consistency
• High-quality conduct and minimal missing data

The draft guidance also raises several practical and strategic considerations for sponsors:

• Continued emphasis on a “totality of evidence” framework—without a clear reduction in evidentiary burden. FDA continues to emphasize that SEE determinations will be made on a case-by-case basis, based on the overall strength of evidence. In practice, these changes may reflect a formalization of flexibility that review pisions have historically exercised, rather than a categorical change in evidentiary expectations.
• Greater discretion at the review pision level. The guidance’s principle-based approach to “regulatory flexibility” and “strength of evidence” may reinforce application specific decision making. While this aligns with FDA’s historical practice, it may increase variability in how evidentiary standards are applied across pisions and therapeutic areas, and it places a premium on early and frequent engagement with FDA.
• Clarification—but not resolution—of the role of non-trial and cross-product evidence. The guidance identifies a broad set of potential sources of confirmatory evidence, including mechanistic data, pharmacologic class effects, real-world evidence, and external clinical data. However, it does not fully resolve the extent to which sponsors can rely on evidence generated from other products or programs—particularly biologics sponsors, given the absence of a statutory analog to the 505(b)(2) pathway.
• Heightened importance of trial design and evidentiary “persuasiveness.” The articulation of a “highly persuasive” trial and the expanded discussion of factors such as estimands, missing data, adherence, and prespecified analyses provide a clearer framework for designing development programs intended to support approval based on a single pivotal study. This additional clarity may be useful for sponsors determining whether to pursue a second trial or proceed with a single-trial submission supported by confirmatory evidence.
• Potential implications for regulatory strategy and advocacy. The guidance may shift, at least at the margins, how sponsors and FDA articulate the justification for requiring multiple trials. Even if this does not materially change approval outcomes, it may provide an additional foundation for sponsors to argue that a single trial plus confirmatory evidence package satisfies the statutory standard during FDA review and, if necessary, in dispute resolution, while requiring FDA to more clearly articulate the rationale for requesting additional trials. However, substantial evidence of effectiveness remains a necessary, but not sufficient, condition for approval. FDA must also determine that the available safety data are adequate to support a favorable benefit-risk assessment, and the revised guidance recognizes that larger, longer, or additional studies may be needed to establish an appropriate safety database even where effectiveness has been demonstrated.
• Interaction with broader policy trends. The guidance should be understood in the context of a broader recalibration of FDA processes following the departure of Dr. Makary, including recent statements from current agency leadership indicating a renewed emphasis on convening advisory committee meetings for contested or high‑profile applications. These trends point toward a “normalization” of FDA decision making—characterized by greater reliance on established procedural mechanisms and pision-level scientific judgment, with evidentiary conclusions increasingly tested both within review pisions and, in some cases, in public advisory settings. These dynamics reinforce the importance for sponsors of developing a well-supported evidentiary record and a clearly articulated scientific rationale for their development approach, rather than a categorial change in agency practices.

Next steps

It is important to remember that whether one “scientifically rigorous adequate and well-controlled clinical investigation with confirmatory evidence” provides substantial evidence of effectiveness is determined on a case-by-case basis. Sponsors should be careful to plan FDA communications and development strategy to ensure that data they generate in a single pivotal trial—and the confirmatory evidence they will offer in support—will satisfy FDA's expectations, and will not result in a complete response letter.

FDA seeks comments on the guidance through September 22. If you wish to submit a comment, or have any questions on using clinical investigations and confirmatory evidence to demonstrate substantial evidence, reach out to any of the authors of this alert or the Hogan Lovells Cadwalader attorney with whom you regularly work.

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