Single pivotal trials: Stakeholders seek definitions, clarification about evidentiary standard

Industry groups and other stakeholders are generally supportive of FDA’s recent draft guidance explaining when single pivotal trials plus confirmatory evidence can be used to support the approval of drugs and biologics; however, the commenters were split over how flexible the agency should be in its approach and asked for additional clarity

While the commenters broadly agreed that two pivotal trials should not be the automatic approach, they sought clarification about the agency’s evidentiary standard and asked for clear definitions of terms and thresholds presented in the guidance, including terms like “highly persuasive” trial results and “strong confirmatory evidence,” as well as how many US patients should be enrolled in multiregional trials to be sufficient.

The comments were submitted in response to FDA’s revised draft guidance on demonstrating substantial evidence of effectiveness for drugs and biologics, which was issued in June alongside other actions meant to hasten clinical development under Operation TrialBlazer. (RELATED: HHS and FDA propose clinical trial reforms to expedite drug development, Regulatory Focus 23 June 2026)

Industry comments

The drug lobby group PhRMA called on FDA to explicitly state that one adequate and well-controlled trial and confirmatory evidence was sufficient to demonstrate substantial evidence of effectiveness, and two pivotal trials is not the default requirement.

The group asked the agency to define key terms such as “source of strong confirmatory evidence” and “early-phase confirmatory evidence,” and to clarify concepts presented in the guidance to support such evidence. PhRMA also urged the agency to clarify that the guidance does not create two subclasses of the evidentiary standard.

"PhRMA is concerned that, by differentiating between an adequate and well-controlled trial supported by strong confirmatory evidence and a highly persuasive adequate and well-controlled trial supported by early-phase confirmatory evidence, the Draft Guidance effectively establishes two subclasses within the substantial evidence standard," said PhRMA. "Creating subclasses would risk disadvantaging affected products in the marketplace.

"The Draft Guidance should instead state that the Agency intends to require confirmatory evidence as appropriate for a given program consistent with the statute, and that the Agency does not intend to suggest an additional bar for demonstrating substantial evidence of effectiveness by describing the elements of what it means to have a highly persuasive adequate and well-controlled trial," the group added. "In addition, FDA should clarify that the Draft Guidance is not intended to change FDA’s position that a 'large multicenter trial can be considered, both scientifically and legally, to be, in effect, multiple trials and can be relied on to provide substantial evidence of effectiveness.'"

Furthermore, PhRMA asked FDA to ensure that it determines whether a trial is highly persuasive using a totality-of-the-evidence framework, and to clarify how pretrial probability may be used to inform evidentiary expectations for highly persuasive, adequate, and well-controlled trials. Both PhRMA and the Biotechnology Innovation Organization (BIO) asked that FDA ensure that it provides predictability to how it applies evidentiary expectations across review divisions and expand on the sources of confirmatory evidence.

PhRMA noted that sponsors are increasingly conducting multiregional clinical trials and that FDA should apply existing standards to evaluate evidence from such trials. "Sponsors must design global development programs that can support regulatory submissions in the United States and across multiple jurisdictions," said PhRMA.

"We request that FDA clarify how the one adequate and well-controlled clinical investigation and confirmatory evidence framework would be aligned with global development programs, including multiregional pivotal trials," the group added.

Additionally, PhRMA asked FDA to detail how it plans to apply the strength-of-evidence framework in the guidance, clarify how observational data can be used to demonstrate substantial evidence of effectiveness, and provide examples of how to use externally controlled trials to demonstrate substantial evidence. The group also asked for clarity on how innovative trial designs can be used to generate substantial evidence of effectiveness, and for more details on circumstances in which applying the substantial evidence standard may require regulatory flexibility.

"The Draft Guidance explains that the 'clinical context is critical' to informing the approach to establish substantial evidence of effectiveness and that some considerations include 'disease severity, unmet need, and disease rarity,'" said PhRMA. "We agree, and we encourage FDA to apply regulatory flexibility as scientifically warranted.

"We also agree that FDA should provide flexibility as to significance level and design where appropriate," the group added. "We encourage FDA to document such flexibilities in formal meeting minutes so that sponsors can rely on them and apply such flexibilities consistently across review divisions."

PhRMA asked FDA to expand on its expectations for safety database planning and benefit-risk assessment, and to ensure the guidance is fully aligned with the statutory framework, noting that the draft guidance doesn't identify certain additional legal considerations it refers to.

"We recommend that FDA revise the Draft Guidance to identify these considerations," said PhRMA. “Specifically, FDA should further clarify the circumstances under which published literature may appropriately be referenced in support of a full [Biologics License Application] BLA in accordance with the governing statute."

PhRMA, BIO, and the Duke-Margolis Institute for Health Policy asked FDA to clarify how the guidance, which replaces related guidances from 1998 and 2019, relates to a 2023 guidance on the same topic.

"We also recognize that the Draft Guidance consolidates and modernizes the still-relevant content of the 1998 guidance with the new content introduced in the 2019 Draft Guidance, which will help to reduce confusion in practice," said PhRMA. "As FDA considers stakeholder feedback and finalizes this draft guidance, we encourage FDA to clarify whether the Agency intends to finalize the 2023 Substantial Evidence Draft Guidance as a standalone guidance document or instead incorporate its content into the final version of this Draft Guidance."

In its comments, BIO asked for clarity on the evidentiary concepts intended to support the framework, including confirmatory evidence and highly persuasive trials.

"In particular, sponsors would benefit from greater clarity regarding the factors that FDA considers most important in determining the appropriate evidentiary strategy for a given development program," said the group.

Bio also sought clarity on the role of statistical considerations, prior evidence, external controls, natural history data, and RWE in assessing the totality of effectiveness, and asked how FDA plans to apply flexibility in rare diseases.

"The draft guidance discusses significance levels, prior probability of effectiveness, Bayesian approaches, and totality-of-evidence considerations," said BIO. "At the same time, external controls, natural history studies, and real-world evidence are increasingly important components of development programs, particularly in rare diseases and serious conditions.

Furthermore, BIO asked regulators to clarify the relationship between the effectiveness framework and broader drug development considerations.

"We support FDA's recognition that substantial evidence may be established efficiently," said BIO. "However, in practice, the number and size of trials are frequently influenced by considerations beyond efficiency alone.

"Given these considerations, BIO encourages FDA to clarify that sponsors may elect to conduct multiple adequate and well-controlled trials to address broader development needs, including safety, global regulatory, and scientific considerations, without implying a preference for one evidentiary approach over another," the group added.

PORTAL

The Program on Regulation, Therapeutics, and Law (PORTAL) was perhaps the most critical of the guidance in its comments. While the group agreed with many of the principles laid out in the document, it wrote that “greater regulatory flexibility should not lower the evidentiary bar or add uncertainty about effectiveness.”

The group also asked FDA to clarify that neither one nor two pivotal trials be considered the default approach and stressed that “the number and design of trials should reflect the remaining evidence gaps and clinical context.”

Additionally, PORTAL wrote that FDA should specify that limitations in the pivotal trial should require clinical follow-up and that postmarketing studies should be required “when meaningful uncertainty remains.”

Duke-Margolis

Duke-Margolis said that it is encouraged by FDA's decision to revisit the legal considerations of evidentiary standard and noted that trial design elements are important to ensure a trial is adequate and well-controlled, and that historical control data may be used to evaluate a product's effectiveness. The group asked the agency to clarify the parameters within which real-world evidence (RWE) study designs fall under its scope and definition of clinical trials to meet the legal standard for substantial evidence.

"Given that RWE is crucial to the single arm trial design, we also ask that FDA provide clarity as to whether it is planning to apply this guidance to additional forms of [real-world data (RWD)] uses beyond historical control data applications," said Duke-Margolis.

Duke-Margolis also asked FDA to clarify the term regulatory flexibility because it is concerned that some may interpret it as a lack of standards.

"Providing additional assurances that while flexibility may be used, evidentiary standards will continue to be strong," said Duke-Margolis. "We also recommend that FDA consider expanding out its criteria to include clinical and therapeutic context to determine and provide examples about when there is substantial evidence that the benefits exceed the risk.

"By considering these contexts then sponsors can be even more assured that FDA is accounting for key aspects such as population size, unmet need, disease severity, and the ethics and feasibility of control methods," the group added.

Friends

Friends of Cancer Research (Friends) also asked FDA to clarify certain terms, including its definition of highly persuasive trials and their characteristics. The group asked the agency to clarify its expectations for patient populations in the trials and how they may represent US patients.

"Expectations for a broad and representative population, multiple sites, and a sufficient enrollment of U.S. patients may need to be adapted for rare diseases or rare and molecularly defined cancers, where patient populations are inherently limited and enrollment may necessarily be global," said Friends.

Friends also noted that while FDA states it would recognize surrogate endpoints to support approvals, it states that the trial design should include a clinically meaningful primary endpoint, which may be confusing.

"This description could create uncertainty regarding how appropriately supported surrogate or intermediate endpoints, such as those commonly used in oncology, are considered within the highly persuasive trial framework," said Friends. "Additionally, expectations for supportive secondary endpoints and results across important trial subsets should likewise be interpreted in context.

"Oncology trials may not be powered to demonstrate independent treatment effects for every secondary endpoint or subgroup, and lack of statistical significance in an individual analysis should not necessarily be interpreted as evidence inconsistent with the overall treatment effect," the group added.