FDA maps new regulatory route for ultra-rare diseases

The FDA has sketched out its new regulatory pathway to market for individualised therapies that treat ultra-rare diseases, based on a 'plausible mechanism' premise.

If finalised, the guidance would provide a rapid way for patients with diseases that have a well-characterised biological mechanism – but too few cases to make conventional clinical testing feasible – to get access to therapies. The FDA first introduced the plausible mechanism concept last November.

In a nutshell, the new framework would allow new technologies like genome editing and RNA-based therapies to be approved based on a "single adequate and well-controlled clinical investigation with confirmatory evidence."

HHS Secretary Robert F Kennedy Jr said the new framework is "cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most."

At a press conference to introduce the plan, he added: "When the biology is clear, and the science is sound, we will evaluate therapies based upon strong evidence and not arbitrary barriers. Individualised medicine is no longer theoretical."

To qualify, a disease will have to have a clear mechanism to address, such as a genetic, cellular, or molecular abnormality, that is targeted by the proposed treatment. Sponsors will also have to demonstrate that the therapy effectively targets the root cause or a closely linked biological pathway.

For comparison, it may be possible to rely on "a well-characterised natural history of the disease in an untreated population," according to the guidance.

FDA Commissioner Marty Makary said that an estimated 30 million people in the US have a rare disease – equivalent to one in 11 Americans – but they are being failed by a system that only caters for the more commonly encountered rare diseases.

Fewer than 5% of the more than 10,000 known rare diseases have an approved treatment, according to the National Organization for Rare Disorders (NORD) advocacy group.

One reason for this is that the current system means that there is no prospect of a financial return for pharma companies working on ultra-rare diseases. Under the new proposals, it is predicted that other organisations, including clinical groups, will find it easier to advance new therapies.

"Designing treatments unique to individual patients has always been the promised goal of personalised medicine," said Makary. "After 25 years the FDA has, for the first time, outlined a framework to facilitate these approvals."

The FDA has previously cited the case of 'Baby KJ', who made history last year when he became the first patient to be treated with a bespoke, in vivo CRISPR gene editing therapy designed to correct the specific mutation behind his illness.

"The FDA recognises that an adequate and well-controlled clinical investigation in this context will include a small sample size, therefore investigation results should be sufficiently robust to exclude chance findings," said the FDA in an introduction to the proposed guidance. For traditional approval, sponsors will need to demonstrate improvement in clinical outcomes.

The guidance is subject to a 60-day public comment period.