On February 23, 2026, FDA issued a Draft Guidance document, called “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” (Docket ID: FDA-2026-D-1256). The Plausible Mechanism Pathway outlines a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data to demonstrate that a drug or biological product is safe and effective for the intended use, and that the product can be manufactured to regulatory quality standards. The FDA has requested public comments on the Draft Guidance Document until April 27, 2026.
The intent of the Draft Guidance is to provide a new pathway to support and facilitate the development of individualized therapies, shortening regulatory review times and bringing safe and effective therapies to market faster. This Draft Guidance is forward-thinking in its specificity for rare diseases with bleak prognoses and severe unmet medical need, that also have well-understood natural histories (e.g., via patient registries) and for which randomized clinical trials are infeasible and/or unethical. The pathway specifies various eligibility criteria, including the requirement that diseases be targetable via personalized therapies, with particular emphasis on genome editing (GE) and RNA-based therapies.
As currently written, there is a provision within the Draft Guidance Document that could prevent this new pathway from being usable for many different treatment modalities* outside of GE or RNA therapies. The Draft Guidance says that “While this guidance specifically discusses genome editing (GE) and RNA-based therapies… the general concepts may apply to other types of individualized therapies” (lines 40-42). This language would be strengthened by simply removing the word “may” in line 41, so that all types of promising individualized therapies meeting the pathway requirements can potentially reach patients sooner.
To access and review this FDA Draft Guidance document, please follow this link. If this topic and potential innovation is important to your disease community, or to you personally, please consider making a public comment by the April 27, 2026 deadline in support of this Guidance. Comments can be submitted as electronic attachments (e.g., a typewritten letter, in Word or PDF documents), or, entered as free-form text within the comment portal. For additional tips on submitting comments, please visit the FDA website, or be sure to click on the “Commenter’s Checklist” within the comment portal. To see other comments already submitted on this topic, please click here.
* Examples of therapies not directly covered by this guidance include: cellular vaccines being developed for oncology, immunotherapies or indirect mechanism treatments such as immune modulating monoclonal antibodies, metabolic modulators for diabetes, neurotransmitter-acting drugs for depression, polygenic/multifactorial disease therapies (Type 2 diabetes, many autoimmune diseases), etc.
