FDA Shifts to Single Pivotal Trial as Default Standard for Drug Approvals

The US Food and Drug Administration will generally require only one pivotal trial to support the approval of new medicines, top agency officials announced Wednesday. In a paper published in the New England Journal of Medicine, Commissioner Marty Makary and Vinay Prasad, director of the Center for Biologics Evaluation and Research, confirmed the change in FDA standards, stating that "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 officials said they are ending the "two-trial dogma," a standard set in the 1960s to ensure the safety and efficacy of medical products. Technological advancements mean the FDA and sponsors can now focus on designing one high-quality trial that can better assess results, they said. While US law has been in place since 1997 stating that approval can be based on a single adequate and well-controlled study when supported by confirmatory evidence, the FDA's standard has been a reliance on two pivotal trials.

Under the new guidance, the single pivotal trial will still need to be combined with confirmatory evidence, and the approval process will put a stronger focus on controls, endpoints, effect size, and statistical protocols. The paper says the move will "substantially reduce costs for sponsors" and "speed drugs to market." Estimates suggest that the cost of a single pivotal study may range from $30m to $150m. Makary and Prasad add that as a result of reducing capital costs for drug developers, it should reduce "justification of lofty and rising drug prices for everyday Americans."

"Default options anchor individuals and institutions psychologically, and we believe that formally articulating the FDA's new position will spur biomedical innovation," they wrote. In practice, many drugs in recent years have sped to market with only one pivotal study, thanks to changes Congress made in 1997. In 2020, more than half of the 49 new medicines that came to market did so with just one pivotal trial, according to an analysis published in 2022.

Makary and Prasad acknowledge that this guidance may be met with criticism that the FDA is "relaxing its standards," but the pair disagree. "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," the paper reads. The pair go on to say: "Second, as we note, the number of clinical studies is no safeguard against valid inference if all other aspects of trial design are deficient. 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."

They add that by putting focus on just one study it may, in fact, improve the FDA's standards and reduce the risk, as greater attention will be placed on the one trial. "Yet modern drug development establishes credibility in multiple ways, relying on both statistical and biologic inferences," they said. "Two trials should be seen as just one of many interlocking facets of clinical credibility and in 2026 there are powerful alternative ways to feel assured that our products help people live longer or better than requiring manufacturers to test them yet again."

There will be cases in which two trials are still required. "If an intervention has a nebulous, pluripotent, or nonspecific mechanism of action; if it affects a labile, short-term, or surrogate outcome; or if a trial has some underlying limitation or deficiency, additional adequate and well-controlled studies may be required," they said. "The FDA will always reserve the right to demand the appropriate scientific study within the bounds of U.S. law."

While there have been cases in which drugs have been approved based on a single pivotal trial, Prasad and Makary said that there has been "confusion" from manufacturers as to the situations in which this would have been acceptable, which is why this is being rolled out for all therapies. As well as traditional approvals, this flexibility will be applied to breakthrough program designations, accelerated approvals, and priority review pathways, which are frequently used in rare diseases.

The new standard is also building on the accelerated approval model that has been increasingly used by drugmakers in recent years, allowing clearance based on one pivotal trial and for confirmatory evidence to be generated afterwards. Makary and Prasad emphasized that the FDA may at times still require two studies and the change will roll out as the agency amps up an initiative to collect postmarketing data.

A former top FDA official raised concerns about how the policy was developed and announced. A former associate commissioner said the announcement raises many questions about how the policy was developed and how the agency intends to implement it, calling it a brave but precipitous announcement that doesn't detail the science that went into the decision behind it. "What drove the process to reach this decision, and equally important, who was part of that process?" the former official asked. "A two-page opinion piece, even in the New England Journal of Medicine, isn't a replacement for a detailed explanation of this policy shift."