FDA Releases Draft Guidance on Plausible Mechanism Framework for Individualized Therapies in Ultra-Rare Diseases

On February 23, 2026, the FDA issued draft guidance titled 'Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause'.1 2 3

The framework accelerates approval of targeted therapies like genome editing and RNA-based treatments (e.g., antisense oligonucleotides) for ultra-rare diseases where randomized controlled trials are infeasible due to small patient populations.1 2 4

Key criteria include identifying the disease-causing abnormality, demonstrating therapy targets the root cause, using natural history data, confirming target engagement, and showing clinical improvements or predictive biomarkers.1 3 5

The guidance is open for public comments within 60 days via Regulations.gov and is expected to drive innovation in personalized medicine.1 6

FDA leaders, including Vinay Prasad and Tracy Beth Høeg, described it as a revolutionary and transformational advance.1 5