Newly permanent CBER and CDER directors Karim Mikhail and Michael Davis are widely expected to continue the FDA’s efforts toward an adaptive framework for rare disease therapies. If approved by the Senate, will commissioner nominee Heidi Overton stay the course?
The difference between regulatory flexibility and regulatory adaptability may seem like semantics, but to rare disease drug developers—and regulators—it means a great deal. In fact, the use of “flexibility” to describe rare disease drug regulation is BIO President John Crowley’s “pet peeve.”
“I hate the word flexibility in rare diseases,” he said during an FDA Town Hall at the BIO International Convention in June. “I think it implies strongly a lower standard.
“Speaking for the rare disease community, that’s not what patients and parents and innovators, that’s not what we want,” said Crowley, who has founded multiple biotechs focused on rare diseases, initially motivated to save his children from Pompe disease. “What we want to see is an elevation of regulatory science and a new framework.”
FDA’s current leadership appears to be on board. “We hope we can truly achieve a truly adapted regulatory framework for rare diseases,” Karim Mikhail, then acting director of the Center for Biologics Evaluation and Research (CBER), said during the Town Hall.
Earlier this month, the FDA appointed Mikhail and Michael Davis as permanent directors of CBER and the Center for Drug Evaluation and Research (CDER), respectively. Prior to the Sept. 8 announcement, Davis had also held his role in an acting capacity.
In a note shared the same day, RBC Capital Markets said both leaders would have a positive impact on the rare disease space. The firm described Mikhail as being a proponent of “flexible trial design for cell and gene therapies, especially for rare indications,” while adding that Davis’ appointment could be a boon for CNS, neuropsychiatry, rare disease and novel modalities.
Indeed, Mikhail has overseen the reversal of FDA guidance for certain rare disease therapies for which former leadership had demanded a higher bar of evidence. Take uniQure, for example. Former Commissioner Marty Makary and former CBER Director Vinay Prasad appeared to publicly criticize the company’s gene therapy for Huntington’s disease and had insisted on a new trial with a sham surgery control before the FDA would consider a regulatory filing for approval. But under Mikhail, the agency decided that uniQure’s existing data were sufficient for review, and the biotech filed its biologics license application (BLA) earlier this month.
This approach is reminiscent of how CBER operated under Peter Marks, who was a strong advocate for adaptive clinical trial designs—particularly for rare disease gene therapies—and was at the divison’s helm when uniQure received its initial guidance. In 2024, Marks argued that non-randomized, single-arm trials could be the best option when testing certain gene therapies for rare diseases.
“There are many rare diseases affecting dozens to a few hundred individuals in the United States where the concept of trying to do a randomized trial is very challenging at best and impossible at worst,” he told BioSpace in January that year.
What’s in an “adaptive” framework?
At BIO’s Town Hall, Mikhail agreed with Crowley that it’s not flexibility per se that his division is after.
“If you have a lot of flexibility, it’s difficult to be predictable, but if we can have an adapted regulatory framework for rare diseases, then I believe we can be very predictable,” Mikhail said.
Crowley, meanwhile, offered examples of several tools that could support such an approach, including accelerated approval, adaptive study designs, Bayesian statistics and “a range of important endpoints that we all agree upon.” UniQure employed what the FDA has called adaptive study designs for its gene therapy—the company used external controls instead of the sham surgery control that Makary and Prasad retroactively said would be required.
Despite their apparent objections to uniQure’s gene therapy, however, Makary and Prasad rolled out new policies and programs that were supportive of rare disease development, including the FDA’s plausible mechanism pathway. Introduced in November 2025, this new pathway is supposed to provide alternate criteria to determine efficacy in exceedingly small patient populations where randomized, controlled trials are not possible.
Nicholas Richardson, vice president of clinical development at Precision for Medicine and a former cancer drug regulator, pointed to Capricor Therapeutics’ Duchenne muscular dystrophy cell therapy as a potential candidate for an adaptive approach for evaluating the clinical data. Like uniQure, Capricor has experienced its fair share of regulatory inconsistency. Deramiocel was rejected in July 2025 after Prasad reportedly canceled an advisory committee for the therapy, and it’s been a rocky regulatory road ever since.
After the company resubmitted and the FDA accepted the BLA application in March, the agency arranged an adcomm meeting in July. There, Capricor and the FDA disagreed over which endpoints were most relevant. Deramiocel met the Phase 3 trial’s primary endpoint, showing statistically significant benefits in upper-limb function. However, a majority of the discussion focused on the trial’s secondary endpoint, a decline in cardiac function as measured by left ventricular ejection fraction. This was the question advisers were asked to vote on, ultimately leading to a 9-3 tally recommending against deramiocel’s approval.
“There was a lot of discussion about alignment,” Richardson said. “The functional outcomes from that trial were really meaningful; it just wasn’t the actual topic of discussion.”
Richardson raised the possibility of using a multi-component endpoint as part of an adaptive framework. While this term has not been officially defined, his understanding is that it consists of “multiple clinically meaningful outcomes that may not be the exact standard for which there’s FDA precedent, but they’re clinically meaningful; they can be objectively measured such that they can inform a benefit-risk determination and hopefully an approval.”
If Capricor could have leveraged a multi-component endpoint, he mused, “would that have led to a very different discussion at the advisory committee?”
The Overton effect
The biggest question for rare disease developers is whether the recent momentum in rare disease will be maintained under Heidi Overton, President Donald Trump’s pick for FDA commissioner.
“For rare disease stakeholders, the key watchpoint is therefore continuity: whether Overton preserves the current movement toward flexible evidence standards, individualized therapies, stronger CDER-CBER coordination, and greater predictability in reviews,” health policy consulting firm Aviva Strategies wrote in an updated memo on Sept. 11 regarding her nomination.
Overton has not explicitly stated her position on flexibility—or adaptability.
“[Overton’s] impact to biopharma and new drug review flexibility is uncertain,” RBC Capital Markets analyst Brian Abrahams wrote in a note to investors on Aug. 19.
BMO Capital Markets wrote in a note the same day addressing Overton’s nomination that “credibility restoration is still unproven” at the FDA. The analyst offered up Taysha Gene Therapies’ Rett Syndrome therapy TSHA-102—for which the biotech is expecting agency feedback on the next BLA steps in the first half of 2027—as a test balloon.
TSHA-102 holds the FDA’s Breakthrough Therapy designation and Taysha has finalized alignment on a single-arm, natural history-controlled design, “precisely the profile the plausible mechanism framework was designed to address,” BMO wrote.
This is a case of prior-leadership alignment untested against new leadership, the analyst noted, “which is the real tell on whether flexible pathways survive under Overton.”
