FDA Announces Rare Disease Evidence Principles to Accelerate Treatments for Ultra-Rare Genetic Diseases

Key Takeaways

• The U.S. Food and Drug Administration (FDA) announced Rare Disease Evidence Principles (RDEP) to allow for faster approval of treatments for ultra-rare genetic diseases. A product is eligible if it targets a population of fewer than 1,000 U.S. patients with a known, in-born genetic defect and a significant unmet medical need.
• Once qualified, an RDEP product can obtain approval based on a single, well-controlled trial plus confirmatory data, such as real-world evidence. Sponsors can apply for RDEP any time before they begin a pivotal clinical trial.

On September 3, 2025, the FDA announced the RDEP, a new framework intended to accelerate the approval of treatments for ultra-rare genetic diseases.¹ The RDEP was jointly developed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

The RDEP acknowledge the difficulty of conducting large, multi-trial studies in ultra-rare conditions and describes how a single well-controlled study, supported by robust confirmatory data, can meet the requirements for marketing approval.²

According to FDA Commissioner Marty Makary, “Drug developer—and the patients they hope to treat—deserve clear, consistent information from the FDA. These principles ensure that FDA and sponsors are aligned on a flexible, common-sense approach within our existing authorities, and that we incorporate confirmatory evidence to give sponsors a clear, rigorous path to bring safe and effective treatments to those who need them most.”³

Sponsors may apply for the RDEP process at any time before beginning a pivotal trial. To qualify, the investigative therapy must be “specific to the correction of the genetic defect in question (i.e., either correcting the gene or is a replacement of an essential physiological protein that is otherwise deficient due to the gene defect)” and meet the following criteria:

• the drug is for a very small, rare disease population or subpopulation (e.g., generally fewer than 1,000 patients in the U.S.);
• the drug is intended to treat a known, in-born genetic defect that is the major driver of the pathophysiology;
• the clinical course of the disease is progressive deterioration in function leading to rapid and/or significant disability or death in a relatively short period of time; and
• there are no adequate alternative therapies that alter the course of the disease.⁴

If a drug meets these criteria, then the FDA anticipates that one adequate and well-controlled clinical study will be sufficient for marketing approval, along with robust confirmatory evidence of the drug’s treatment effect, such as:

• strong mechanistic or biomarker evidence
• evidence from relevant non-clinical models
• clinical pharmacodynamic data
• case reports, expanded access data, or natural history studies⁵

Sponsors can submit a request for the RDEP process in a formal meeting request to their investigational new drug (IND) application at any time before initiating a pivotal trial. The IND review team will consult with the Rare Disease Policy and Portfolio Council to determine whether the product is eligible. If the request is accepted, the FDA review team will provide separate advice concerning the specific data needed for approval.⁶ RDEP qualification is independent of orphan drug designation but may be combined with it.⁷

[1] U.S. Food and Drug Administration, CDER/CBER Rare Disease Evidence Principles (RDEP) (Sept. 2023), https://www.fda.gov/industry/fda-rare-disease-innovation-hub/cdercber-rare-disease-evidence-principles-rdep.

[2] Id.

[3] U.S. Food and Drug Administration, FDA Advances Rare Disease Drug Development with New Evidence Principles (Sept. 3, 2025), at 1, https://www.fda.gov/news-events/press-announcements/fda-advances-rare-disease-drug-development-new-evidence-principles.

[4] RDEP, note 1 above, at 2.

[5] FDA Advances Rare Disease Drug, note 2 above, at 1.

[6] RDEP, note 1 above, at 3.

[7] Id.