FDA Publishes Long-Awaited Draft Guidance on “Plausible Mechanism Framework” to Spur the Development of New Individualized Medicines

At a Glance

• The guidance is informative for therapies targeting severely debilitating or life-threatening conditions that are well-characterized and linked to a specific gene or genes.
• The guidance focuses on genome editing and RNA-based therapies such as antisense oligonucleotides. The concepts also apply to other types of individualized therapies and should facilitate the development of “platform” technologies.
• The plausible mechanism framework provides an alternative to randomized controlled trials in rare populations, with reliance on well-characterized natural history to facilitate externally controlled trials — a critical aspect of flexibility for rare and ultra-rare trials.
• The draft guidance also promotes the importance of data-sharing so that researchers and companies benefit from each other’s evidence generation. This will be a critical area for stakeholder advocacy and input, since the degree and speed of data-sharing that will be required is not common and will likely require significant investments of time and money from developers, providers, and other parties in the rare disease treatment ecosystem.
• Of particular importance in the comment process will be input from those who have developed, or who are actively developing, individualized treatments consistent with the guidance’s focus and who want their experiences to inform any final guidance.

Following months of anticipation after Food and Drug Administration (FDA) leadership in late 2025 outlined in the New England Journal of Medicine (NEJM) a novel regulatory pathway for individualized therapies to treat rare conditions, the agency on February 23, 2026, marked Rare Disease Week by issuing a draft guidance document to further flesh out the new framework.

Dubbed the “Plausible Mechanism Framework,” the draft guidance, Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies That Target Specific Genetic Conditions with Known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 aims to provide crucial information for therapy developers, clinicians, and other stakeholders, including patient organizations, who greeted the November article positively but who were eager to see the agency lay out more specific details.

The draft guidance was launched at an event featuring leaders of the Department of Health and Human Services (HHS) and FDA, as well as members of Congress. The new draft guidance was also accompanied by a piece by Commissioner Makary in the Wall Street Journal titled “FDA: How We’re Approving More Drugs to Treat Rare Diseases.” Commissioner Makary described the new framework as one to “facilitate the development of bespoke therapies that target a specific problem, such as a genetic abnormality, that causes severely debilitating or life-threatening diseases,” where “no randomized trial will be required because it’s simply infeasible.”

Summary of Key Provisions in the Draft Guidance

Consistent with the NEJM article, FDA notes in the draft that the guidance is intended for individualized therapies targeting severely debilitating or life-threatening conditions that are well-characterized and linked to a specific gene or genes. The guidance is focused on conditions or genotypes impacting a small number of patients where randomized controlled trials are not feasible. This could include truly individualized single-patient or “n of 1” product candidates, as well as those beyond a single patient, and rare genotypes within more common conditions. While the guidance focuses on genome editing and RNA-based therapies such as antisense oligonucleotides, the concepts apply to other types of targeted therapies.

The guidance provides a framework under which therapy developers could produce evidence from a limited number of patients to justify safety and efficacy aims. FDA anticipates developers will often rely on data from a single externally controlled investigation paired with a plan to obtain confirmatory evidence post-approval. Externally controlled trials mean that randomized clinical trials are not necessary, which is a critical aspect of flexibility for rare and ultra-rare trials. The guidance maintains standard FDA requirements for substantial evidence of effectiveness, while providing suggestions for evidence generation in very small trials. Use of confirmatory evidence is encouraged. Relevant review divisions would need to offer specific guidance on topics such as patient populations, endpoints, regulatory pathways, and other elements.

The document offers specific guidance on design of clinical trials, genetic confirmation, establishing of dosing levels, identification of outcomes including surrogate biomarkers, and manufacturing expectations. The guidance facilitates “platform trials” through support of master protocols that can be used to, for example, target different mutations within the same gene under one clinical trial protocol. Once the initial mutation is approved, more mutations could be added under the same therapy mechanism, helping reduce time and costs.

The draft guidance notes that developers could pursue either traditional approval, or if using surrogate endpoints, accelerated approval. It encourages developers to use New Approach Methodologies (NAMs), consistent with larger departmental and agency interests, and it promotes the importance of data sharing so that researchers and companies benefit from each other’s evidence generation. This will be a critical area for stakeholder advocacy and input, since the degree and speed of data sharing that will be required is not common and will likely require significant investments of time and money from developers, providers, and other parties in the rare disease treatment ecosystem.

Next Steps

This draft guidance represents an important first step toward providing a more predictable regulatory framework for individualized therapies, which in many cases are not well-suited to FDA’s current paradigms. However, the draft guidance is broad, and itself contains multiple references to other draft or final guidance documents on many important issues. The ultimate impact of the framework will depend not only on whatever form the guidance takes once finalized, but also how FDA operationalizes the guidance and applies the criteria in practice — especially the design of clinical trials and how sponsors will meet FDA’s expectations regarding external controls via natural history data, biomarker validation, and confirmatory evidence, among other factors. Additionally, the draft guidance does not go into much detail on the nonclinical and the chemistry manufacturing and controls (CMC) flexibilities that FDA may exercise for therapies under this framework, where Good Manufacturing Practices and other requirements are often a significant obstacle to scaling up the development and manufacturing of therapies for very small populations. Of particular importance in the comment process will be:

• input from those who have developed, or who are actively developing, individualized treatments consistent with the guidance’s focus and who want their experiences to inform any final guidance; and
• input on ways to facilitate and incentivize rapid knowledge sharing so that researchers and companies benefit from each other’s evidence generation.

Now that FDA has published a formal policy document with details of the new framework, stakeholders will have the opportunity to engage with the agency, including through comments. FDA has requested comments no later than 60 days after publication of the notice for the guidance in the Federal Register, so the anticipated deadline for comments will be April 26, 2026. Given the prime attention to this topic from senior HHS and FDA leadership — it is rare for a draft guidance document to be announced at a formal launch event featuring the HHS secretary, FDA commissioner, members of Congress, and many rare disease stakeholders — there is a strong potential for FDA to finalize this guidance faster than with other draft guidance documents.

Beyond the near-term focus on commenting and other means of engagement to shape the development of this new framework, the guidance and its core topics will likely be a topic of interest on Capitol Hill, particularly as committees of jurisdiction ramp up activities ahead of the September 2027 user-fee program reauthorization deadlines. For example, Senator Bill Cassidy, chair of the Senate Health, Education, Labor, and Pensions (HELP) Committee recently released a white paper titled Patients and Families First: Building the FDA of the Future. This white paper noted that FDA’s current approval framework is “ill-suited for personalized medicines,” and raised that Congress could do more to support FDA’s modernization efforts in this area. Most immediately, on Thursday, February 26, 2026, the Senate Aging Committee will be hosting a hearing titled From Regulator to Roadblock: How FDA Bureaucracy Stifles Innovation, featuring several rare disease stakeholders, where this topic is likely to come up.