FDA Issues Draft “Plausible Mechanism” Guidance

On Monday, Feb. 23, the Food and Drug Administration (FDA) published a draft guidance titled “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known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.” FDA Commissioner Marty Makary first presented the concept of a “plausible mechanism” framework in a podcast appearance on April 17, 2025, and was later expanded in a Nov. 12, 2025, New England Journal of Medicine article that announced, “FDA’s New Plausible Mechanism Pathway.” The draft guidance provides new insight into FDA’s thinking about the framework, but additional questions about the scope of the framework remain.

Generally, the FDA intends the guidance to promote the development of so-called “N of 1” or bespoke therapies for severely debilitating or life-threatening diseases, interventions that modify a disease-causing genetic anomaly in a single patient. In addition, the FDA intends the guidance to provide a roadmap by which the evidence of clinical effectiveness and safety for such an intervention can serve as the evidence to approve interventions for the disease or diseases caused by the same or similar genetic anomalies for which randomized clinical trials are not possible because there are too few patients with the disease(s). For example, a gene-editing intervention may edit (or correct) a single gene within which different mutations cause different diseases, and evidence of effectiveness when correcting one mutation may serve as evidence of effectiveness for correcting the other mutations.

The FDA requests comments on the draft guidance by April 27, 2026.

A summary and our analysis of the draft guidance follow.

Draft Guidance Summary

The FDA states that the plausible mechanism framework involves:

• Identifying a specific genetic, cellular or molecular abnormality with a clear connection between specific alteration and disease indication;
• Developing a therapy that targets the underlying or proximate pathogenic biological alterations;
• Relying on a well-characterized natural history of the disease in an untreated population;
• Confirming that the target was successfully drugged or edited or both; and
• Demonstrating improvement in clinical outcomes or course.

Such therapies would typically be genome editing (GE) (and regulated by FDA’s Center for Biologics Evaluation and Research (CBER)) or RNA-based therapies (such as antisense oligonucleotides (ASOs) that are regulated by the FDA’s Center for Drug Evaluation and Research (CDER)), but the FDA notes that the concepts may apply to other types of individualized therapies.

The draft guidance discusses several topics that are part of any drug development program, including the regulatory pathway, nonclinical issues, clinical issues and chemistry, manufacturing and controls (CMC) issues.

With respect to the regulatory pathway, the FDA expects that a single adequate and well-controlled clinical investigation and confirmatory evidence (such as mechanistic or pharmacodynamic data or confirmed target engagement) can demonstrate substantial evidence of effectiveness (as required by law for drug approval). The agency notes that the study will include a small sample size and so the results of such study should be robust to exclude chance findings of effectiveness. Either traditional approval or accelerated approval is available, depending on whether the study endpoints measure clinical benefit or are reasonably likely to predict clinical benefit. The FDA notes that safety data from the clinical trial will be limited due to the small number of patients treated, and so the agency may require additional safety data to be collected post-approval, including as to durability of response, and that the agency will monitor adverse events.

In terms of nonclinical issues, the FDA observes that the objective of the nonclinical program is to demonstrate proof of concept and safety to support the first-in-human study. The agency cites several previously issued guidance documents that address nonclinical issues for GE products and for ASO products. It also provides recommendations for the approach to proof of concept studies and safety assessments for each type of product. For GE products, the FDA discusses how data may be leveraged across programs using different genome editors, for example, as well as what additional studies may be needed to support approval, including the targeting of mutations not studied in the clinical trial for approval. For ASO products, the FDA discusses additional nonclinical studies to address unexpected or significant toxicity as well as reproductive toxicity.

As for clinical issues, the FDA notes that it expects the first-in-human study to be the primary source of evidence for approval, and so the study should be adequate and well-controlled. The trial design should be justified, including why it is not feasible to conduct a randomized controlled trial. The agency also encourages careful consideration of clinical outcomes and biomarkers and collection of data on those measures as early as possible (e.g., before the clinical trial begins) to, for example, establish patient lead-in baseline and characterize disease trajectory. The FDA also discusses ethical and human subject considerations; clinical trial design; establishing genetic mutation or diagnosis; dosing; trail outcomes, including clinical outcomes, biomarker assessments, and safety outcomes; and post-marketing considerations.

With respect to CMC issues, the FDA emphasizes that CMC development will occur rapidly and that prior manufacturing knowledge and development experience should be leveraged to meet CMC requirements. The FDA recommends early engagement with the agency on these issues.

Context and Analysis

The draft guidance comes 10 months after Makary first spoke about the concept of a “new pathway for drugs … based on a plausible mechanism” in April 2025 on the “Megyn Kelly Show.” At the time, Makary presented “plausible mechanism” as a new approval pathway whereby treatments for rare diseases would be approved “on sort of a conditional basis” in cases where a randomized controlled trial is not feasible. Months later, in November 2025, Makary and CBER Director Vinay Prasad published a short article in The New England Journal of Medicine. The article further previewed what the authors envisioned for bespoke therapies that could be approved after demonstrating success in several consecutive patients, and how “platform data” could be leveraged to approve additional therapies, a concept they said was developed after meetings with internal and external stakeholders.

In its current form, the draft guidance represents a further evolution of the concept under discussion, confirming that the plausible mechanism framework would not include a new formal regulatory approval pathway, and instead would adhere to the statutorily recognized traditional approval and accelerated approval pathways. Further, drugs approved under the framework would not receive “conditional approval,” as it is commonly understood, but expedited withdrawal procedures may be used if a drug is approved under accelerated approval and a confirmatory trial does not demonstrate clinical benefit (or the trial is not conducted with due diligence).

The draft guidance helpfully explains how data generated from individualized therapies may support approval for that therapy. It also summarizes and links to information from many other FDA guidance documents, including those on rare diseases and on cell and gene therapies and ASO products, which may be helpful for developers planning a regulatory strategy.

However, those interested in investing in and developing these therapies may need more clarity on how the assessment of an intervention in one trial (including a trial with a single participant) can be leveraged for approval of the intervention to treat diseases different from the disease studied in the trial. Future guidance may provide additional detail on the types of considerations that will determine such a decision and the kinds of data and information that may be needed.

For example, developers may have additional questions about how and when a clinical study that shows substantial evidence of effectiveness when dosed in one disease (based, for example, on clinical outcomes and natural history for that disease) can be justified to provide substantial evidence of effectiveness in diseases with different clinical outcomes or potentially different required dose (for example, when the disease manifests through the genetic anomaly in a different tissue or organ).

Further clarity on the factors to be considered when deciding when a randomized controlled trial is not feasible may also be helpful for developers. Presumably, the number of patents with the disease is a necessary limiting factor, yet CDER Center Director Tracy Beth Høeg has suggested the pathway could apply to “common diseases.”

Next Steps

Stakeholders interested in commenting on the draft guidance may do so until April 27, 2026. Brownstein is available to assist clients in submitting comments and will continue to follow developments on rare disease policy at the FDA.

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