FDA Shifts to Single-Trial Standard for New Drug Approvals

The FDA has announced that a single pivotal clinical trial will now be the default requirement for the approval of novel medicines, marking a shift away from the agency's decades-old reliance on two adequate and well-controlled studies. The new standard represents a significant policy change under the leadership of Commissioner Marty Makary.

The policy was detailed in an editorial written by Makary and Vinay Prasad, director of the FDA's Center for Biologics Evaluation and Research (CBER), and published in the New England Journal of Medicine. "Going forward… one adequate and well-controlled study, combined with confirmatory evidence, will serve as the basis of marketing authorisation of novel products," the authors state, noting that the reform will be rolled out synchronously with the agency's post-market initiative to collect robust data on all drugs.

A primary driver for the policy shift is the escalating cost of drug development. By moving to a single-trial mandate, the FDA aims to remove the financial pressures that many sponsors cite when justifying high launch prices. "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 [R&D]," Makary and Prasad said in the editorial.

The agency argues that advances in precision medicine and scientific discovery, including genomic sequencing and molecular modelling, allow researchers to understand drug–body interactions at a molecular level, providing biological evidence that can replace a second trial. Historically, the FDA required two trials because drug development was a "black box", i.e. if a drug worked twice in separate, identical tests, it proved the result was not just a statistical fluke.

At the moment, a single pivotal trial is already an option for some applications, for example, for cancer drugs or where it would be impractical to run two, so the agency has flexibility in this area. In 2020, more than half of approved drugs were supported by a single pivotal trial, according to a JAMA analysis published in 2022, but Makary and Prasad argue that there remains confusion among sponsors about the circumstances in which a single trial is sufficient.

If broadly implemented, the change could streamline development timelines, reduce costs, and reshape evidentiary standards, particularly for therapies addressing unmet medical needs. Analysts foresee potential benefits for mid-stage biotech programmes in areas such as obesity and chronic disease, which are being researched widely.

Makary and Prasad say the change could actually enhance standards, as greater attention will be placed on the one trial. The transition has prompted shifts in the agency's internal structure, notably the exit of FDA veteran Richard Pazdur, who reportedly objects to the proposal. Despite this friction, the agency maintains that the move focuses evidentiary standards rather than relaxing them.

The move is the latest in a series of initiatives designed to speed up the approval of new medicines and reduce red tape for drug developers, which some observers fear could undermine standards designed to make sure new therapeutics are safe and effective. Some experts have questioned the need for an initiative that could lead to a blanket reduction in standards for demonstrating safety and efficacy.