On Monday, the FDA released more details about the Plausible Mechanism Framework, first announced by FDA Commissioner Makary and Director Prasad in the New England Journal of Medicine in November 2025.
In an event at the Health and Human Services (HHS) headquarters yesterday, FDA leadership reaffirmed their commitment to accelerating innovation for individualized therapies and their belief that the Draft Guidance – “Considerations for the use of the Plausible Mechanism Pathway to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause” — will drive new interest and opportunities for the communities that qualify. HHS and FDA leaders were also joined by rare disease parents and advocates, whose expertise and experiences in driving ‘N of 1’ therapy development programs in efforts to save the lives of their own children, sparked the momentum behind today’s progress.
Representing some of those present, Judy Stecker shared, “Today’s announcement recognizes the unique nature and enormous opportunity of individualized therapies to address the health crisis of severe and life-limiting genetic diseases, and that an innovative process can in and of itself be a product.” Researchers from the teams that successfully developed the world’s first individualized therapies for Mila Makovec (Milasen ASO approved in 2018) and ‘Baby KJ’ (CRISPR gene editing in 2024) were also in attendance.
What is the Plausible Mechanism Framework?
The Plausible Mechanism Framework is a set of recommendations to help those developing individualized therapies generate sufficient evidence that they are safe and effective, and that they can be manufactured appropriately. The framework is inspired by the success of recent individualized therapies, such as the one developed for Baby KJ, an infant with a urea cycle disorder that impacts 1 in a million births.
The framework is NOT a new regulatory pathway that is typically established by an act of Congress, but it IS an updated approach to how individualized therapies could be approved through the existing pathways. Rare disease therapy development requires predictability and consistency in the FDA’s approach to product evaluation, and for those conditions that meet the criteria described in the framework, today’s release marks an important step forward. Whenever the FDA provides additional insights into its approach to the complexities inherent in rare disease therapy development, strategies can be refined, uncertainty is reduced, and potential delays in getting a therapy to a patient in need are avoided.
Who does the Plausible Mechanism Framework apply to?
The framework requires five key criteria to be met:
- A known genetic, cellular, or molecular cause of the disease;
- The therapy targets the specific cause of the disease;
- A well-characterized natural history of the disease when it is not treated;
- Confirmation that the genetic or other target was successfully modified; and
- Evidence of meaningful clinical improvement.
Initially, the FDA applied the framework to genome editing and RNA-based therapies, such as antisense oligonucleotides, but it indicated that it could apply to other types of individualized therapies. The framework does not specify a cutoff for the number of patients a therapy is intended to treat, but they have indicated that it is primarily designed to support situations with small numbers of patients where randomized controlled trials are typically not feasible. The framework could apply to therapies intended for evaluation through the traditional or accelerated approval pathways. The pathway used will, in part, determine if and what confirmatory evidence is required.
What’s Next?
We are encouraged by the release of the draft Guidance, and what it represents for the eligible communities for whom traditional approaches to clinical trials and regulatory requirements are fundamentally at odds with the reality of their conditions. We are grateful to the FDA for taking on this challenge of ensuring no disease is too rare to deserve treatment. And we are incredible grateful to the many families and experts who applied their personal expertise to yield transformational change.
But we also recognize that for many in our rare disease community, the Plausible Mechanism Framework will not apply, and we urge FDA leadership to continue pursuing solutions that will ensure the tools and policies that Congress has created over decades, are deployed in a predictable and consistent manner that can unleash scientific innovation and speed safe and effective therapies to patients across the more than 10,000 rare diseases.
The EveryLife Foundation team will closely review the draft Guidance, alongside the Community Congress Regulatory Working Group in the coming weeks and together, we will continue to press for policy solutions that acknowledge the differences in how rare disease products must be developed and evaluated. Today’s release of the Plausible Mechanism Framework Draft Guidance was a meaningful step in that direction.
