‘Threading The Needle:’ Finding A Regulatory Foundation For Ultra Rare Disease Development

Ultra-rare diseases could find a smoother path to US Food and Drug Administration approval with a new evidentiary standard, but current and former agency officials worry the change carries too much risk for the regulatory community, as well as patients.

Drug development often is difficult in ultra-rare disorders, which generally affect a fraction of the 200,000-patient threshold for a traditional rare disease. Patients are hard to find, and efficacy can be hard to show in one or more clinical trials, as the current statute requires.

The FDA uses its oft-trumpeted regulatory flexibility to compensate, but it still can be limited when well-controlled clinical trials are not feasible.

Attorney Frank Sasinowski, a director at Hyman, Phelps and McNamara who frequently works in the rare disease space, said many FDA reviewers recognize the problem and have granted approvals based on the extent of scientific evidence available. But while the agency’s judgment is not necessarily questioned, the regulatory reasoning for the decision is not defined.

“I feel tremendous empathy for FDA reviewers and decision-makers because they are left on their own,” Sasinowski said in an interview with the Pink Sheet. He also spoke at the 21 May EveryLife Foundation Scientific Workshop.

The FDA staff “are doing good reviews on these datasets and then when they decide they want to approve, they don’t try to explain,” he added. “You can’t thread the needle right now. I’m trying to find a way to thread the needle.”

Sasinowski said the US should consider outlining a new approval standard for ultra-rare diseases that allows the FDA to assess all available scientifically valid evidence, such as mechanistic information, including clinical pharmacology and animal models, real-world evidence, and externally controlled comparisons like natural history studies.

He also said FDA regulations should evolve to recognize evidence outside of well-controlled clinical trials, just as science has evolved since the current standard was enacted.

“The agency is being correct and being remarkably flexible and responding to the needs of patients, but doing so in a very strange system,” Sasinowski said. “It doesn’t need to be that difficult.”

EveryLife in 2023 announced that it wanted Congress to explore creating a new ultra rare disease designation, as well as associated incentives and an approval pathway. The scientific conference in part explored that idea. (Also see "Ultra-Rare Orphan Drugs: Advocates Begin Laying Groundwork For New Incentive, Special Pathway" - Pink Sheet, 3 March, 2023.)

But FDA officials remain wary of the potential benefits of it. (Also see "Push To Create Ultra-Rare Orphan Drug Designation Finds Resistance At US FDA" - Pink Sheet, 21 August, 2023.)

Sasinowski said during the conference that several approvals, including Kyowa Kirin Co., Ltd.’s Lenmeldy (atidarsagene autotemcel) and Reata Pharmaceuticals, Inc.’s Skyclarys (omaveloxolone), suggest the idea already is incorporated into FDA practice, but they are exceptions.

Lenmeldy was approved by the FDA in March for early-onset metachromatic leukodystrophy (MLD). (Also see "Orchard Will Launch Lenmeldy At Just Five Centers" - Scrip, 20 March, 2024.) Skyclarys was approved in February 2023 for Friedreich’s ataxia. (Also see "Reata’s Skyclarys Approval Aided By Natural History And Delayed-Start Analyses" - Pink Sheet, 5 March, 2023.)

Avoiding Potential Regulatory Threats

Current regulations from the 1980s could offer some support if legislation is not possible. However, Sasinowski said without a clear delineation of the regulatory framework, payers could refuse coverage, arguing the decision does not meet FDA standards.

Former FDA Principal Deputy Commissioner Janet Woodcock agreed that a statutory allowance for consideration of mechanistic understanding and the totality of evidence would be the best maneuver, but added that opening FDA regulations and the Orphan Drug Act to changes could be dangerous. Lawmakers and special interests could further erode incentives in the process.

“Sticking with the current standard avoids some of these other threats,” she said during the conference.

“My assessment is it’s kind of a bridge too far for some people,” added Woodcock, who was director of the Center for Drug Evaluation and Research for more than 20 years and now is advising the Haystack Project, a coalition of ultra-rare and rare disease patient groups. (Also see "Woodcock Takes On Rare Disease Challenges In Retirement, Keeps FDA, Industry At Arm’s Length" - Pink Sheet, 17 April, 2024.)

Center for Biologics Evaluation and Research Director Peter Marks also said during the session that his greatest fear is changing the FDA standard for safety and efficacy.

“We have insurance companies fighting against giving kids gene therapies that are potentially life-changing because of their cost and ‘oh well, accelerated approval. Does it really mean it works or not?’” he said.

“I don’t want to see us in a place where we have haves and have-nots in this country, which I already am concerned that we may see with Medicaid and gene therapies for sickle cell disease,” he added. “You can imagine it happening on a broader scale if we change the standard.”

CBER cleared two gene therapies for sickle cell disease in December 2023, Vertex Pharmaceuticals Incorporated/CRISPR Therapeutics AG’s Casgevy (exagamglogene autotemcel) and bluebird bio’s Lyfgenia (lovotibeglogene autotemcel). Casgevy was priced at $2.2m and Lyfgenia $3.1m. (Also see "Gene Therapy: US FDA Labeling For Vertex’s Casgevy, Bluebird’s Lyfgenia Reflect Different Risks" - Pink Sheet, 9 December, 2023.)

The preference against pushing Congress to adjust a foundational law is not new. Previous calls to change the Orphan Drug Act in part to adapt to modern science and drug development practices have been nixed because of concerns about unexpected consequences. (Also see "Woodcock Says Blowing Up Orphan Drug Act Not Advisable In Current Climate" - Pink Sheet, 17 October, 2011.)

Opponents of change also have an example of what could happen even when the community is not pushing for updates. Congress in 2017 eliminated a tax credit that many orphan sponsors used to offset costs despite arguments the move would hinder rare disease drug development. (Also see "Does The Orphan Drug Act Need A Tune-Up?" - Pink Sheet, 1 March, 2023.)

Could An FDA Attitude Change Help Ultra Rare Development?

A legislative alternative may be a change in attitude and approach for FDA reviewers and other staff who handle rare disease applications.

Reviewers learn quickly upon joining the FDA that they must uphold the law that requires two adequate and well-controlled clinical trials for approval. Woodcock said the standard is in direct conflict with the flexibility that patients and advocates want them to employ for rare disease products.

“The reviewers are put in a terrible position,” she said. “They are told they have to uphold the standard. That’s the role of the FDA is to enforce the law at the end of the day. It’s a scientific law enforcement agency.”

“You can be flexible, flexible, flexible and then pretty soon you’re gonna break.” – Janet Woodcock

“People who develop for larger diseases, they come in with all kind of stories about why it was OK that the p-value is .06 and that there are trends and this and that,” Woodcock added. “How do you enforce a standard here and not enforce a standard there?”

The agency also is reaching the limits of regulatory flexibility, Woodcock said.

“What we’ve seen is a lot of cognitive dissonance internally, of people who are being asked to at one hand enforce a standard, another hand be flexible,” she said. “You can be flexible, flexible, flexible and then pretty soon you’re gonna break.”

Marks said the cognitive dissonance is a greater worry than the FDA’s authorities needing a refresh.

“One of the things we’re trying to do in our center is regs are important, we’ve got to follow them, but start to focus on the patient,” he said.

“The expanded access regulations, they’re very beautiful,” Marks added. “That said, like who cares right? It’s what can you do for a given patient. I think it really is changing this focus.”

Marks said FDA employees can follow the law and still prioritize patients in the application assessment process.

“I think we have people that are smart enough that we can focus on the patient and actually still stay on the right side of the regs,” he said. “I think it’s just a matter of in some cases just changing how we think about things and how we approach them.”

Campaign For Increased Flexibility Continues

Advocates continue to push the agency to employ regulatory flexibility for more applications.

Rep. Gus Bilirakis, R-FL, claimed during a 22 May House subcommittee hearing with Marks and Center for Drug Evaluation and Research Director Patrizia Cavazzoni that CDER has become less flexible since Woodcock relinquished her role as head of the drugs center. He argued that CBER is more flexible now. (Also see "Woodcock Nostalgia: GOP Rep. Bilirakis Wants CDER To Recapture Her Flexible Approach" - Pink Sheet, 22 May, 2024.)

The argument over the correct amount of regulatory flexibility, and when to employ it, has spanned decades.

FDA officials had no real proof that the agency's flexibility policy had been employed until Sasinowski published a paper outlining the extent of the agency’s use of the authority in 2011. (Also see "Orphan Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds" - Pink Sheet, 17 October, 2011.)