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# FDA’s Single-Trial Policy Faces Uneven Implementation: Experts
- URL: https://www.fdaweb.com/fdas-single-trial-policy-faces-uneven-implementation-experts/
- Published: 2026-10-19T23:45:00.000Z
- Updated: 2026-10-19T23:55:54.000Z
- Author: David McFarland
- Tags: Drugs

FDA's move toward accepting one adequate and well-controlled study supported by confirmatory evidence is encountering uneven implementation across review divisions, while sponsors seeking to use real-world evidence to support accelerated approvals continue to face demanding regulatory expectations, according to experts participating in a new FDA Watch [webcast](https://fdawatch.net/2026/10/19/the-rise-of-real-world-evidence-in-regulatory-strategy-part-3-rwe-in-accelerated-approvals/?ref=fdaweb.com).

The discussion examined the agency's evolving evidentiary standards, the role of real-world data in accelerated approvals and heightened postmarketing obligations under the Food and Drug Omnibus Reform Act of 2022 (FDORA).

Kodiak Strategic Consultants president **Mark Robbins** said FDA's shift toward a single pivotal trial, outlined in a February *New England Journal of Medicine* article ([see earlier story](https://www.fdaweb.com/fda-officials-discuss-one-trial-standard/)) by former FDA commissioner **Marty Makary** and then-CBER director **Vinay Prasad** has not yet produced consistent changes in review practices.

Robbins said one of his clients is preparing for an FDA meeting and plans to challenge the agency's initial request for two studies by presenting a successful Phase 3 trial, real-world evidence and the agency's published position favoring a single pivotal trial with confirmatory evidence.

“I think that's going to be a division-by-division decision from the division directors,” Robbins said. “I don't think you're going to see it all the way through the agency to be widely accepted at this point.”

Analysis Group managing principal **Maral DerSarkissian** also cautioned that FDA review divisions have different histories, precedents and levels of comfort with single-trial approvals. She noted that FDA's June 2026 [revised draft guidance](https://www.fdaweb.com/fda-revises-guide-on-demonstrating-drug-effectiveness/), *Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products*, treats one adequate and well-controlled trial supported by confirmatory evidence as an established regulatory pathway rather than an exception. However, the strength of the pivotal trial, the quality of supporting evidence and the clinical context remain critical to FDA's assessment.

The agency may accept natural history studies, disease registries and other real-world sources as confirmatory evidence, particularly for rare diseases with substantial unmet medical needs, DerSarkissian said.

She identified three potential uses of real-world evidence in accelerated approval applications: supporting the relationship between surrogate endpoints and clinical outcomes, documenting disease progression through natural history studies, and providing external control groups for single-arm trials.

“So first, supporting the surrogate itself,” she said. “To get accelerated approval, you have to show the endpoint is reasonably likely to predict clinical benefit. And longitudinal real-world data can show that patients whose marker improves go on to do better clinically.

“Secondly, natural history studies, especially in rare diseases, where the natural course of disease may be poorly characterized or highly variable from patient to patient. Real-world data can be used to fill that gap and to show that the change seen in the trial reflects the impact of the drug and not the natural disease progression.

“And third,” DerSarkissian continued, “external control arms, where a single-arm trial is compared against similar patients drawn from real-world sources. And this is where the bar is highest. A credible external control needs to match the trial eligibility criteria and endpoint definitions, as well as make sure the analysis methodology appropriately addresses sources of bias like confounding. And contemporaneous data is necessary to make sure you're not comparing against an outdated standard of care, because we know that the FDA cares most about what's available to patients now and the standard of care now that patients are using.”

DerSarkissian also highlighted that pragmatic randomized trials that capture outcomes through real-world data can be an efficient way to run a confirmatory trial that converts accelerated approval into traditional approval, especially for products like vaccines.

“The idea is that you still randomize, but the trial runs within routine care within a healthcare system with broad eligibility criteria and outcomes that, for a vaccine, for instance, demonstrate prevention of severe outcomes like hospitalization and are captured through electronic health records rather than dedicated study visits like in a trial,” she said. “And for a vaccine with a large target population, that lets you enroll at scale and capture the clinical outcomes needed to verify clinical benefit.”

It’s also important to recognize that the bar rises with the role that evidence plays, according to DerSarkissian. “Real-world data used for contexts like natural history is held to a different standard than real-world data offered as the main comparison for an effectiveness claim,” she said. “The closer real-world data sits to the regulatory decision, the more scrutiny it's going to receive from the FDA… Reviewers take real-world evidence seriously when it's planned like a trial, and they're skeptical when it looks like it was pieced together after the fact.”

Robbins warned that differences between U.S. and foreign standards of care can undermine the acceptability of real-world evidence, even when the underlying data supported regulatory approvals overseas.

The discussion also highlighted stricter oversight of accelerated approvals following FDORA, which expanded FDA's authority to require confirmatory studies to be underway before approval, establish enrollment and completion milestones, and expedite withdrawal proceedings when clinical benefit is not verified.

The experts emphasized that early engagement with FDA remains essential, particularly when sponsors intend to rely on a single pivotal trial or real-world evidence to satisfy the agency's substantial evidence standard.