FDA Proposes New Approval Pathway for Individualized Ultra-Rare Disease Therapies

Today, the FDA issued draft guidance outlining a new regulatory pathway intended to help sponsors gain approval for highly targeted, individualized therapies when traditional randomized controlled trials (RCTs) are not feasible due to small patient populations.¹

The guidance introduces what the agency describes as a “Plausible Mechanism Framework,” which would allow sponsors to generate substantial evidence of safety and effectiveness using alternative approaches when large RCTs are not possible. This scenario is common in ultra-rare diseases, where patient populations may be too small to support traditional trial designs.

Rare diseases are defined as conditions affecting fewer than 200,000 individuals.² Currently, more than 10,000 rare diseases collectively affect over 30 million people in the US. Despite growing scientific advances, access to diagnosis, treatment, and coordinated care remains limited.

Issued by the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, the draft guidance, “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies That Target Specific Genetic Conditions With Known Biological Cause,” focuses on genome editing and RNA-based therapies.¹ However, the agency noted that the framework may also apply to other tailored therapeutics that directly address the underlying biological cause of disease.

The draft guidance applies to therapies that target a specific genetic, cellular, or molecular abnormality that are designed to correct or modify the underlying cause of disease. Key criteria include identifying the disease-causing abnormality, demonstrating that the therapy targets the root cause or proximate biological pathway, leveraging well-characterized natural history data from untreated patients, and confirming successful target engagement or gene editing. For traditional approval, treatments should also demonstrate improvement in clinical outcomes, disease course, or biomarkers if they are established to predict clinical benefit.

“President Trump promised to accelerate cures for American families—and we are delivering, especially for children with ultra-rare diseases who cannot afford to wait,” HHS Secretary Robert F. Kennedy, Jr, said in the news release. “We are cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most.”

Because genome editing technologies are designed to be highly specific to unique DNA sequences, the FDA noted that a product targeting different mutations in a single gene could potentially be included in a single product application and evaluated using master protocols that assess multiple product variations within a single trial. A well-supported “plausible” mechanism of action may then be used to support the addition of other genome-editing product variants intended to treat patients with mutations not included in the clinical trial supporting the original approval.

The agency acknowledged that adequate, well-controlled clinical investigations in this context will involve small sample sizes. As a result, study findings must be sufficiently robust to exclude chance results. When determining effectiveness, the FDA explained it will consider the specific disease, the strength of the evidence, and the challenges associated with conducting clinical investigations for individualized therapies.

“We anticipate our Plausible Mechanism draft guidance will inspire industry to place increased focus on individualized therapies, thereby driving innovation, improving safety, lowering costs, and offering more patients with ultra-rare diseases a unique shot at a life-saving treatment,” Tracy Beth Høeg, MD, PhD, acting director of the Center for Drug Evaluation and Research, said in the news release.

References

1. FDA launches framework for accelerating development of individualized therapies for ultra-rare diseases. News release. FDA. February 23, 2026. Accessed February 23, 2026. https://www.fda.gov/news-events/press-announcements/fda-launches-framework-accelerating-development-individualized-therapies-ultra-rare-diseases
2. Shaw ML. Is rare disease policy a stress test of US health care? AJMC^®. February 3, 2026. Accessed February 23, 2026. https://www.ajmc.com/view/is-rare-disease-policy-a-stress-test-of-us-health-care-