The Food and Drug Administration plans to begin requiring one clinical study, instead of the standard two, for medical products before consideration for approval, FDA Commissioner Marty Makary told STAT on Wednesday. 

While historically the FDA has required two trials for added assurance of a drug’s safety and efficacy, it has become increasingly flexible and many drugmakers already submit just one pivotal clinical trial for approval. Makary said that while the agency will still require two in some cases, the default will be one trial.

“You can achieve the same statistical power with one trial as you would with two trials when it’s designed and controlled appropriately,” Makary told STAT by phone.  

The agency will publish a press release soon, a spokesperson told STAT. Makary said the agency will also start updating policies to reflect the change, which could take three to six months. The change will take effect once the guidance is updated. STAT obtained a draft press release that laid out the plans, but it’s not clear if it was the final version. 

Makary and others in the Trump administration have said they want to accelerate review times and speed new drugs and medical devices to market, in part by eliminating perceived bureaucracy, and have taken some steps to do so. 

But agency sources and outside experts told STAT they were confused by the FDA’s plan. The agency already has policies in place to allow flexibility in situations where running two clinical trials would be impractical or infeasible. They worried that the blanket change would needlessly lower the agency’s standards for evidence on efficacy and safety. 

“I don’t understand what this does, other than ratchet down the expectation that the FDA will seek high quality trials for the drugs that are being approved,” said Aaron Kesselheim, a professor of medicine and member of the Center for Bioethics at Harvard Medical School. “It’s self disempowerment.”

Makary said the agency was being more practical, and that no standards are being lowered. 

Two sources in the FDA’s drug center, who spoke on condition of anonymity because of fears of retaliation, told STAT that Makary’s push to issue the press release contributed to the decision of top drug regulator Richard Pazdur to suddenly retire. The sources said reviewers and Pazdur view the one trial standard change as undermining the agency’s ability to ask for more evidence. 

It looks to be giving significant flexibility across the board,” one official said. “But it’s not legally sound, and it’s scientifically concerning.” 

Late on Wednesday, the FDA announced that Tracy Beth Høeg, a top lieutenant to Makary, would be Pazdur’s replacement at the drug center. Pazdur doesn’t retire until the end of the month, so it’s not clear who’s currently in charge.

Two agency sources told STAT that scientific staff were not consulted on the press release. Makary said the initiative has support from scientific staff, and was proposed in meetings with industry stakeholders.

The draft press release includes quotes from Makary and Vinay Prasad, the agency’s top regulator of biologics, but not Pazdur. Pazdur did not respond to STAT’s request for comment. Makary told STAT he was grateful for Pazdur’s work.

The release also states that FDA review divisions will have the authority to make exceptions to the one-trial rule on a case-by-case basis.  

In 1962, Congress gave the FDA the authority to require that companies prove their drugs are safe and effective through substantial evidence. The FDA interpreted substantial evidence to mean two adequate and well-controlled clinical trials. In 1976, Congress gave the FDA the authority to regulate medical devices. 

“Two independently conducted trials obviously increases your confidence, especially before it goes into a very large population,” said Jeff Allen, the president and CEO of Friends of Cancer Research.  

In the 1990s, Congress clarified that the agency could consider data from just one trial, plus confirmatory evidence, if the agency felt such data were sufficient. The agency might require just one trial for rare disease or specific cancer drugs, for example. Confirmatory evidence might be clinical data from a related condition, animal data, or data considering the drug’s mechanism of action. 

The practice of requiring one trial and confirmatory evidence has become relatively commonplace. In 2020, more than half of approved drugs were supported by a single pivotal trial, according to an analysis published by JAMA. In 2023, the FDA released draft guidance clarifying its thinking on when just one trial and confirmatory evidence is appropriate. 

The FDA has explicit authority to require just one trial and confirmatory evidence when it sees fit, but legal experts told STAT that it’s not clear whether the agency can ignore the two-trial standard altogether. 

“Even FDA’s current policy, in which approving drugs based on one trial is not the default, has been criticized as being used too frequently and setting the bar too low for effectiveness to the detriment of patients and innovation,” said Patricia Zettler, an FDA law expert at the Ohio State University. 

Eva Temkin, an FDA lawyer at Arnold and Porter, said the law might allow the FDA to make one trial plus confirmatory evidence the standard, as it already allows for significant adaptability. 

The FDA’s policies on flexibility versus increased regulatory scrutiny have been difficult to pin down. Makary and Prasad have put forth several proposals to streamline drug approvals, such as a new program promising one- to two-month reviews, a new rare disease pathway, and guidance reducing animal testing.

At the same time, the two have come down hard on vaccines, pledging to raise the regulatory bar to a level that might make it impossible for manufacturers to develop new products. And the agency recently asked Uniqure for more evidence on its Huntington’s disease treatment after both parties agreed to a set trial design and endpoints. 

“We are moving in a deregulatory direction and each day, continually think about ways that we can reduce red tape, reduce uncertainty, and reduce onerous requirements,” Makary said. “But there are some areas where we are saying that we are going to bring back the scientific evaluation of data to a process where there has not been proper scientific evaluation of data.”

Makary did not specify exactly what he thought was wrong with the current vaccine oversight system. He said that new vaccines have to show the FDA convincing data, and then had to end the call. 

He said his relationship with the Health and Human Services department and the White House was strong, despite reports indicating tensions after a series of sudden personnel changes over the past few weeks. 

FDA to lower number of trials required for approval of drugs, other medical products