FDA Issues Draft Guidance on Using the “Plausible Mechanism” Framework to Develop Individualized Therapies for Rare Genetic Diseases
On February 23, 2026, the U.S. Food and Drug Administration (FDA) released its Draft Guidance for Industry, “Considerations for the Use of Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” (Guidance). This Guidance describes FDA’s current thinking on how developers can generate substantial evidence of effectiveness and adequate safety data for highly targeted, “individualized therapies” based on a plausible mechanism framework, an approach that uses a well-characterized, scientifically sound basis for how a therapy is expected to work against a clearly defined molecular or cellular abnormality that causes disease.
The Guidance is intended for treatments that address specific pathophysiologic abnormalities such as particular pathogenic genetic variants — that cause severely debilitating or life-threatening conditions in a very small patient population, where traditional randomized controlled trials are often not feasible. Examples include gene editing (GE) products or RNA-targeted modalities such as anti-sense oligonucleotides (ASOs). These therapies must aim at the underlying abnormality, its proximal pathogenic pathway, or a well-defined downstream mechanistic pathway that has been shown to affect the course of disease.
Among its key points, the Guidance:
- Expands upon FDA’s current thinking on drug development and trial design for individualized therapies aimed at rare genetic disorders.
- Outlines recommendations to help sponsors collect and analyze clinical safety and efficacy data when few patients exist for enrollment.
- Discusses conditions under which a first-in-human study could be designed as a pivotal trial to support approval.
- Addresses manufacturing considerations, ensuring products meet regulatory quality standards even when produced for extremely small patient groups.
The draft provides possible approval pathways for individualized genetic and RNA-based interventions where a strong mechanistic rationale exists thereby opening doors for faster development of life-saving therapies for patients with no other treatment options.
This initiative is another significant milestone in the advancement of personalized medicine. By providing a structured path to evaluate novel, highly targeted therapies rooted in molecular understanding, FDA is reinforcing its commitment to advancing precision medicine and mechanistic research. The Plausible Mechanism Framework acknowledges that for ultra-rare genetic diseases, the science of “why a treatment should work” can be a critical driver for regulatory decision-making helping to bring promising, life-changing treatments to patients more efficiently while maintaining rigorous standards for safety and efficacy.
Public Comment Period
The FDA is inviting written comments on this draft Guidance. Submissions should be sent to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should clearly identify the docket number provided in the Federal Register notice of availability.
