FDA’s One-Pivotal-Trial Default: Scendea’s Perspective
Author:Dr Dmitry Zamoryakhin
Principal Medical Consultant
Introduction
The US Food and Drug Administration’s (FDA’s) February 2026 announcement, made public in the New England Journal of Medicine (NEJM), outlines that one adequate and well-controlled pivotal study, together with confirmatory evidence, will now be the agency’s default basis for product approval. This differs from the FDA’s previous general expectation of two independent, adequate, and well-controlled pivotal trials to demonstrate substantial evidence of effectiveness. The FDA advises that the new requirement (of only one pivotal study) should not be interpreted as a lowering of the evidentiary bar, but instead, as a shift away from counting trials and towards judging the overall credibility of the evidence package.
Scendea considers the evidence developed by the sponsor (to demonstrate the drug’s reliability, durability, and safety) more imperative than the number of pivotal studies conducted. When a drug has a very high level of efficacy, is biologically plausible, and has a significant clinical impact, a single, well-designed study can often demonstrate all of those things sufficiently for regulatory approval. This is particularly true for rare or life-threatening diseases, where there are fewer patients to recruit and enrol, and the benefits of the drug may be much clearer.
On the other hand, we acknowledge the risk of reducing the number of pivotal trials to one lies in the common scenario where a program achieves statistical significance but does not clearly change clinical practice. In such cases, a one-trial strategy can create a higher degree of risk for the sponsor because there may only be one chance to develop the correct endpoint, control arm, analysis plan, and confirmatory package. Furthermore, if a less-than-optimal single pivotal trial is carried out, the possibility of having to conduct another trial could significantly affect timing and eventual patient availability.
What is actually changing?
There is nothing new about the FDA’s jurisdiction to approve a product on the basis of one adequate and well controlled study plus confirmatory evidence. Since 1997, FDA has had this statutory authority and in 2023 issued a draft guidance called ‘Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence’. What is changing is the agency’s willingness to more broadly consider this as the default requirement for approval, rather than the exception.
The FDA also made it clear that there will be more scrutiny on the quality of the single pivotal study. The authors of the article emphasized that effect size, the use of a modern control group, the appropriateness of the comparator to the current standard of care, the selection of the primary endpoint(s), the statistical rigor employed, and the operational quality of the conduct of the trial, contribute to the credibility of the single pivotal study.
What is not changing?
This is not a simple rule that one trial with p < 0.05 is adequate. The FDA is not replacing the former two-trial mindset with a single numerical threshold. The emphasis remains on overall evidentiary strength. Furthermore, the concept of confirmatory evidence is not new. The agency has included it in their guidance documents, review practices, and regulatory communications for many years. However, the problem with confirmatory evidence is that it remains subjective and interpretative. Reviewers from different divisions of the agency may assign differing weights to factors such as, but not limited to, biomarkers, mechanistic data, natural history, real world evidence, regulatory precedence, and related indication experience.
Therefore, the new policy may offer sponsors greater clinical trial planning flexibility than predictability. Sponsors should not assume that confirmatory evidence will be interpreted broadly unless this has been discussed with the FDA in advance.
How Scendea interprets the policy announcement:
In cases where a program is obviously transformative and demonstrates a positive, significant, and long-lasting effect, and the biological rationale and selection of the primary endpoint(s) are convincing, a one trial approach is reasonable both scientifically and ethically. This is especially true in the rare disease space.
However, for the many programs where the potential therapeutic advantage is not as clear cut, the one-trial policy creates a single shot development model and a myriad of challenges. For example, a Phase II study may be described as "pivotal-ready" before the selected endpoint has been fully vetted, the optimal dose and regimen established, or the chosen control strategy has been properly stress tested. In many instances, the FDA has regarded Phase II studies as “hypothesis-generating” limiting its future use to support confirmatory evidence. Furthermore, if the subsequent pivotal study is later criticized regarding the chosen endpoint, dose and regimen, or the chosen control strategy, there may be no second pivotal study available to rectify the issues identified in the first pivotal study.
In addition, Scendea believes that the article’s acknowledgement of the need for "contemporary controls" and "best available standard of care" to indicate that the FDA will likely be less willing to accept suboptimal external controls or historical comparators unless the specific disease environment warrants such approaches and the associated biases have been thoroughly and formally evaluated.
Biological correlates, target engagement, and/or biomarker data can certainly enhance the credibility of a program, but alone rarely clarify an uncertain clinical story. Therefore, confirmatory evidence should help reduce remaining uncertainty and not serve as a substitute for unavoidable shortcomings in the original pivotal study.
What should sponsors do now?
Scendea recommends that sponsors:
Develop a clear target product profile and define your safety and efficacy evidence strategy early.
Clearly identify which study is pivotal and which aspects of your program are expected to provide confirmatory support.
Choose your primary endpoint(s) with great care and ensure that you have settled on the clinical meaning, measurement properties, timing of assessment, responder definitions, and missing-data assumptions prior to initiating your pivotal study. Make a thorough assessment of their acceptability from a precedent and regulatory perspective.
Use the most credible control arm possible. Where feasible, this means a contemporaneous randomised control using the best available standard of care.
Design your pivotal trial to stand on its own with a solid statistical approach that ensures reliability of the data to be generated. Confirmatory evidence should increase confidence in your findings, not provide a "safety net" for an inferior design.
Seek early FDA alignment and document it carefully. The narrower the development program, the less room there is for late changes in regulatory expectations.
Plan your post marketing evidence generation activities concurrently with your pivotal study, especially where the long-term durability, safety or real-world effectiveness of the drug will significantly affect the labelling and ultimate commercial success of the product.
Carefully consider regulatory requirements in other regions (e.g. EU, UK) where the general approach of two adequate well-designed clinical trials has not changed as of today.
Conclusion
At Scendea, we do not perceive the movement toward a one pivotal trial default as a weakening of the standard for approval. Rather, we see it as a strengthening of the requirements for trial design, execution, and interpretation for the pivotal trial that will drive approval.
In those instances where a product clearly demonstrates compelling efficacy and a well-understood biological rationale for the condition being treated - development and availability of the drug to patients can be accelerated. However, for the majority of programs demonstrating modest efficacy and/or evolving endpoints, a single trial approach will increase the risks associated with successful execution. Thus, we encourage sponsors to consider the new policy not as permission to do less, but as a requirement for trial rigor to ensure that the pivotal study counts for something meaningful and conclusive.
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