FDA Revises Draft Guidance on Demonstrating Substantial Evidence of Effectiveness

Overview

On June 24, 2026, FDA published a revised version of its draft guidance titled “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” (the revised guidance).FDA, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products: Guidance for Industry (June 2026), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products. The revised guidance addresses public comments received in response to the December 2019 draft guidance of the same name. The revised draft guidance is part of Operation TrialBlazer, a broader US Department of Health and Human Services (HHS) initiative to modernize and accelerate all stages of medical product development in the US.FDA, FDA Actions to Accelerate and Modernize Early and Late-Stage Clinical Development (June 22, 2026), https://www.fda.gov/industry/fda-actions-accelerate-and-modernize-early-and-late-stage-clinical-development.

In the Federal Register notice announcing the revised guidance, FDA explains that changes from the 2019 guidance include: 1) streamlining discussion of the history of the substantial evidence of effectiveness standard to focus on current statutory and regulatory requirements; 2) addressing how confirmatory evidence to support a single-trial development program may vary depending on the strength of the single adequate and well-controlled clinical investigation; and 3) providing more discussion of meeting the substantial evidence of effectiveness standard with one adequate and well-controlled clinical investigation plus confirmatory evidence across the breadth of development programs.

The draft guidance opens with an introduction and discussion of the statutory standard for substantial evidence of effectiveness. It then turns to four substantive topics:

• First, it includes a section on the factors that FDA believes impact the strength of evidence of effectiveness. These include the design, conduct, analysis plan, and results of a clinical trial, as well as other aspects of the overall development plan for the product.
• Second, it describes various approaches for designing “high-quality development programs” to meet the statutory standard for substantial evidence of effectiveness, including one adequate and well-controlled clinical investigation plus confirmatory evidence, more than one adequate and well-controlled clinical investigation, and reliance on the known effectiveness of an approved drug.
• Third, it discusses regulatory flexibility, addressing the clinical circumstances in which flexibility may be warranted and how that flexibility may be applied to trial design, analysis, and the sources and strength of confirmatory evidence.
• Finally, it notes that safety is a key part of any development program, and that a larger or longer trial — or even an additional trial — may be needed in certain cases to ensure a safety database of adequate size and duration to support an appropriate benefit-risk assessment.

With these revisions, the draft guidance essentially rewrites the 2019 draft guidance, which FDA published to complement and expand upon its separate 1998 guidance titled “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.”FDA, Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998), https://www.fda.gov/media/71655/download. Once final, the revised guidance will replace the 1998 guidance.

In 2023, FDA separately issued a draft guidance titled “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence” (2023 draft guidance).FDA, Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence: Draft Guidance (Sep. 2023), https://www.fda.gov/media/172166/download. The 2023 draft guidance provides a comprehensive discussion about meeting the substantial evidence of effectiveness with one adequate and well-controlled clinical investigation plus confirmatory evidence. This revised guidance builds upon the 2023 draft guidance in meaningful ways, including by stating that either a highly persuasive trial or strong confirmatory evidence will generally be needed to support a single-trial development program. Given both the differences and overlap between the two draft guidance documents, sponsors should carefully read both before initiating a single pivotal trial. The 2023 draft guidance, for example, includes a more comprehensive discussion of the sources of confirmatory evidence that can support a single-trial program.

Overall, the revised guidance meaningfully rewrites the 2019 guidance, but it largely expresses what has become FDA’s current practice and what FDA has described in other guidance and documents.For example, in a 2026 New England Journal of Medicine piece, then-Commissioner Martin Makary and then-CBER Director Vinay Prasad declared one pivotal trial the FDA’s default standard. See Vinay Prasad, M.D., M.P.H. and Martin A. Makary, M.D., M.P.H., One Pivotal Trial, the New Default Option for FDA Approval – Ending the Two-Trial Dogma, N.E.J.M., https://www.nejm.org/doi/abs/10.1056/NEJMsb2517623. The key takeaway is that it formally positions one adequate and well-controlled investigation plus confirmatory evidence as the default requirement for drug and biologic development programs. In the 2019 guidance, FDA states that “substantiation of a drug’s effectiveness obtained with two trials, especially with complementary design... will provide more convincing evidence of effectiveness than would a single trial.” The revised guidance departs from this characterization of a two-trial program, stating only that “[s]ubstantiation of results across independent, adequate and well-controlled trials can help provide strong evidence of effectiveness” and that sponsors “may opt to conduct more than one adequate and well-controlled investigation based on the needs of their specific development programs.” 

The revised guidance does appear to set forth a new standard for single-trial programs. FDA states that it generally expects that a demonstration of substantial evidence of effectiveness with the single-trial approach will involve “a highly persuasive trial or a source of strong confirmatory evidence.” In cases when “strong confirmatory evidence may not be available, evidence from “a highly persuasive adequate and well-controlled trial will be needed to establish substantial evidence of effectiveness.” This also appears to be a move from FDA’s 2023 draft guidance, which described more of a sliding scale review, noting that “[i]t may be possible for a highly persuasive adequate and well-controlled clinical investigation to be supported by a lesser quantity of confirmatory evidence, whereas a less-persuasive adequate and well-controlled clinical investigation may require a greater quantity of compelling confirmatory evidence to allow for a conclusion of substantial evidence of effectiveness.”

Factors Impacting the Strength of Evidence

FDA highlights in the revised guidance the key factors that it believes impact the strength of evidence of effectiveness. As previewed above, these include key clinical trial design elements, the quality of trial conduct, aspects of the trial analysis, the clinical and statistical persuasiveness of trial results, and aspects of the overall drug development program.

• Trial Design: FDA states that two critical elements are the choice of control and the method of assignment to treatment (e.g., randomization). The choice of trial endpoints — particularly the primary endpoint — is another important design element, and a clinical endpoint is the preferred measure when feasible. FDA also flags that trial designs should provide information that is relevant to patients and prescribers in clinical practice. To this end, eligibility criteria should be selected to reflect the intended-use population.
• Trial Conduct: FDA highlights the importance of clinical trial conduct, stating that “[p]oor execution can render a trial of any design not adequate or not well-controlled and, therefore, unable to contribute to substantial evidence of effectiveness.”
• Trial Analysis Plan: FDA indicates that it expects an adequate and well-controlled trial to have a “prespecified primary analysis that is aligned with a clinically meaningful primary estimand.” The prespecified analysis plan, FDA notes, should include “appropriate statistical methods.” Notably, FDA states that when regulatory flexibility is warranted, it may consider “flexibility in the significance level expected,” and that there should be “early communication and agreement with FDA at the design stage of the specification of the prior distribution and the success criteria.”
• Trial Results: FDA notes that many different considerations influence the overall persuasiveness of a trial’s results. It specifically mentions that the effect shown in the adequate and well-controlled trial must be, in FDA’s judgment, “clinically meaningful.” According to FDA, this determination depends on the relevance of the endpoint and the magnitude of the estimated treatment effect.
• Aspects of the Overall Development Program: FDA will consider the persuasiveness and interpretation of an individual trial’s results in the context of the overall drug development program, including any trial data FDA considers relevant for assessing the effectiveness of the drug, such as data from early-phase trials. FDA explains that if a program has multiple adequate and well-controlled trials, a trial producing an estimate of no effect, or even harm, could cast doubt on the results from other trials in the program.

Approaches to Meeting the Substantial Evidence Standard

FDA lays out three approaches for sponsors to meet the substantial evidence standard, focusing in particular on the single-trial approach. For this route, FDA says that it “generally expects” that a demonstration of substantial evidence of effectiveness will involve a highly persuasive trial or a source of strong confirmatory evidence. FDA expects that a single highly persuasive trial will:

• Use a design that provides information that is generalizable and relevant to clinical practice in the US
• Use a design and analysis plan intended to provide clinically and statistically highly persuasive results, meaning it uses a clinically meaningful primary endpoint and has sufficient statistical power
• Generate primary analysis results that are clinically and statistically highly persuasive based on the clinical meaningfulness of the estimated magnitude of benefit
• Generate results that are supportive for distinct prespecified secondary endpoints and are largely supportive across important trial subsets
• Have high-quality conduct, including comprehensive follow-up and minimal missing data

If a trial is highly persuasive based on these characteristics, FDA expects that available early-phase information may be able to provide sufficient confirmatory evidence. FDA also notes that the results from such a trial may even render a second trial “impractical or unethical.”

FDA states that sponsors may also conduct multiple adequate and well-controlled trials to provide strong evidence of effectiveness, but unlike the 2019 draft guidance, it does not frame this approach as the default route. FDA states that review divisions “may . . . recommend more than one adequate and well-controlled trial in some settings,” and it provides examples of when a second trial “may be appropriate.” But even in these circumstances, FDA states that sponsors can “propose alternative single adequate and well-controlled trial designs intended to address the limitations.”

When scientifically justified and legally permissible, sponsors can also leverage the “known effectiveness of an approved drug” to provide substantial evidence of effectiveness for a new use or condition. In these cases, the effectiveness of a new dose, regimen, route of administration, or dosage form may be demonstrated by the trial(s) that used the original dose, regimen, route of administration, or dosage form, together with evidence that the new modification yields similar pharmacokinetic (PK) profiles or evidence that any differences in pharmacokinetics are not expected to produce clinically relevant differences in effectiveness.

Regulatory Flexibility

FDA dedicates a section of the revised draft guidance to its exercise of regulatory flexibility. FDA says that, in certain critical settings, it may accept somewhat greater uncertainty about effectiveness when that uncertainty is weighed against the risk of rejecting or delaying an effective therapy. FDA identifies three clinical considerations that influence its decision to exercise regulatory flexibility — disease severity, unmet medical need, and disease rarity — and stresses that it weighs these considerations holistically rather than individually. FDA explains that regulatory flexibility can also be applied to trial design and analysis. FDA may, for example, accept a significance level higher than the common one-sided 0.025 level when prespecified, justified, and agreed upon in advance. It may also exercise flexibility with the sources and strength of confirmatory evidence for a single-trial program, such as relying on mechanistic evidence where the disease pathophysiology and the drug’s mechanism of action are well understood.

Practical Implications for Sponsors

• Plan for a single-trial program as a viable possibility: FDA suggests that one adequate and well-controlled trial plus confirmatory evidence is the new norm, shifting the focus away from the prior default of two adequate and well-controlled trials.
• Engage FDA early: Regardless of the approach taken, FDA stresses that sponsors should discuss their proposed development program with FDA early in development, and no later than at the end-of-phase 2 meeting.
• Build toward a highly persuasive trial: Sponsors considering a single-trial approach should read the revised guidance closely to ensure their trial matches the characteristics FDA associates with a highly persuasive trial. These include a generalizable, representative design across multiple sites, a control arm, a clinically meaningful primary endpoint, and sufficient power to convincingly demonstrate an effect.
• Ensure an adequately sized safety database: FDA emphasizes that a finding of substantial evidence of effectiveness is necessary but not sufficient for approval, which also requires sufficient safety data and a favorable risk-benefit determination. In addition to ensuring a trial is highly persuasive, sponsors should plan to generate a safety database of adequate size and duration.

Conclusion

While the revised draft guidance does not change the underlying statutory or regulatory paradigm for demonstrating substantial evidence of effectiveness, it introduces new concepts that sponsors should carefully examine. To ensure that FDA considers comments on the revised draft guidance before it begins work on the final version, sponsors should submit written or electronic comments by September 22, 2026. FDA is soliciting comments on any aspects of the 1998 guidance that are not captured in the revised draft guidance and should be captured in the final guidance. FDA will also consider comments received on the revised draft guidance to inform future action, which may include further action regarding the 2023 draft guidance.