FDA Adopts Single Pivotal Trial Standard as Default for New Drug Approvals

The FDA has announced a major change in its new drug application policy supporting the regulatory approval of new drugs: an end to the "two-trial dogma" standard established to ensure the safety and efficacy of medical products. The shift was announced in a New England Journal of Medicine article published earlier this month by the director of the Center for Biologics Evaluation and Research and the FDA Commissioner.

Going forward, the FDA's default position is that one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorization of novel products. The FDA will carefully examine all aspects of study design with particular focus on controls, end points, effect size, and statistical protocols. Without examination of the quality of a study, two trials may even provide a false assurance.

Under Section 505(d) of the Federal Food, Drug, and Cosmetic Act, the FDA's clinical data standard for new drug applications has been based on the requirement for "substantial evidence" supporting an investigational candidate's safety and effectiveness. Generally speaking, this has translated to at least two adequate and well-controlled clinical investigations that independently show statistically significant benefits.

However, in some cases, the FDA has also demonstrated disease-by-disease flexibility and granted approvals based on one large, multicenter trial with confirmatory evidence, permitted under U.S. law since 1997, or smaller datasets with compelling evidence for rare diseases. In fact, a 2022 analysis of new drug application-approved medications in 2020 found over 50% did so with only one pivotal trial.

Confirmatory evidence could include data demonstrating a drug's work on a mechanistic, biological level or in animal models, data supporting related indications or other drugs within the same class, as well as real-world data—any of which could qualify as supportive and confirmatory evidence.

The updated one-trial standard is intended to resolve the ongoing "confusion from manufacturers regarding settings in which a single trial will be accepted" that has ensued over the last several decades. In their argument against the two-trial requirement, the authors noted that, in 2026, "there are … alternative ways to feel assured that our products help people live longer or better than requiring manufacturers to test them yet again."

Requiring only one trial will "substantially reduce costs for sponsors" as well as speed drugs to market. A single pivotal study can cost between $30-150 million and require years to complete, further increasing the average time it takes to commercialize a drug. With just one instead of two trials to conduct, "lowering capital costs for drug developers may remove a persistent argument in justification of lofty and rising drug prices for everyday Americans — the onerous cost of research and development."

The authors addressed potential criticism with a two-part response. First: "The FDA has never been perfect, and even with a default requirement of two trials, the FDA has approved numerous products that were later found to have serious safety concerns or lack efficacy." Second: "As we note, the number of clinical studies is no safeguard against valid inference if all other aspects of trial design are deficient." They added: "If the control arm is substandard, the endpoints dubious, the statistical plan generated post hoc, the power inadequate, or all of the above, erroneous conclusions may be reached even with two, three, or four studies."

Reduced dependence on duplicate Phase III trials could shorten development timelines, lower capital requirements, and encourage earlier filings or adaptive designs, especially in small populations and high unmet-need settings. The statutory standard—"substantial evidence"—does not explicitly require two trials.

From a supply chain perspective, earlier approvals based on one pivotal trial could compress commercial launch timelines. Manufacturing scale-up, technology transfer, packaging validation, and distribution planning may need to align more tightly with clinical milestones. Shorter development cycles can reduce long-term forecasting visibility for contract manufacturing organizations.