Developing treatments for ultra-rare diseases has always been one of the toughest challenges in drug development. With small patient populations and limited trial options, many promising therapies stall before reaching patients. The FDA’s new Rare Disease Evidence Principles (RDEP) aim to change that by offering a clearer, faster, and more flexible path to approval.
This week, the FDA announced the launch of the Rare Disease Evidence Principles (RDEP), a new framework designed to guide sponsors through the rare disease drug development and approval process. For years, drug developers have struggled to generate the substantial evidence of safety and effectiveness typically required under the FDA’s approval process for ultra-rare diseases, with very small patient populations and genetic defect-driven conditions. RDEP offers a more predictable and flexible pathway by clarifying what types of evidence can be used to demonstrate effectiveness without lowering regulatory standards.
Under the RDEP, drug approval may be based on one adequate and well-controlled clinical study combined with strong confirmatory evidence. This is to acknowledge that the traditional requirements, which call for multiple large-scale clinical trials, are not feasible in ultra-rare disease populations. The FDA notes that confirmatory evidence can include mechanistic or biomarker data, non-clinical models, pharmacodynamic data, natural history studies, case reports, or expanded access data. These flexible evidence standards for rare diseases are designed to make the FDA approval process both rigorous and achievable.
RDEP is available for therapies that address a known genetic defect that drives the disease and serve a very small patient population, typically fewer than 1,000 people in the United States. The disease must also be progressive, leading to rapid deterioration, disability, or death, and there must be no adequate alternative therapies available. Sponsors must apply for RDEP review before launching a pivotal trial, giving the FDA and developers the opportunity to align early on trial design, data requirements, and confirmatory evidence strategies.
The review process under RDEP involves close collaboration between sponsors and FDA review teams. Sponsors submit their request through an Investigational New Drug (IND) application, and once accepted, they work with the FDA to define the evidence needed for approval. Patient and expert input is strongly encouraged throughout. The program is available for drugs and biologics, not medical devices.
It’s important to note that participation in RDEP is separate from orphan drug designation. While both processes focus on rare diseases, RDEP does not automatically grant orphan status under the Federal Food, Drug, and Cosmetic Act. Sponsors seeking orphan-drug designation must still follow the procedures outlined in federal regulations.
Even with these new flexibilities, drugs approved under RDEP may carry additional postmarketing requirements to monitor long-term safety and effectiveness once they are approved. For patients and families affected by devastating rare diseases, time is often the most precious resource. The Rare Disease Evidence Principles provide a science-driven, flexible, and patient-focused approach to ultra-rare disease drug development.
