FDA’s handling of rare disease therapies criticized in Senate hearing

Senators and expert witnesses voiced concerns about the US Food and Drug Administration’s (FDA) oversight of rare disease therapies during a hearing of the Senate Special Committee on Aging on Thursday. These concerns included claims of inconsistent review processes, the agency’s failure to apply regulatory flexibility, and the issuance of nearly two dozen complete response letters (CRLs) for rare disease treatments since the start of 2025.

The panel also recommended that FDA reinstate its practice of holding advisory panel meetings for drugs under review.

The hearing was held to evaluate the FDA's regulatory process for reviewing treatments for rare diseases. Committee Chair Rick Scott (R-FL) opened the hearing by highlighting that the FDA is facing criticism for not fully utilizing the regulatory flexibilities granted by Congress. These flexibilities are intended to expedite the review of drugs that treat serious and life-threatening conditions.

Senator Kirsten Gillibrand (D-NY), the ranking member of the committee, also weighed in, and stated that Congress provided the FDA with "significant regulatory flexibility" to promote both biotech innovation and therapies for rare diseases. This includes authorizing the accelerated review pathway, establishing the rare disease endpoint program, and enhancing the use of patient experience data and real-world evidence in the drug review process.

Yet Gillibrand said these mechanisms are “not working how it should be. FDA’s approach to transparency and flexibility varies widely between offices, divisions and centers. We have seen a pattern of hesitation to use authorized flexibilities, limited communication with drug sponsors, failure to incorporate patient experience and real-world evidence review and FDA shifting its regulatory position on trial design at the last minute, rejecting drug applications, and requiring new clinical trials sponsors may not be able to perform. This is heartbreaking for patients.”

Experts detail rare disease setbacks

The panel, which consisted of patient advocates and physicians from the rare disease community, agreed with Gillibrand’s assessment.

Annie Kennedy, the Chief Mission Officer for the EveryLife Foundation for Rare Diseases, expressed that the organization has been heartened by the FDA's support for initiatives aimed at developing therapies for rare diseases. These include the Rare Disease Evidence Principles (RDEP) framework and the plausible mechanism pathway. However, she noted that the group has faced a series of FDA decisions regarding rare disease product applications that are “inconsistent with recent public commitments to enhance regulatory flexibility in the evaluation of rare disease therapies.”

Kennedy stated that since the beginning of 2025, the FDA has issued at least 23 CRLs declining to approve rare disease therapies submitted under the accelerated approval pathway.

“Several of the recent CRLs include comments that indicate a hesitation to apply regulatory flexibility on issues such as the use of surrogate endpoints, natural history studies, external controls, and real-world evidence,” she said.

Kennedy noted that previously, novel product reviews would lead to the convening of a product advisory committee to solicit the input of external experts to inform decision-making. She urged FDA to resume its use of advisory committee meetings to receive external expertise on product reviews and to “optimize the Rare Disease Innovation Hub’s ability to improve outcomes for rare disease patients through enhanced coordination and alignment between medical product centers.”

Kennedy also urged Congress to oversee FDA's use of the accelerated approval pathway for rare diseases therapies and to address the “inconsistent and unpredictable application of regulatory flexibility.”

Kennedy said that “the uneven application of rare disease policies and recent actions across the agency are resulting in increased unpredictability and risk that we fear could slow or prevent promising therapies from reaching those who need them most.”

Jeremy Schmahmann, a neurology professor at Harvard Medical School, highlighted inconsistencies in the FDA's review process and ultimate rejection of Biohaven's drug, troriluzole, which was developed to treat ataxia. He said that this rejection is particularly noteworthy given the agency's collaboration with the company during the drug's development. Schmahmann is an expert on ataxia and founded the first Ataxia Center in the United States at Massachusetts General Hospital in 1994.

Schmahmann said that “Italian studies in the early 2010s showed that riluzole, the drug used to treat ALS for the past 30 years, seemed to improve ataxia. Based on this finding and the plausible mechanism of action as a treatment for spinocerebellar ataxia, Biohaven developed troriluzole, which metabolizes into riluzole, but the pill is taken just once a day, with better absorption and brain penetration, and a remarkable side effect profile that is similar to placebo.”

Schmahmann added that “at every step of the clinical development program Biohaven relied on input and collaboration with the ataxia experts across the globe and incorporated FDA feedback into each protocol.”

Yet FDA issued a complete response letter, rejecting the troriluzole new drug application in November 2025. The agency required a large, double-blind, placebo-controlled trial in the CRL.

Schmahmann said that “in this rare disease context, such a trial would take five to eight years to complete and would require withholding a drug that has been shown to slow decline. During such a trial, patients will worsen and die from their disease. There was even the suggestion by FDA to perform a randomized withdrawal study. This would entail blinding patients to whether they were being taken off treatment and then seeing if they worsen to further prove the effect of the drug. My colleagues and I find either approach to be unethical. It violates the principle of beneficence in human studies research, to act with charity, mercy, and kindness to promote the well-being of others.”

He said he wrote six letters to FDA leadership between 2023 and 2025, cosigned by 17 ataxia colleagues around the country, asking FDA to review the application and work with Biohaven to make the drug available. He still has not heard back from FDA.

He noted that “this medication is safe, it is well-tolerated, and to reiterate, it metabolizes into a drug that has been on the market for 30 years. We are at a loss to understand how this has been allowed to take place.”

Schmahmann said that the drug remains unavailable to patients outside clinical trials and is now to be denied even to those patients on the expanded access program.

In another case, Cara O’Neill, chief science officer and cofounder of the Cure Sanfilippo Foundation, discussed FDA’s review of a drug intended to treat Sanfilippo syndrome, a form of childhood dementia. She has a daughter who is afflicted with this ultra-rare, neurodegenerative disease.

O’Neill said that “thanks to NIH funding and support from non-profit foundations, including our own, a promising gene therapy was developed and propelled towards a clinical trial at Nationwide Children’s Hospital in Ohio. Parents like us anxiously awaited news of the trial opening.”

O’Neill said that “last summer, patients’ hopes were dashed when the drug was denied approval – not for safety issues or concerns about how the children were responding to the treatment, but because of questions about the manufacturing process. While an important issue, a flexible regulatory approach could have allowed the application review to proceed while addressing any outstanding questions in parallel.”

She said that “the deficiencies cited in the CRLs raise the question of whether the FDA is indeed using its regulatory flexibility in rare diseases.”

O’Neill said that the CRL cited only manufacturing concerns, not safety or efficacy concerns.

Hearing

FDA’s handling of rare disease therapies criticized in Senate hearing

Related topics

Recommended content

Welcome to the new RAPS Digital Experience