On September 3, 2025, the FDA announced the Rare Disease Evidence Principles (RDEP). This new regulatory framework is meant to provide more explicit guidance, enhanced communication and collaboration, and offer greater flexibility in how therapies for ultra-rare, genetically driven diseases are developed and reviewed.
For companies targeting ultra-rare populations (fewer than ~1,000 U.S. patients) with no adequate treatment options, RDEP is in place to help guide and reshape the development process. Below, we explain what the program does, how it functions, and what it means for sponsors.
What RDEP Offers Sponsors
- Early Engagement: Sponsors can request an RDEP meeting before initiating a pivotal trial, aligning expectations at the right time. In some cases, the FDA has noted discussions could take place even prior to IND clearance, with the formal request submitted later.
- Clarity on Evidence Requirements: FDA will define, in advance, what constitutes "substantial evidence of effectiveness" when large, traditional trials are not possible.
- Integration of Patient & Expert Input: The process incorporates patient and external expert voices through mechanisms such as listening sessions, ensuring perspectives beyond sponsor and agency are reflected.
- Flexibility in Evidence Sources: Beyond a single well-controlled trial, the FDA may accept confirmatory data from biomarkers, natural history studies, expanded access, case reports, or pharmacodynamic evidence.
- Communication Across FDA Centers: Reviews are supported jointly by both CDER and CBER, ensuring consistency in decision-making across advanced therapy modalities.
Key Eligibility Criteria
To qualify for RDEP, the therapy must:
- Be intended for an ultra-rare disease population or subpopulation (generally fewer than ~1,000 persons in the United States).
- Target a defined, inborn genetic defect that is the primary driver of disease pathophysiology.
- Address a disease with a progressive clinical course that leads to rapid and/or significant disability or death within a relatively short timeframe.
- Address a disease for which no adequate alternative therapies are available that meaningfully alter the natural course of the disease.
The RDEP Process
According to the information FDA has published so far; to participate, sponsors must first submit a request through the IND before beginning pivotal testing, demonstrating how the program meets the eligibility criteria. If the request is accepted, an initial FDA meeting is scheduled to align on the types of evidence required for approval. Sponsors then proceed with evidence development, typically involving a single, adequate, and well-controlled trial supplemented by confirmatory data such as biomarkers, natural history studies, or expanded access experience. Once the evidence package is agreed upon and generated, sponsors may move forward with regulatory submission. Following approval, the FDA may require post-marketing studies to ensure long-term safety and effectiveness.
Why RDEP Matters
For many ultra-rare, genetically defined diseases, traditional development models are not feasible. Conducting extensive, randomized controlled trials is often impossible due to extremely small patient populations, geographic dispersion, and the urgency of rapidly progressive conditions. These challenges have historically stalled or prevented promising therapies from advancing.
RDEP could be the program that developers of medicines for ultra-rare diseases have been waiting for: a structured pathway for approval that balances scientific rigor with regulatory flexibility. It introduces predictability that can reduce investment risks and guide trial planning. Most importantly, it sets a precedent for patient communities that have faced limited development activity, offering hope that treatments once considered infeasible may now have a viable regulatory path forward.
Practical Steps for Sponsors
While the program is in its (very) early days, Sponsors should start assessing eligibility early to confirm the program aligns with RDEP's criteria and consider integrating the RDEP request into the IND strategy and timeline.
If you are considering applying for the RDEP process or if you have questions about whether your program may qualify, please get in touch with us: contactus@raremoonconsulting.com.
Authoritative Sources
- FDA — FDA Advances Rare Disease Drug Development with New Evidence Principles (Press Release, Sept 3, 2025).
- FDA — CDER/CBER Rare Disease Innovation Hub: Rare Disease Evidence Principles (RDEP).