One Pivotal Trial as the “New Default” for FDA Approval: Is FDA Really Changing Course?
FDA’s February 2026 New England Journal of Medicine article, “One Pivotal Trial, the New Default Option for FDA Approval,” generated immediate attention across the biopharmaceutical industry.1 Many sponsors and investors interpreted the article as signaling a major shift away from FDA’s longstanding expectation that two successful pivotal studies are generally required to support approval of a new drug.
If this is true, then the implications would be substantial, as a second Phase 3 study can add years of development time and potentially hundreds of millions of dollars in cost. Therefore, this announcement would significantly impact product development strategies across the industry.
However, the reality may be more nuanced. FDA’s legal authority and scientific framework have allowed approval based on one adequate and well-controlled study for decades. The February 2026 announcement may therefore represent an operational and culture shift within FDA, rather than establishing a new evidentiary standard.
The Historical Framework
The modern FDA effectiveness standard originated with the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act, which established the requirement for “substantial evidence” of effectiveness from “adequate and well-controlled investigations.” Historically, FDA interpreted substantial evidence to mean at least two adequate and well-controlled clinical investigations providing independent substantiation of experimental results, reducing the risk that positive findings occurred because of chance, bias, operational problems, or unrecognized confounding factors.
Over time, however, rigid application of the two-study paradigm became increasingly difficult as the industry expanded further into serious conditions and orphan product development. Rare diseases lacked sufficient patient populations for multiple large studies, and in some situations, treatment effects for serious conditions were sufficiently dramatic that requiring a second confirmatory study appeared unnecessary and even unethical.
Congress addressed this issue through the Food and Drug Administration Modernization Act (FDAMA) of 1997, which explicitly allowed FDA to conclude that “one adequate and well-controlled clinical investigation and confirmatory evidence” could constitute substantial evidence of effectiveness.2 That statutory change formed the basis for FDA’s influential 1998 guidance, “Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.”3
What the 1998 Guidance Already Allowed
The 1998 guidance is often remembered as preserving the traditional two-study paradigm while allowing rare exceptions. In reality, however, the guidance introduced considerable flexibility regarding FDA’s acceptance of a single adequate and well-controlled study under appropriate circumstances.
The guidance explained that a single study could support approval when the findings were especially persuasive and supported by additional confirmatory evidence. Importantly, the definition of confirmatory evidence was broad and could include pharmacodynamic findings, related clinical data, mechanistic evidence, epidemiologic information, or evidence from related indications.
In certain circumstances, a single adequate and well-controlled study, by itself, may be sufficient for approval without additional confirmatory evidence, if the study has demonstrated a clinically meaningful effect on mortality, irreversible morbidity, or prevention of a disease with potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible.
Factors strengthening a single study approach include a large multicenter design, statistically very persuasive findings, consistency across study subsets, and multiple endpoints involving different effects.
In retrospect, many elements emphasized in FDA’s 2026 policy announcement were already present in the 1998 guidance released nearly thirty years ago.
The 2019 and 2023 Guidances
In the last 10 years, FDA issued two additional draft guidances building on the 1998 evidentiary framework. The 2019 draft guidance, “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products,” broadened the concept of FDA’s evidentiary flexibility by emphasizing the clinical context and the persuasiveness of the overall evidence to support approval.4
Draft guidance in 2023, “Demonstrating Substantial Evidence of Effectiveness Based on One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence,” expanded further on acceptable confirmatory evidence, with examples including real-world evidence, natural history data, mechanistic evidence, pharmacodynamic biomarkers, and evidence from related products in the same pharmacologic class.5 This guidance also introduced the consideration that highly persuasive single trials may require only modest confirmatory evidence, while less compelling studies would require stronger supporting data.
What FDA’s 2026 Announcement Really Changes
While it is notable that the statutory requirements for “substantial evidence of effectiveness” have not changed since FDAMA in 1997, the February 2026 NEJM article is still important, not because it creates or invokes new legal or statutory authority but because it appears intended to reshape the review culture and operational approach at FDA. Historically, many sponsors have negotiated development programs with FDA assuming the practical default consists of two successful pivotal studies unless extraordinary circumstances justified an alternative approach.
FDA’s new messaging is intended to reverse that presumption. The Agency is now overtly signaling to both internal FDA personnel as well as industry stakeholders that one pivotal study should be considered a routine development option rather than a rare exception. Trial quality and persuasiveness matter more than the number of studies, and FDA review divisions should avoid reflexively requiring a second confirmatory study when one study is sufficiently convincing.
What This Means for Trial Sponsors
The key issue is not whether FDA will continue accepting one-study approvals in oncology, rare diseases, gene therapy and precision medicine, where flexibility already exists. Instead, the more important question is whether FDA will increasingly permit one-study registration strategies for non-serious and more prevalent conditions.
Although this distinction may seem subtle, it can profoundly affect a sponsor’s development strategy and approach when engaging with FDA. In any therapeutic area, sponsors should now feel more empowered to try to negotiate streamlined registrational strategies with FDA involving a single pivotal study, and the future debate should not center on whether one study is enough. Instead, sponsors must be ready to address the critical question early in development: What combination of evidence, including strong confirmatory data, will make one study sufficiently convincing to support approval, and what needs to be done to generate that evidence?
In turn, FDA reviewers have greater flexibility to evaluate these modern approaches, supporting the acceptance of one robust study rather than defaulting to two based on historical precedent.
As has always been the case, not every development program will be well suited for a one-study strategy. Characteristics favoring a single-study approach likely include large and clinically obvious treatment effects on objective endpoints, strong mechanistic plausibility, consistency across analyses, high-quality trial conduct, and significant unmet medical need.
Conclusion
FDA’s February 2026 “One Pivotal Trial, the New Default Option for FDA Approval” announcement has been widely portrayed as a major departure from historical approval standards. In reality, FDA has possessed the statutory authority and regulatory flexibility to approve drugs based on one adequate and well-controlled study since FDAMA in 1997 and subsequent guidances have only expanded the framework for doing so.
What appears genuinely new is FDA’s effort to reposition the one-study paradigm from an exceptional pathway requiring special justification to a mainstream development option. Whether this ultimately produces materially faster approvals across broader therapeutic areas remains to be seen.
But the most significant impact may occur much earlier in development. Sponsors should now be more willing to engage FDA early regarding what evidence package may be sufficient to support approval based on a single pivotal study.
References
- Prasad V, Makary MA. One Pivotal Trial, the New Default Option for FDA Approval—Ending the Two-Trial Dogma. N Engl J Med. 2026;394:815-817. doi:10.1056/NEJMsb2517623.
- Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, §115, 111 Stat. 2296 (1997).
- U.S. Food and Drug Administration. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products: Guidance for Industry. May 1998.
- U.S. Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products: Draft Guidance for Industry. December 2019.
- U.S. Food and Drug Administration. Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence: Draft Guidance for Industry. September 2023.
