At an FDA Town Hall at the BIO International Convention in June, Karim Mikhail set out a case for changing how rare-disease treatments are assessed. Mikhail, then acting director of the Center for Biologics Evaluation and Research, said: “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.”
The Food and Drug Administration is now initiating its Rare Disease Framework Initiative, describing it as a fresh approach to reviewing therapies for these conditions. Its stated aim is to make fit-for-purpose evidentiary expectations standard across rare-disease applications, while working with sponsors and patients on ways to generate evidence that meets the agency’s statutory standard for safety and effectiveness.
The policy is intended for a large population with few approved options. Thirty million Americans, approximately one in ten people, live with a rare disease. As of 2025, only approximately 5% of recognised rare diseases had an FDA-approved treatment.
Under the Federal Food, Drug, and Cosmetic Act, a rare disease affects fewer than 200,000 people. Globally, an estimated 300 million people are affected across 7,000 to 10,000 distinct conditions.
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Mikhail has since been appointed permanent director of CBER, while Michael Davis has been appointed director of the Center for Drug Evaluation and Research, or CDER. The two review centres have begun reshaping their assessment of evidence for rare-disease treatments under the agency’s new leadership.
There is already an example of that approach in practice. Under Mikhail’s direction, uniQure’s gene therapy for Huntington’s disease was allowed to proceed using existing data. Additional trials involving sham surgery controls were not required.
The FDA’s shift comes despite rare diseases accounting for about half of novel approvals from CBER and CDER in recent years. The gap between that share and the proportion of diseases with an approved treatment is central to the agency’s effort to develop evidence standards suited to small and often constrained patient populations.
Former FDA leaders Marty Makary and Vinay Prasad introduced the plausible mechanism pathway in November 2025. The pathway provides alternate criteria when limited patient numbers make randomised controlled trials impossible or infeasible.
John Crowley, president of BIO, has argued that the proposed framework should not be understood as a relaxation of standards. Speaking publicly on 21 September, he said: “I think it implies strongly a lower standard. That's not what patients and parents and innovators want. What we want to see is an elevation of regulatory science and a new framework.”
The stakes extend beyond the approval process. Rare-disease care costs approximately ten times more per patient than care for common diseases. A 2019 economic analysis of 379 rare diseases put the annual burden on the US economy at $997 billion, including $449 billion in direct medical costs, $437 billion in indirect costs including lost productivity, and $73 billion in non-medical costs.
The absence of an approved treatment is independently associated with a 21.2% annual rise in total per-patient costs. The FDA has yet to specify a timetable for the initiative, which diseases it will prioritise, or the detailed evidence standards it will apply across different conditions.
Heidi Overton, President Donald Trump’s nominee for FDA commissioner, would inherit stewardship of the agency’s direction on rare-disease approval policy.
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