On February 19, 2026, the FDA announced that a single adequate and well-controlled clinical trial, paired with confirmatory evidence, is now the default standard for drug approval. The two-trial doctrine that has governed NDA and BLA strategy since the Kefauver-Harris Amendment of October 10, 1962 is no longer the starting assumption. That is a structural shift in how development programs get designed, resourced, and submitted — and most sponsors have not yet updated their protocols to reflect it.
The signal is buried in a correspondence piece in the New England Journal of Medicine, Volume 395, Issue 2, published July 9, 2026. It arrives five months after the FDA’s February policy announcement, and its appearance in NEJM suggests something important: the academic and regulatory communities are now converging on this shift as settled doctrine, not as a pilot. Sponsors who are still building two-trial programs as the default are not being conservative. They are running an outdated playbook at significant cost to time and capital.
The Doctrine That Replaced the Dogma
The Kefauver-Harris Amendment demanded proof of effectiveness, and the FDA interpreted that over six decades into a practical standard: two independent, adequate, and well-controlled investigations. The logic was reproducibility. One trial could be noise. Two trials confirmed a signal. That reasoning made sense in an era of large, homogeneous trial populations, limited biomarker stratification, and no adaptive design infrastructure. It makes less sense now.
The FDA’s 2023 Draft Guidance on single pivotal trial pathways outlined what “confirmatory evidence” can look like when only one controlled investigation anchors a package. According to Premier Research’s analysis of that guidance, confirmatory evidence options include robust mechanistic data, consistent results across subgroup analyses, corroborating biomarker readouts, and real-world data that support the primary endpoint signal. The agency is not asking sponsors to do less work. It is asking them to do different work — to build evidentiary depth into a single, well-designed trial rather than breadth across two thinner ones.
The February 2026 policy announcement formalized that guidance into operating default. The NEJM correspondence piece published this month closes the loop: the scientific community now recognizes this as the new baseline, which means advisory committees, peer reviewers, and agency statisticians will all be calibrating their expectations accordingly. Sponsors who submit two-trial packages without explaining why two trials were necessary may find themselves answering questions they did not anticipate.
The precedent for single-trial approvals is not new, but it was previously treated as the exception. Amgen’s LUMAKRAS (sotorasib), cleared in May 2021 as the first targeted therapy for KRAS G12C-mutated non-small cell lung cancersmall cell lung cancerlung cancer, reached approval on the basis of a single study under Breakthrough Therapy designation. That approval was treated as a feature of the designation, not a replicable template. The February 2026 policy removes that distinction. Single-trial submission is now available as a default pathway, regardless of designation status.
Who Gets Disrupted First
The sponsors most immediately affected are those running Phase 2/3 programs in rare disease, oncology, and CNS indications where enrollment is slow, patient populations are small, and the cost of a second confirmatory trial often exceeds the commercial return on investment. Between December 1992 and December 2021, 278 drugs were approved under the FDA’s Accelerated Approval pathway, with 50% converting to traditional approval by the end of that period. Many of those programs relied on surrogate endpoints precisely because running two full trials to confirmatory standard was operationally impossible. The single-trial default, combined with Accelerated Approval infrastructure, gives those sponsors a cleaner path: one rigorous trial with a pre-specified primary endpoint, supported by mechanistic data and biomarker consistency, rather than two trials staggered across years.
The disruption cuts differently for large-molecule programs in crowded therapeutic categories. A sponsor developing a fourth-in-class PCSK9 inhibitor or a biosimilar adjacent to an established market faces a different evidentiary bar. The FDA’s confirmatory evidence standard assumes the single trial is “adequate and well-controlled” in a way that is demonstrably robust — pre-registered, properly powered, with transparent methodology. In a crowded category where comparative effectiveness matters, a single trial without a head-to-head arm may not satisfy that bar even if it technically meets the regulatory threshold. The policy sets a floor, not a ceiling.
PDUFA VII, signed into law on September 30, 2022 as part of the FDA User Fee Reauthorization Act of 2022, included explicit commitments to advance complex adaptive and Bayesian trial designs. Those design tools are exactly what makes a single pivotal trial credible: a seamlessly adaptive Phase 2/3 that accumulates evidence without protocol amendments, Bayesian interim analyses that allow sample size re-estimation without inflating Type I error, and pre-specified subgroup analyses that function as internal replication. Sponsors who have already invested in complex innovative design infrastructure are positioned to move faster under the new default. Those still running fixed-sample, two-arm trials with traditional frequentist analyses are not.
The Protocol Decision You Cannot Defer
If you are currently designing a Phase 3 protocol with a two-trial confirmatory strategy, the February 2026 policy requires you to make an active choice, not a passive one. Defaulting to two trials now carries an implicit cost: you are consuming budget, time, and patient exposure to generate a second dataset the agency no longer requires as a baseline. That is a defensible decision in some contexts — high-prevalence conditions where enrollment is feasible, categories where two trials strengthen reimbursement negotiations with payers, or programs where a second trial tests a different dosing arm or subpopulation. But it must be a decision, documented in your protocol rationale and surfaced in your Type B meeting request, not an inherited assumption from 1962.
The practical directive for clinical operations leaders: before your next IND or pre-NDA meeting, audit your confirmatory evidence package as if the single trial is already complete. Can your biomarker data stand alone as mechanistic support? Are your subgroup analyses pre-specified with adequate power? Has your statistical analysis plan been reviewed against the 2023 Draft Guidance’s confirmatory evidence standards? If any of those answers are uncertain, resolve them before the trial starts — because the FDA’s new default means the agency will ask those questions at submission, and the answer cannot be “we were planning to run a second trial.”
Watch the comment period activity on the 2023 Draft Guidance, which has not yet been finalized as of this writing. Finalization would convert the single-trial pathway from a policy default backed by a draft document into a binding regulatory standard with defined evidentiary thresholds. That finalization date is the next signal. When it publishes in the Federal Register, every sponsor with an active IND will need to reopen their confirmatory evidence strategy from scratch — and those who have already built adaptive, biomarker-anchored protocols will have a substantial head start on those who have not.
References
- New England Journal of Medicine — “One Pivotal Trial for FDA Approval — Ending the Two-Trial Dogma,” Volume 395, Issue 2, July 9, 2026
- OnBiostatistics — “From Two-Trial Dogma to Single Pivotal Trial: The Kefauver-Harris Amendment Origin”
- Premier Research — “The FDA’s Shift to One Pivotal Trial: What It Means for Modern Development Programs”
- Amgen — “FDA Approves LUMAKRAS (sotorasib), First Targeted Therapy for KRAS G12C-Mutated NSCLC,” May 2021
- PubMed Central — “FDA Accelerated Approval Pathway Performance: 1992–2021”
- FDA — PDUFA VII Performance Reports, Complex Innovative Design Commitments
- ArentFox Schiff — “FDA Announces Single Pivotal Trial as New Default Standard for Drug Approval,” February 2026
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
