Stakeholders call for knowledge sharing, patient voices in rare disease endpoint pilot

As the US Food and Drug Administration (FDA) prepares to accept proposal requests for the Rare Disease Endpoint Advancement (RDEA) Pilot Program, some stakeholders are calling on the agency to clarify its definition of “novel” endpoints and others want to see the program expanded.

The comments are in response to a public workshop convened by the FDA and the Duke-Robert J. Margolis, MD Center for Health Policy. The workshop, held in June 2023, focused on the RDEA pilot program and novel endpoint development in rare disease drug development. (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)

At the workshop, FDA officials said they would prioritize applications to the pilot program that had endpoints with the potential to be applied broadly to other diseases. Sponsors can submit RDEA proposals from 1 July 2023 through 30 September 2023 for one available spot. In fiscal years 2024 through 2027, the agency will accept up to three proposals per year. Sponsors admitted to the program will have an initial meeting with the FDA and up to three follow-up meetings, if requested.

Proposal selection

The CLL Society, an advocacy and research group focused on the unmet needs of patients with chronic lymphocytic leukemia and small lymphocytic lymphoma, generally supported FDA’s plan to give preference to proposals with the potential to impact drug development more broadly. However, the group wrote that FDA should not exclude a novel endpoint that more reliably predicts clinical benefit than existing endpoints in conditions with significant unmet needs, such as CLL. The CLL Society also asked FDA to give preference to promising novel endpoints in life-threatening rare diseases when existing treatments are not effective in later stages of the disease.

The Child Neurology Foundation asked FDA to focus on common symptoms of rare child neurology conditions, such as seizures, ataxia, and behavior regulation, rather than looking at a single disease state. “We also ask that the FDA focus on accurately capturing the symptom as it is expressed within rare pediatric patients. By shifting endpoints from a single disease state to a larger patient population, the FDA can alleviate bottlenecks that negatively impact the patient community, sponsors, and the research community more generally,” the group wrote.

EveryLife Foundation for Rare Diseases, an advocacy group for patients with rare diseases, urged the FDA to prioritize the selection of surrogate or intermediate clinical endpoints for the pilot program. The group noted that in the RDEA program announcement, FDA said preference would be given to surrogate endpoints that “use novel approaches for collecting additional clinical data in the pre-market stage to advance the validation of these endpoints.” The EveryLife Foundation said the language in the announcement suggested that novel surrogate endpoints considered vital for rare disease drug development would be deprioritized.

Defining ‘novel’ endpoints

The CLL Society also asked FDA to clarify when an endpoint is considered novel. “The FDA suggests that the endpoint must be one that has ‘never been used to support drug approval’ or is ‘substantially modified from previous use to support drug approval.’ CLL Society urges the FDA to determine whether an endpoint is novel within the context of the specific disease state. MRD, for example, would be a novel endpoint in CLL even if the concept were used in other blood cancers or conditions,” the group wrote.

Expanding the program, knowledge sharing

The EveryLife Foundation also called on FDA to expand the pilot beyond the three proposals per year in FY 2024-2027. “Given the over 10,000 rare diseases and the over 100 developers of drugs for rare diseases, we have concerns that 3 pilot proposals per year over a 3-year span will not sufficiently address endpoint development challenges,” the group wrote. “To the degree possible - we would like to see FDA commit even more to advance rare disease policy, including by going above and beyond the commitments set in the [PDUFA VII] letter, such as by exceeding the number of proposals accepted and the stated deadlines.”

Given the small size of the pilot, the Biotechnology Innovation Organization (BIO) urged FDA to consider knowledge sharing beyond the pilot, so that lessons can be learned from proposals for novel endpoints for rare diseases that are handled outside the pilot program.

“Because a key feature of the program is transparency for the purpose of enhancing understanding among all stakeholders, we encourage FDA to capture the best practices and lessons learned from these proposals that are discussed outside of the RDEA pilot program. We further encourage FDA to determine on a case-by-case basis whether general knowledge sharing is possible for these proposals without the need to have a formal disclosure agreement. This would enable stakeholders to benefit from a potentially larger population of novel endpoint proposals than only those accepted into the pilot,” BIO wrote.

Similarly, the Pharmaceutical Research and Manufacturers of America (PhRMA) asked FDA to use the same approach with the RDEA pilot that it took with the Complex Innovative Trial Design (CID) Pilot, where it tracked trial design innovation outside of the pilot to identify trends beyond the single development programs that were selected for the pilot.

Public comments on the RDEA workshop

Stakeholders call for knowledge sharing, patient voices in rare disease endpoint pilot

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