FDA Leadership Outlines "Plausible Mechanism" Pathway For Bespoke Therapies

Key Takeaways:

• The US Food and Drug Administration (FDA) is proposing a new "plausible mechanism" pathway that will enable the limited approval of bespoke therapies when randomized trials are impractical.
• FDA will consider mechanistic alignment and demonstrable, clinically meaningful outcomes when authorizing products based on plausible mechanism.
• Success across multiple patients can support marketing authorization of a platform, enabling subsequent individualized products targeting different mutations to leverage cumulative data, with post-marketing commitments and real-world evidence integral to ongoing evaluation.
• Although the example given was gene therapy, the FDA saw no reason that the principles of the pathway could not extend to other types of drugs.

FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research (CBER) Director Vinay Prasad recently authored an article in the New England Journal of Medicine that articulated a new regulatory approach—the "plausible mechanism" pathway—to enable individualized, bespoke therapies to reach patients where traditional randomized trials were not feasible. This is the second time that the Commissioner has used a journal publication to announce new agency policy over traditional means, such as FDA press releases and Federal Register notices.

In the article, Drs. Makary and Prasad discuss the details of a recent case involving DNA base editing to address a mutation in a newborn. In that case, FDA processed an expanded‑access IND within one week and the newborn received experimental medication to address the mutation. Makary and Prasad used the experience to clarify the factors that FDA would consider when authorizing personalized products.

Core Elements of the Plausible Mechanism Pathway

At its foundation, the plausible mechanism pathway is designed for conditions with a well‑defined, proximate biological alteration and for products that directly address that alteration. Even though Makary and Prasad use the example of treating a newborn with a rare genetic condition, the pathway will not be limited to rare pediatric genetic disorders. FDA will prioritize rare, severe, and early‑onset conditions with a focus on fatal or disabling diseases; however, the pathway will be available for common diseases that do not have proven alternative treatments. The authors anticipate that the program will mostly apply to cell and gene therapies and other CBER-regulated biologics, but that the principles of the plausible mechanism pathway are expected to extend, over time, to small molecules and antibodies that can be individualized to specific molecular alterations.

Factors the FDA Will Consider When Permitting Bespoke Therapies

The Commissioner highlighted considerations that sponsors should be prepared to address when applying for authorization through the plausible mechanism pathway. These factors include:

• Defined, causal abnormality. The biological cause for the disease being treated must be known "(e.g., genetic conditions with a clear connection between specific alteration and disease presentation)." The pathway would not be available for "diseases defined by a constellation of clinical findings or dozens of unclear genomewide associations . . . ."
• Therapy targeting the proximate causal abnormality. The product must act directly on the inciting pathophysiologic alteration (e.g., gene editing of a pathogenic variant), rather than exerting effects distant from the alteration.
• Well-characterized natural history. Such is employed to justify use and timing of the intervention. Historical trajectories can serve as benchmarks when designing a plausible mechanism pathway submission.
• Evidence of on‑target engagement. The sponsor must be able to demonstrate that the target has been successfully modified, edited, or treated. This can be achieved through animal models, non-animal systems, or clinical biopsy. FDA will consider feasibility constraints (e.g., retinal tissues) and may accept evidence from a subset of patients or even first‑in‑class dosing, provided the totality of data coheres.
• Clinically meaningful improvement. FDA will look for durable, congruent clinical benefits consistent with disease biology. In progressive diseases, sustained improvement is favorable, while in relapsing conditions, prolonged remission periods matter. Data should be sufficient to exclude regression to the mean, with patients sometimes serving as their own controls.
• Risk–benefit in disease context. Safety will be weighed against underlying disease severity, therapeutic efficacy, and toxicity mitigation capabilities. Sponsors should provide scientific strategies to reduce off‑target effects and FDA may require verification in trials or postmarketing studies. Allowable risk will vary by indication and the strength of efficacy evidence.
• Feasibility‑aligned evidence generation. The Agency will accommodate practical constraints around certain assessments (e.g., neural off‑target evaluation) and encourage alternative, tractable systems (e.g., hematopoietic monitoring) where appropriate. Non-animal models may be favored when animal studies are not informative.
• Platform generalizability. Success across several consecutive patients with individualized products targeting different mutations can enable marketing authorization for the platform, with subsequent approvals for analogous products supported by cumulative data. Depending on evidence strength, accelerated or traditional approval may be used.
• Postmarketing commitments and real‑world evidence. Sponsors should expect obligations to confirm ongoing efficacy, monitor off‑target effects within agreed risk–benefit parameters, and study outcomes such as growth and developmental milestones. FDA may adjust concomitant medication expectations, limit indications, or refine warnings as signals emerge.
• Unmet need and lack of alternatives. Beyond rare pediatric disorders, common diseases without proven treatments or conditions with substantial unmet need after available therapy will remain in scope where mechanistic plausibility and observed clinical effects align.

Practical Implications for Sponsors and Developers

The plausible mechanism pathway invites a disciplined yet efficient development strategy for bespoke therapies. Early development of mechanism evidence and engagement with FDA to define the mechanistic rationale, natural history comparators, and feasible on‑target and clinical endpoints will be essential. Sponsors developing products that potentially meet the above criteria should structure manufacturing and quality systems to support rapid, individualized production while maintaining consistency across a platform. Finally, anticipating post-marketing real‑world data capture—and designing product families that leverage shared platform learnings—can accelerate broader access across mutations and indications.

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