After Recent Leadership Departures, Is the FDA Returning to Form?

Some experts say the FDA’s recent change of heart on a handful of drugs for rare diseases suggests a return to regular order after a tumultuous year, while others argue the flip-flopping signals more chaos.

During the tenure of former FDA Commissioner Marty Makary, MD, MPH, and the agency’s top vaccine official Vinay Prasad, MD, MPH, several rare disease drugs were rejected or sponsors were asked to complete additional studies.

For example, in January, the FDA sent a complete response letter to Atara Biotherapeutics and its partner Pierre Fabre Pharmaceuticals rejecting the T-cell immunotherapy tabelecleucel (Ebvallo) for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease. The next month, the agency rejected Regenxbio’s gene therapy RGX-121 for mucopolysaccharidosis II, also known as Hunter syndrome.

Then in March, the FDA closed the door on an accelerated approval of AMT-130, uniQure’s treatment for Huntington’s disease, sparking controversy by recommending a sham surgery-controlled study. Finally, in April, the agency panned Replimune’s drug candidate for treating advanced melanoma.

Prasad left the agency in March, and Makary resigned in May.

In the last several weeks, all four drugmakers have been given a chance to resubmit their applications.

Stephen Majors, vice president of global communications at the Alliance for Regenerative Medicine, told MedPage Today that he views these reversals as “a turning of the page” from a less predictable chapter in which agency leaders seemed to surprise sponsors with new ideas on what constitutes sufficient evidence.

He pointed to an uptick in the proportion of FDA complete response letters for cell and gene therapy approvals, from 18% of decisions in 2020-2024 to 38% in 2025-2026.

While his organization does not advocate for the approval of every drug, “the fact that we’re on a much more seemingly predictable and consistent path in terms of regulation is a big step forward,” he said. And the shift away from requiring a bunch of randomized controlled trials for rare disease drugs, given the fast-moving nature of these illnesses, is a “positive signal,” he added.

However, Robert Steinbrook, MD, director of the Health Research Group at Public Citizen, a nonprofit consumer advocacy organization, took a different view.

“To me, this speaks more of chaos and confusion than a clear pattern, one way or the other, about the FDA standards for reviewing drugs and biologics,” he said, citing the FDA’s “flip-flop” on Moderna’s mRNA flu vaccine as one example.

Companies have a “vested interest” in telling investors that the FDA views drug candidates favorably, Steinbrook noted, “but until the FDA actually reaches a decision, that’s just company spin.”

He said that a return to normal order would mean issuing decisions sans media broadcasts, holding more advisory committee meetings, and staffing up.

“The FDA cannot be a good regulatory authority without sufficient staff with scientific expertise,” he argued.

Robert Califf, MD, a former FDA commissioner and an adjunct professor at Duke University School of Medicine in Durham, North Carolina, said FDA leadership under the Trump administration, “since day one, has been politically overriding staff, which almost never happened before.”

While different people may reach different judgments about the same drug, the agency has protocols for dissent, he told MedPage Today.

Those processes weren’t always followed, he said, pointing to a memo that Mike Davis, MD, PhD, acting director for FDA’s Center for Drug Evaluation and Research, wrote about the diabetes drug teplizumab (Tzield). It signaled that his predecessor, Tracy Beth Høeg, MD, PhD, who left the agency in May, had left no written record of her “counter-perspective,” despite reported disagreements with staff over the drug’s approval.

“Things do seem to be more settled down, but that’s only temporary,” Califf noted, adding that the agency’s stability going forward hinges on who is chosen to lead it.

Steven Grossman, a public policy and FDA regulatory consultant for HPS Group, a health policy and public affairs company, said the FDA has always had a “fixation on due process.”

“They may turn you down in the end, but they want to make sure that everybody, including you, knows that they gave you every opportunity to be heard and to put your best foot forward,” Grossman said.

Many companies that make drugs for rare diseases had worked with the agency for a long period and talked through their disagreements. They were entitled to an advisory committee meeting, at the very least, before their drugs were rejected, Grossman said.

“What’s needed now is a process that gives them a fair review,” he noted.