Regulatory News: When are single pivotal trials enough for approval? FDA’s latest position and what it means for sponsors

On 19 February 2026, the FDA confirmed that one adequate and well controlled pivotal clinical trial may serve as the default basis for drug approval. This marks a shift from the long standing expectation of two pivotal studies and reflects evolving thinking around trial design, precision medicine, and development efficiency.¹

For sponsors, the opportunity is real — but with one pivotal study carrying more weight, trial quality, endpoint selection, and the supporting evidence package becomes even more consequential.¹

Why is the FDA moving to a single trial approach?

For decades, approval has relied on “substantial evidence,” typically demonstrated through two independent Phase 3 trials. However, several factors including :

• Advances in trial design and analytics: adaptive designs, biomarker-driven endpoints, and improved statistical approaches can strengthen evidence from a single study
• Smaller, targeted populations: precision therapies and rare diseases make large, duplicate trials impractical
• Development efficiency and access: reducing duplication can accelerate timelines, lower cost, and improve patient access

In practice, this is not entirely new, in the US, a cross-sectional analysis of novel therapeutics approved between 2005–2012 found 36.8% of indications were approved on the basis of a single pivotal trial.² In the EU, an analysis of marketing authorizations (2012–2016) reported 45% of new active substances were approved based on a single pivotal trial, with variation by therapeutic area.³

The key difference now is that this approach is being formalised and expanded across more therapeutic areas.

Does the FDA expect less evidence from a single pivotal trial?

No. The requirement for “substantial evidence” of effectiveness remains unchanged—and the bar may be higher.⁴

A single trial must deliver^1,4:

• Clear, clinically meaningful endpoints
• Strong statistical power and methodological rigor
• A compelling and interpretable treatment effect
• Supporting evidence where needed

Recent regulatory decisions highlight the risk: when evidence from a single study is not considered robust, submissions may be rejected or delayed.³

FDA and EMA expectations: global alignment still matters

While the FDA has clarified its position, the EMA continues to focus on robust, definitive evidence of efficacy, without prescribing a fixed number of studies.⁵

For global programs, this reinforces the need for:

• Early engagement across multiple health authorities
• Alignment on evidence expectations
• A development plan that supports both approval and market access

What does this mean for development strategy?

A single pivotal trial can reduce timelines and cost—but only if the study is designed to withstand regulatory and commercial scrutiny.

Single pivotal trials are not a shortcut—they are a strategic commitment: if you choose one study to carry the full weight of approval, its design must anticipate every regulatory question before it’s ever asked.

-    Alicia Baker McDowell, Vice President and Head of Global Regulatory Strategy

Because reliance on a single pivotal trial concentrates decision risk, sponsors should act early to:

• Stress test pivotal design and endpoints against what FDA defines as adequate and well-controlled (controls, bias minimisation, analysis transparency).
• Develop an integrated clinical development plan that considers both approval and reimbursement pathways. Designing with approval in mind: Not just statistical success, but clinical relevance and real-world impact.
• Plan confirmatory evidence intentionally; what it is, how it supports the pivotal findings, and how it will be justified.
• Align across regions — EMA expectations vary by context, and in constrained populations the EMA has specific guidance addressing design and evidence challenges.

Regulators may still expect two trials where mechanisms are unclear, endpoints are variable, or outcomes rely on short term or surrogate measures—making early strategic decisions critical.

Getting ahead of regulatory change with Fortrea

The shift toward single pivotal trials creates an opportunity to accelerate development—but only for programs built on strong foundations.

Fortrea integrates regulatory strategy, intelligence, and execution across the full asset lifecycle—helping sponsors make confident decisions earlier and design development programs that stand up to regulatory and commercial scrutiny. Through continuous regulatory insight, regional understanding, and thoughtful use of advanced technology, we can help reduce risk, prevent re-work, and keep development on track.

If you are assessing whether a single pivotal trial could support your program—or need to strengthen your current strategy—now is the time to act.

Engage Fortrea’s regulatory strategy group to review your project objectives and available data, and define the most effective path forward.

References

1. One Pivotal Trial, the New Default Option for FDA Approval - Ending the Two-Trial Dogma. N Engl J Med . 2026 Feb 19;394(8):815-817. doi: 10.1056/NEJMsb2517623.
2. Clinical trial evidence supporting FDA approval of novel therapeutic agents, Downing NS, et al. 2005-2012. JAMA. 2014 Jan 22-29;311(4):368-77. doi: 10.1001/jama.2013.282034. PMID: 24449315; PMCID: PMC4144867.
3. European Marketing Authorizations Granted Based on a Single Pivotal Clinical Trial: The Rule or the Exception? Morant AV, Vestergaard HT. Clin Pharmacol Ther. 2018 Jul;104(1):169-177. doi: 10.1002/cpt.900. Epub 2017 Nov 6. PMID: 29023675.
4. Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence Guidance for Industry. (Draft, Dec 2019): https://www.fda.gov/regulatory-information/search-fda-guidance-documents/demonstrating-substantial-evidence-effectiveness-human-drug-and-biological-products(Last accessed May 2026)
5. 5. EMA Reflection paper on establishing efficacy based on single arm trials submitted as pivotal evidence in a marketing authorisation application Considerations on evidence from single-arm trials. https://www.ema.europa.eu/en/establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing-authorisation#current-version-10171(Last updated September 2024. Last accessed May 2026)

FAQs

1. What did the FDA change about single pivotal trials in 2026?

   The FDA publicly stated that one adequate and well controlled pivotal study, combined with confirmatory evidence, can serve as the default basis for marketing authorization.¹ 
   This signals a greater openness to more flexible development pathways, particularly where additional supportive data can reinforce the primary study findings.

2. Does “one pivotal trial” change the legal standard for effectiveness?

   No. FDA’s legal standard remains “substantial evidence” of effectiveness, which is primarily supported by adequate and well controlled investigations under FDA regulations.^1,4 The number of trials may vary, but the evidentiary threshold—and the need for robust, reliable data—remains unchanged.

3. What is an “adequate and well controlled” study (FDA definition)?

   FDA regulations describe the purpose and key characteristics of adequate and well controlled studies (including clear objectives, valid comparison with a control, and sufficient detail for critical evaluation).^1,4 
   These elements are designed to ensure that study results can be reliably interpreted and attributed to the intervention rather than bias or confounding factors.

4. How does the EMA view pivotal evidence—does it mandate one or two pivotal trials?

   The EMA does not prescribe a single rigid template, but expects definitive evidence of efficacy, making early engagement with relevant health authorities important during Phase 3 planning. In practice, this means sponsors should align on evidentiary expectations early, as requirements may vary depending on the therapy, indication, and overall data package.^3,5