Rare Disease Industry Awaits FDA Chief’s New Drug Pathway Plan

FDA Commissioner Marty Makary’s proposal to roll out a new drug approval pathway is heightening hope for the rare disease industry, but attorneys say implementation may face challenges for spurring rare drug development.

Makary outlined on the Megyn Kelly Show in April a plan to approve drugs for rare conditions based on a “plausible mechanism,” allowing medicines to be approved without data from a randomized controlled clinical trial. A drug could be eligible for the pathway if it “makes sense physiologically,” and “the mechanism is scientifically plausible,” he said.

“Even though we don’t have a randomized control trial, because it’s not feasible, we will allow that, and at the same time, monitor everybody who gets it so that we can make inferences as soon as the data speaks,” Makary said.

A new pathway has the potential to open the door for more rare disease drug approvals, which has been a long-standing challenge due to the high costs of development for diverse patient populations that often limit clinical trial designs.

But the proposal hinges on how Makary will move the plan forward, which could range from lawmakers introducing legislation, the agency issuing guidance, or even expanding the FDA’s existing authority.

“It’s a wait-and-see in terms of which mechanism FDA might use and whether they will need a legislative vehicle or not to implement something here,” said Julie Tibbets, chair of Goodwin Procter LLP’s life science regulatory and compliance practice.

“The current access gap that patients face while they’re waiting for new treatments to reach approval in the rare disease space really heightens the need for this flexibility of getting promising new treatments to patients,” Tibbets said.

The FDA has approved hundreds of drugs to treat rare diseases, but developing them remains a challenge due to regulatory requirements sponsors must meet. Some of the obstacles relate to data collection, limited patient pools and trial designs, and limitations to natural history studies that would show the progression of rare diseases.

“We’ve seen programs come to a halt because of the inability to get an agreement with FDA,” said James Valentine, a director at Hyman, Phelps & McNamara PC. “And it’s not the FDA reviewers’ fault—they’re being asked to color outside of the lines in terms of applying the regulatory framework.”

Congress, Guidance

A new approval process could be introduced through various methods, including new legislation that would create a conditional approval pathway and give rare drug sponsors more flexibility.

There have been attempts from Congress to grant a time-limited conditional approval process for drugs targeting rare diseases.

Senators in 2024 reintroduced the Promising Pathway Act, which would create a conditional approval pathway for drugs intended to treat rare, progressive and congenital diseases. House lawmakers that same year introduced a version of that measure that would create a quick and provisional approval pathway for drugmakers.

While legislation would likely take the longest, it would be the “cleanest” vehicle to bring a pathway forward and establish a clear and strong framework, Tibbets said.

Other approaches the FDA could take include issuing guidance that would invite feedback from industry and advocacy groups. The agency could also roll out a roadmap for how it will execute its plans, just as it did April 10 when it issued an agenda for reducing animal testing in preclinical safety studies.

Some industry watchers also say the FDA could seek to expand its authorities under its current accelerated approval pathway.

“In those types of situations where you’re able to demonstrate the restorative function, for example, of a cell therapy, it could be very difficult to conduct a randomized trial,” said Jeff Allen, CEO of Friends of Cancer Research. “I don’t necessarily discourage a different pathway here because I think it could help identify those situations even more clearly where flexibility may be necessary.”

There’s also the chance that the FDA could initially implement this without Congress or regulation, some attorneys say.

“I think it is possible for FDA to do this not only without Congress, but also without regulation, at least maybe initially,” Valentine said. “FDA could approve a product and articulate how it meets the statutory standard and its review memos.”

Other Hurdles

The proposed pathway is likely to increase rare disease drugs on the market, but attorneys are eyeing how medicines will ultimately reach patients.

Such treatments come with a high price tag that can range between hundreds of thousands to millions of dollars, making it difficult for patients to receive drugs long term.

“A lot of folks think that the most difficult part of getting to the market is FDA approval, and that’s a huge hurdle, but it’s equally as challenging when there’s insufficient coverage or lack of coding or no payment,” said Matthew Wetzel, a partner at Goodwin.

Rare disease drug development also continues to be tested under the Inflation Reduction Act’s drug price negotiation program, another area attorneys are watching, even if the FDA clears a conditional approval pathway.

That law slashes the price of some of the most widely used and expensive drugs covered under Medicare, but exempts orphan drugs with a single FDA-approved indication to treat a rare disease.

However, drugs with designations to treat more than one rare disease or condition won’t qualify for the exclusion and may be subject to price cuts, even if they haven’t been approved for any indications for an additional rare disease or condition.

The rare disease community has long pushed for changes in the program, as they say it forces drugmakers and investors to reconsider development of drugs to treat small patient populations.

“All those benefits aren’t going to really mean much if they are stuck with that limitation under the IRA,” Wetzel said. “That pressure will continue to bear on drug developers who are looking to be in the rare disease space.”