FDA Launches Pilot Program to Develop Better Rare Disease Endpoints

Pictured: An illustration of patients, doctors, medicines, computers, data and other elements of clinical research/iStock, elenabs

On July 1, the FDA began accepting proposals from industry and stakeholders to participate in a new pilot program supporting the development of novel FDA-grade efficacy endpoints to treat rare diseases. While the program was well-received, experts told BioSpace there is room for improvement.

The Rare Disease Endpoint Advancement (RDEA) Pilot Program was established in October 2022 as a joint initiative between the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

The focus of RDEA is to promote innovation and evolving science to advance rare disease drug development programs and enhance FDA staff capacity to develop novel endpoints to evaluate the efficacy of the resulting therapies. The program defines a novel endpoint as one that has never been used to support the approval of a drug or has been “modified substantially” from its previous use.

The FDA will accept one drug development program in the fourth quarter of 2023 and no more than three programs for fiscal years 2024 to 2027.

Novel endpoints developed via the program may be presented by the FDA in a guidance document, public workshop or as case studies on a public-facing website.

At a workshop held by the FDA and Duke-Margolis Health Policy Center in June, Peter Stein, director of CDER’s Office of New Drugs, said the pilot program and its associated initiatives exemplify the center’s “longstanding commitment to the development of therapies for rare diseases.”

The area of endpoint design selection is challenging, Stein said, noting a lack of regulatory precedence, small trial populations and an often-limited understanding of the disease’s natural history. Clinical trials for these diseases require sensitive endpoints with as little variability as possible, he said. “The RDEA program will focus specifically on . . . developing clinically meaningful and measurable endpoints.”

While the proposal criteria require that the sponsor have an active pre-IND application or an IND for a rare disease, exceptions will be made for natural history studies that include a novel efficacy endpoint intended to establish substantial evidence of effectiveness for rare disease treatment.

Karin Hoelzer, director of policy and regulatory affairs at the National Organization for Rare Disorders, said this is a unique aspect of the pilot.

To help facilitate the development of novel endpoints, the RDEA pilot program will provide additional meeting opportunities for the sponsors whose proposals are accepted. Up to four meetings will be held between each sponsor and CDER or CBER.

The early-stage meetings are intended to provide guidance on how a proposed novel endpoint can be used in a specific rare disease drug development program and promote innovation by publicly presenting the proposed novel endpoints.

Max Taylor/Photo by Max Taylor

“It is helpful for sponsors to be able to have more [and] earlier interactions with FDA, especially as part of this pilot program where we’re talking about endpoints,” Jessica Tyson, senior director of science and regulatory advocacy at the industry trade association Pharmaceutical Research and Manufacturers of America (PhRMA), told BioSpace.

Tyson and Hoelzer agreed that the RDEA program will provide crucial lessons in terms of early interactions with the FDA.

Experts who attended the FDA and Duke-Margolis workshop and spoke with BioSpace agreed that the RDEA pilot program will serve as a foundation for rare disease drug development and the key to unlocking the potential of other FDA initiatives underway.

The program brings together several ongoing efforts to provide regulatory clarification around the use of digital health technologies, biomarker surrogate endpoints, clinical outcome assessments (COAs) and composite and multicomponent endpoints in clinical trials.

With each program, “we want to make sure that we’re building, and we’re learning from each prior initiative,” Adora Ndu, chief regulatory affairs officer at BridgeBio Pharma, told BioSpace.

Leslie Harden, who served as a director at the Biotechnology Innovation Organization (BIO) when she spoke with BioSpace and recently joined Kyowa Kirin as an associate director, said an important component of improving drug development for rare diseases is the “timing and the speed of the regulatory review.” To this end, the FDA is expected to launch the Operation Warp Speed for Rare Diseases program by the end of 2023. Identifying endpoints via the RDEA program can facilitate this program, Harden said.

Patient-reported outcomes (PROs) recently became recognized as COAs. Using PROs as COAs was the focus of the fourth and latest guidance document that the FDA planned in May 2017 to issue under its patient-focused drug development initiative.

Harden said there has been “a relatively steady current of sponsors” attempting to be more patient-centric in how they design their studies. “The biggest hurdles have come from the regulatory acceptance of clinical outcome assessment tools and navigating when and how to develop them with patients, as well as solidifying what FDA needs [for] regulatory acceptance or utility of COAs of PRO tools in general.”

There is consensus among rare disease leaders, however, that there is still room for improvement in RDEA. This includes having a patient engagement strategy, allowing non-participants to implement lessons in their respective development programs before the conclusion of the program, a more forthcoming and iterative process and greater regulatory flexibility.

Harden said that patient engagement is critical. To participate in RDEA, sponsors will be required to have a plan to engage and seek input from patients in developing the novel endpoint. But Harden, Hoelzer and Ndu all urged the FDA to place an emphasis on this aspect, recommending that sponsors present a patient engagement strategy that states patients will be engaged early and often.

“From the perspective that patients are the experts in their disease . . . it is critical both in drug development as well as in the regulatory process to ensure that they have a seat at the table,” Harden said.

With one development program in 2023 and a total of nine more over the following three years, the program is too limited, Ndu said.

While recognizing that the FDA has resource limitations, she recommended that the regulator expand the program and suggested it develop learnings for reviewers internally and share those externally throughout the program instead of waiting for its conclusion. This will enable sponsors to incorporate those learnings in a time-sensitive manner, she said.

Harden added that the FDA could be more forthcoming by providing program updates at multiple touchpoints in a public forum. This would allow all stakeholders to understand operational challenges as they arise and enable course correction, she said. “We would really like that kind of iterative information-sharing so that the pilot itself can be successful for everybody.”

Both PhRMA and BIO have provided additional feedback via the submission of comment letters to the RDEA program public workshop Federal Register docket set to close on July 23.

Representatives from CDER and CBER told BioSpace that they may incorporate stakeholder feedback into the program.

Ana Mulero is a freelance writer based in Puerto Rico. She can be reached at anacmulero@outlook.com and @anitamulero on Twitter.

Correction (July 26): This story has been updated from its original version to correct that PhRMA and BIO have both prospectively submitted additional feedback regarding the RDEA program. BioSpace regrets the error.