The FDA has typically required two studies from companies seeking approval for most new drugs, although in recent years it has approved some drugs based on a single well-run trial.
“The FDA has demonstrated disease-by-disease flexibility and has granted approvals based on a single premarket study with confirmatory evidence. In some fields, such as oncology, single trials have supported the majority of drug approvals,” Dr. Marty Makary, the FDA’s commissioner, and Dr. Vinay Prasad, head of the FDA’s Center for Biologics Evaluation and Research, said in an article published Feb. 18 by the New England Journal of Medicine.
“However, although we have exercised flexibility in the past, there remains confusion from manufacturers regarding settings in which a single trial will be accepted. Moving forward, we are announcing that a one-trial requirement will be the FDA’s new default standard. This reform is being rolled out synchronously with the agency’s postmarket initiative to collect robust data on all drugs and devices.”
The two-study standard for drugs dates to the early 1960s, when Congress passed a law requiring the FDA to review data from “adequate and well-controlled investigations” before clearing new medications. For decades, the agency interpreted that requirement as meaning at least two studies, preferably with a large number of patients and significant follow-up time.
The reason for requiring the second study was to confirm that the first trial’s results weren’t a fluke and could be reproduced.
Beginning in the 1990s, the FDA increasingly began accepting single studies for the approval of treatments for rare or fatal diseases that companies often struggle to test in large numbers of patients. Over the past five years, roughly 60 percent of first-of-a-kind drugs approved each year have been cleared based on a single study.
Makary and Prasad said that the historical reliance on multiple studies “was intended to provide credible causal evidence that a therapy could improve clinical outcomes with acceptable safety in a world where biologic understanding was more limited than it is today.”
They later added: “In the modern world, as drug discovery becomes increasingly precise and scientific, the FDA considers not just effects on survival, but biochemical and intermediate changes that tell a complete biologic story: does this drug actually work? In this setting, overreliance on two trials no longer makes sense.”
The change will save drug developers money and reduce the time it takes to get drugs to market, the officials said. They expect more drug development in response.
Dr. Janet Woodcock, the FDA director who led the agency’s drug center for about 20 years before retiring in 2024, said the change makes sense and reflects the FDA’s decades-long move toward relying on one trial, combined with supporting evidence, for various life-threatening diseases, including cancer.
“The scientific point is well taken that as we move toward greater understanding of biology and disease we don’t need to do two trials all the time,” Woodcock said.
Dr. Reshma Ramachandran, assistant professor of medicine at the Yale School of Medicine, said in a post on X that it’s true most FDA approvals in recent years have been based on single, strong trials.
“But as the authors noted (& have for years!), patients are increasingly left with uncertainty of their effectiveness,” she said, “so why set a standard continuing the (bad) same old instead of demanding more?”
Makary and Prasad said that they reserve the right to demand additional testing if a trial has limitations or deficiencies.
“Instead of prioritizing finite reviewer time reading and assessing two or more pivotal trials, we will focus our energies on ensuring that the one clinical trial we require provides the most up-to-date and useful information for American patients,” they wrote.
