DIA: Marks rejects ‘cookie cutter’ approach to rare disease reviews

BOSTON – Peter Marks, director of the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research, rejected the idea of using a “cookie-cutter” approach for reviewing rare disease treatments under the accelerated review pathway. He also acknowledged that there is a problem of inconsistent product reviews for rare diseases and said he is working to address the issue.

Marks made these assertions at the Drug Information Association’s 2023 Global Annual meeting on Monday. Panelists at the meeting also noted that accelerated reviews for rare diseases needs to be “tweaked” to make it a more feasible review pathway.

Adora Ndu the chief regulatory officer for BridgeBio, set the stage for the discussion by commenting on four recent accelerated approvals for rare diseases – Qalsody (tofersen) to treat amyotrophic lateral sclerosis (ALS) in adults, Viltepso (viltolarsen) to treat Duchenne muscular dystrophy (DMD), Skysona (elivaldogene autotemcel) to treat patients under 18 with early cerebral adrenoleukodystrophy, and Voxzogo (vosoritide) to increase linear growth in children with achondroplasia.

Other recent developments with potential impact on rare disease drug development include the enactment of the Food and Drug Omnibus Reform Act (FDORA), which requires sponsors to have confirmatory studies underway before receiving accelerated approval, and the launch of the rare disease endpoint advancement program (RDEA) pilot program. (RELATED: FDA officials say high priority will be given to applications with endpoints that can be leveraged for other rare diseases, Regulatory Focus 9 June 2023)

Ndu also commented FDA’s recent decision to grant accelerated approval to Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy Elevidys (delandistrogene moxeparvovec-rokl) in children 4 and 5 years of age, saying the approval was a “huge win” for the rare disease community. Marks overrode staff reviewers who felt the gene therapy should not be approved, according to a decision memo released alongside the drug’s approval.

Accelerated approval has generated controversy

Ndu asked Marks how he would characterize how the agency is progressing in its accelerated approval program for rare diseases.

“I think accelerated approvals is clearly an area that has generated a lot of controversy. The controversy here is whether the agency is doing things too fast or too slow. I would like to believe that if we are doing accelerated approval correctly, we are doing this just right,” Marks said.

No ‘cookie cutter’ approach

Marks asserted that it is not possible to generalize the amount of clinical data needed to support accelerated approval for rare disease therapies, and that the amount of data required depends on the drug’s effect.

“If one has a remarkably robust benefit and it is eminently clear that the results are reproducible from person to person,” this is different from a treatment “that produces a very small effect,” Marks said, noting that demonstrating a robust and easily measurable effect is difficult in some disease areas.

This means that it is not possible to have a one-size-fits-all approach to accelerated approvals for rare diseases.

“While I would love to have one recipe for all, I think we are going to have to individualize development here depending on the nature of the endpoints that we are seeing.”

Challenges for rare diseases

Several panelists at the meeting discussed the challenges in pursuing the accelerated approval pathway for rare diseases. Getting the approval depends on conducting the necessary confirmatory studies to demonstrate the drug’s benefits in an adequately sized patient population.

Annie Kennedy, chief of policy, advocacy and patient engagement for EveryLife Foundation, said it is easier to conduct such confirmatory studies for oncology treatments where there is often a larger patient population to draw from, whereas conducting such studies in rare diseases that affect a very small patient is more difficult due to recruitment challenges.

Shamim Ruff, chief regulatory and quality officer for Stoke Therapeutics, which has one early clinical stage drug candidate in development and several preclinical development programs, said that “it has been a long journey, but it has been a rewarding journey to get here,” adding that “tweaks” are needed to support the accelerated approval pathway for rare diseases.

Ruff also said that approvals for rare diseases often take longer than approvals in other areas, such as oncology, noting that she worked on a treatment for breast cancer that was approved four years earlier than expected. She also said that Sarepta’s Elevidys approval “was a very long journey,” and that the challenges of doing a confirmatory study after that are “tremendous … you cannot do the same study in the same patient population.”

Variability in reviewers

Another challenge for sponsors in developing rare disease treatments is inconsistent reviews for rare diseases. Ndu said she wanted to “target the variability of these reviews. This is a real pain point that we have all experienced. Sometimes we have different responses coming from the review divisions.” She asked Marks to comment on whether he plans to address and “reconcile” these inconsistencies.

Marks said he is aware of some inconsistencies and is working to address them.

“I very much hear you about this issue of variability. I think we need to acknowledge what we can do to eliminate that.” He said that some of the specific actions the center can take to address this are to have the necessary leadership in place and to collaborate more with other centers on review decisions. He said that “we can do better there.”

DIA Global

DIA: Marks rejects ‘cookie cutter’ approach to rare disease reviews

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