FDA Signals Greater Flexibility for Single-Trial Drug Approvals

On June 22, 2026, the U.S. Food and Drug Administration (“FDA” or the “Agency”) announced a new draft guidance, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” (the “2026 Draft Guidance”).¹See FDA, Draft Guidance for Industry, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (June 2026) [hereinafter 2026 Draft Guidance], https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products. The 2026 Draft Guidance provides an updated framework for how sponsors may satisfy the “substantial evidence of effectiveness” standard under 21 U.S.C. § 355(d), with a particular focus on when one adequate and well-controlled clinical investigation, plus confirmatory evidence, may support approval of a new drug application (NDA) or biologics license application (BLA).

For pharmaceutical and biologics manufacturers, this guidance carries strategic significance as it shifts from the 2019 “quality and quantity” evidentiary framework to a more integrated “strength of evidence” framework that evaluates design, conduct, analysis, results, confirmatory evidence, and the overall development program. It is also part of a broader U.S. Department of Health and Human Services (HHS) initiative, Operation TrialBlazer, which is intended to strengthen U.S. leadership in clinical research and accelerate development of innovative therapies.²See FDA, FDA Actions to Accelerate and Modernize Early and Late-Stage Clinical Development (updated June 22, 2026), https://www.fda.gov/industry/fda-actions-accelerate-and-modernize-early-and-late-stage-clinical-development. Operation TrialBlazer also includes additional FDA efforts to shorten early trial timelines and clarify evidentiary standards, National Institutes of Health support for AI, real-world data, and other trial modernization tools, Office of the National Coordinator for Health Information Technology work to connect patients with trials through electronic health records, Advanced Research Projects Agency for Health programs to modernize clinical research, and HHS OIG review of potential anti-kickback and beneficiary-inducement safe harbor issues related to clinical-trial participation. See HHS, Press Release, HHS Launches Unprecedented Department-Wide Effort to Restore American Leadership in Clinical Trials (June 22, 2026), https://www.hhs.gov/press-room/hhs-launches-clinical-trials-reform-initiative.html.

As part of this initiative, the HHS Office of Inspector General (OIG) published a Request for Information (RFI) seeking public input on whether modifications are needed to anti-kickback statute safe harbor regulations or civil monetary penalty exceptions for remuneration provided to clinical trial participants.³See HHS OIG, Request for Information, Medicare and State Health Care Programs: Fraud and Abuse; Request for Information Regarding the Federal Anti-Kickback Statute and Beneficiary Inducements CMP, 91 Fed. Reg. 37902 (June 24, 2026), https://www.federalregister.gov/documents/2026/06/24/2026-12676/medicare-and-state-health-care-programs-fraud-and-abuse-request-for-information-regarding-the; see also HHS, Press Release, HHS Launches Unprecedented Department-Wide Effort to Restore American Leadership in Clinical Trials (June 22, 2026), https://www.hhs.gov/press-room/hhs-launches-clinical-trials-reform-initiative.html. The RFI solicits comment on issues including whether remuneration facilitates trial participation, the types and amounts of remuneration stakeholders seek to provide, associated fraud and abuse risks, and appropriate safeguards. Comments on the OIG RFI are due by August 24, 2026.

When finalized, the 2026 Draft Guidance will replace FDA’s 1998 guidance⁴See FDA, Draft Guidance for Industry, Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (May 1998), https://www.fda.gov/media/71655/download. and supersede the December 2019 draft guidance on the same subject.⁵See FDA, Draft Guidance for Industry, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products (Dec. 2019),  [hereinafter 2019 Guidance], https://www.regulations.gov/document/FDA-2019-D-4964-0002. FDA is accepting comments on the 2026 Draft Guidance through September 22, 2026, and the Agency indicated that comments may inform further action regarding its 2023 draft guidance, “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence.”⁶See FDA, Notice of Availability, Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products; Revised Draft Guidance for Industry, 91 Fed. Reg. 37994, 37996 (June 24, 2026).

Statutory Requirements

The Federal Food, Drug, and Cosmetic Act (FDCA) requires that an NDA be supported by “substantial evidence” of effectiveness—defined as evidence from adequate and well-controlled investigations, including clinical investigations, by qualified experts from which it can fairly and responsibly be concluded that the drug will have the effect claimed in its labeling.⁷21 U.S.C. § 355(d). FDA may on the basis of “relevant science,” consider data from one adequate and well-controlled clinical investigation and confirmatory evidence obtained prior to or after that investigation as sufficient to constitute substantial evidence.⁸Id. For biologics, section 351(a) of the Public Health Service Act requires demonstration of safety, purity, and potency, with “potency” interpreted by FDA to encompass effectiveness.⁹21 C.F.R. § 600.3(s).

The 2026 Draft Guidance reflects FDA’s acknowledgment of continued advances in drug development science and the increasing availability of high-quality data sources.¹⁰See 2026 Draft Guidance § I at 1. The 2026 Draft Guidance includes substantial revisions from the 2019 Draft Guidance, which FDA frames as intended to help sponsors generate rigorous scientific evidence efficiently while maintaining the statutory standard for approval. In particular, the latest iteration reflects a move away from FDA’s prior default posture of two adequate and well-controlled investigations to a more expansive set of circumstances in which FDA may consider one adequate and well-controlled trial plus confirmatory evidence to be sufficient for demonstrating substantial evidence of effectiveness.

Single Clinical Trial with Confirmatory Evidence Framework

The 2026 Draft Guidance clarifies that one adequate and well-controlled clinical investigation, together with confirmatory evidence, may satisfy the substantial evidence standard. However, the strength of the single trial affects the strength of confirmatory evidence needed. As outlined below, where the single trial is less independently persuasive, FDA generally expects stronger confirmatory evidence from related adequate and well-controlled trial data. Conversely, where the single trial is designed and executed to be highly persuasive, FDA may accept early-phase confirmatory evidence if the totality of the evidence is sufficient.

Adequate and Well-Controlled Trial Plus Strong Confirmatory Evidence

Under this approach, FDA generally expects “strong confirmatory evidence [to] come from related adequate and well-controlled trial data, such as trial data in related diseases or conditions or for related products.”¹¹Id. § IV.A at 9. FDA assesses the strength of confirmatory evidence by considering:

• For a new indication of an already approved drug: similarity in disease pathophysiology and mechanism of action between the confirmed and target indications, as well as consistency of efficacy endpoints used across the relevant trials;
• For same-pharmacological-class evidence: mechanism similarity, endpoint consistency, effect consistency, number of approved drugs in the class, and whether the new drug demonstrates similar effects.

FDA cautioned that reliance on data concerning a different drug for confirmatory evidence may, in the absence of ownership or a right of reference, convert an NDA to a 505(b)(2) application.¹²2026 Draft Guidance at 10 n.34. For BLAs, an applicant cannot rely on FDA’s previous determination for another biologic and would need to meet 351(k) requirements for biosimilarity or obtain a right of reference.

Highly Persuasive Trial Plus Early-Phase Confirmatory Evidence

Where strong confirmatory evidence is unavailable at the time of planning the pivotal trial, the trial itself must be “highly persuasive.”¹³Id. §§ IV.A at 10-11. FDA articulates specific expectations for what constitutes a highly persuasive trial, including:

• A trial design that provides information that is generalizable and relevant to U.S. clinical practice;
• A trial design and analysis plan that uses clinically meaningful primary endpoints and is “sufficiently power[ed] to convincingly demonstrate an effect”;
• Clinically and statistically highly persuasive primary results, considering benefit magnitude and p-values;
• Supportive results on distinct prespecified secondary endpoints;
• Consistency of results across important patient subsets; and
• High-quality conduct, comprehensive follow-up, minimal missing data, and robust results under plausible assumption violations.¹⁴Id. § IV.A at 11.

FDA indicates that, when a single trial is designed to produce highly persuasive results, early-phase information used to justify proceeding to that trial may serve as sufficient confirmatory evidence. The final assessment, however, depends on the persuasiveness of the single trial results and the sufficiency of the confirmatory evidence.¹⁵Id. §§ IV.A at 11-12.

Practical Considerations and Limitations

• Strength of Evidence: FDA identifies several factors that can affect the strength of evidence of effectiveness, including the choice of control, quality of trial conduct, analysis plan, clinical and statistical persuasiveness of results, and the context of the overall development program.¹⁶See id. §§ III at 3-9. Accordingly, a statistically positive trial will not necessarily be persuasive if the design is vulnerable to bias, the endpoint is not clinically meaningful, the analysis depends on fragile assumptions, or the broader development program contains inconsistent results. In addition, FDA states that all relevant trial data will be considered, including evidence that may conflict with an otherwise positive trial.¹⁷See id. §§ III.E at 8–9.
• Safety Assessments: Sponsors should avoid conflating a single-trial effectiveness strategy with a single-trial development program. FDA states that effectiveness evidence sufficient for approval may still leave safety questions that require a larger, longer, or additional trial to support an adequate benefit-risk assessment.¹⁸See id. § VI at 16-17.
• Externally Controlled Trials: FDA clarifies that while such designs “often have a high potential for bias,” they can support effectiveness in certain circumstances, specifically where natural history is well defined, external and treatment populations are similar, concomitant treatments and endpoint ascertainment are comparable, and the prespecified effect size is sufficiently large to be unlikely attributable to bias alone.¹⁹Id. § III.A at 5.
• Regulatory Flexibility: FDA may apply scientific judgment to trial design, endpoint selection, analysis plans, success criteria, and the sources and strength of confirmatory evidence where the clinical context supports accepting greater uncertainty, such as in serious or life-threatening diseases, areas of unmet medical need, or rare disease settings. Even in those settings, substantial evidence of effectiveness must still be demonstrated. Real-world data fits into this framework as a potential source of confirmatory evidence, particularly where natural history data or registries can help corroborate the results of a single adequate and well-controlled trial.²⁰See id. § V.B.2 at 15-16. FDA cautions that such data should be distinct from any data used as the trial control.
• Timing: FDA recommends that sponsors discuss their anticipated approach to demonstrating substantial evidence early in development, such as at a pre-investigational new drug application meeting, and no later than the end-of-phase 2 meeting.²¹See id. § I at 2. Sponsors should be prepared to justify the proposed trial design, analysis plan, and confirmatory-evidence strategy.

Conclusion

The 2026 Draft Guidance is best understood as a roadmap for building a persuasive evidentiary package, not as a shortcut around the statutory standard. Sponsors considering reliance on one adequate and well-controlled trial should evaluate early whether their program can support either strong confirmatory evidence or a highly persuasive trial supported by sufficient confirmatory evidence.

The 2026 Draft Guidance is not yet in effect for implementation purposes. FDA is accepting comments until September 22, 2026. If you have questions or would like assistance drafting and submitting a comment, please do not hesitate to contact us.