One-Trial FDA Approvals: Efficiency Gain or New Regulatory Paradox?

For the first time, FDA has declared that one pivotal trial plus confirmatory evidence will be its default pathway for drug approval—effectively ending the informal “two-trial” expectation that has shaped development strategies for decades. What’s notable is that this shift comes just as the Agency doubles down on postmarket evidence generation and modern statistical tools, rather than simply relaxing standards (FDA, 2023, Prasad and Makary, 2026).

The legal basis is not new. Since 1997, FDA has had explicit authority to accept “one adequate and well-controlled clinical investigation and confirmatory evidence” as substantial evidence of effectiveness, a framework clarified in draft guidance issued in 2023. Confirmatory evidence now explicitly spans mechanistic data, related indications, class effects, high-quality real‑world data, and even a second, smaller adequate and well-controlled study. At the same time, FDA’s 2026 Bayesian draft guidance signals that pivotal trials can formally borrow prior and external data while still meeting agreed operating characteristics for error control (FDA, 2023, FDA, 2026, Studna, 2026).

The economic stakes are stark. In oncology for example, a single pivotal trial can cost 30–150 million dollars and add years to development timelines, on top of a median 7.3‑year path from first activity to drug approval. If one robust trial becomes the norm rather than the exception, capital-at-risk falls materially—and one of industry’s standard justifications for high launch prices (multibillion‑dollar R&D narratives) looks increasingly fragile. Yet the new default also raises a harder question for sponsors: with no second “confirmatory” trial as a backstop, regulators will scrutinize control-arm quality, endpoint selection, effect size, and post-progression therapy more aggressively than in traditional two-trial programs (Prasad and Mailankody, 2017, Prasad and Makary, 2026).

Implementation will not be uniform. FDA signals that two or more studies will still be required for products with vague mechanisms, poorly validated surrogate endpoints, or other design deficiencies, meaning sponsors cannot treat “one trial” as an entitlement. And the promise of lifecycle evidence cuts both ways: more routine use of post-market data and external controls, under a Bayesian lens, heightens the probability of label changes and even withdrawals when real-world performance diverges from the pivotal result. This creates a paradox—lower premarket burden, but higher exposure to ongoing evidentiary challenge (FDA, 2023, FDA, 2026, Studna, 2026).

The practical path forward is clear. Development teams should design a single, highly credible pivotal trial—contemporary, optimally controlled, rigorously blinded—while pre‑specifying a package of mechanistic, class, and real‑world evidence that can function as formal confirmatory support. Early, structured FDA dialogue on borrowing external data and Bayesian decision rules will be critical to lock in expectations and protect against post hoc disputes. For sponsors willing to embrace this model, the reward is faster market entry and cleaner narratives on value; for those who are not, the era of default two-trial programs is quietly closing (FDA, 2023, FDA, 2026).

References

1. Food and Drug Administration. (2023). Demonstrating substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence (Draft guidance for industry). U.S. Department of Health and Human Services, Food and Drug Administration. https://www.fda.gov/media/172166/download
2. Food and Drug Administration. (2026). Use of Bayesian methodology in clinical trials of drug and biological products (Draft guidance for industry). U.S. Department of Health and Human Services, Food and Drug Administration. https://www.fda.gov/media/190505/download
3. Studna, A. (2026, January 13). FDA issues draft guidance to advance Bayesian methods in clinical trials. Applied Clinical Trials. https://www.appliedclinicaltrialsonline.com/view/fda-issues-draft-guidance-advance-bayesian-methods-clinical-trials
4. Prasad, V., & Mailankody, S. (2017). Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Internal Medicine, 177, 1569–1575.
5. Prasad, V., & Makary, M. A. (2026). One pivotal trial, the new default option for FDA approval—Ending the two-trial dogma. New England Journal of Medicine, 394(8), 815–817.