FDA Outlines "Plausible Mechanism" Approval Pathway For Personalized Therapies, But Significant Questions Remain

FDA Commissioner Martin Makary and Center for Biologics Evaluation and Research Director Vinay Prasad recently published an article in the New England Journal of Medicine ("NEJM") outlining the guiding principles of a new regulatory approach—the "plausible mechanism" pathway ("PM pathway")—under which certain bespoke, personalized therapies may be able to obtain FDA marketing authorization.¹ Since Commissioner Makary first hinted at the "plausible mechanism" pathway concept during a media appearance in April 2025, the biopharmaceutical industry, especially companies focused on the development of cell and gene therapy products and other products intended to treat rare diseases, has been anxiously awaiting details from FDA. This Alert summarizes the key aspects of the proposed PM pathway and the significant open questions that remain regarding its implementation.

Background of the PM Pathway

FDA is proposing the PM pathway largely in response to concerns from patient advocates and industry stakeholders that FDA's existing product approval pathways lack sufficient flexibility for individualized therapies, where randomized trials are often not feasible or practical. As described in the NEJM article, the PM pathway is intended to be a phased operational model that begins with treating consecutive patients with bespoke therapies. Makary and Prasad use the story of "Baby K.J."—a newborn with a rare genetic disorder treated with a personalized gene editing therapy that FDA reviewed and authorized via a single-patient expanded-access investigational new drug ("IND") application—to illustrate the PM pathway and the criteria FDA will consider when authorizing personalized products under it.

Key Elements of the Proposed PM Pathway

Using Baby K.J.'s story as a case study, Makary and Prasad highlight five key characteristics that will define eligibility for the FDA's PM pathway:

1. Identification of a specific molecular or cellular abnormality. FDA intends to limit the PM pathway to conditions with a known and clear molecular or cellular abnormality with a direct causal link between the specific alteration and the disease presentation, as opposed to diseases defined by a range of diagnostic criteria or genome-wide associations.
2. Targeting the underlying biological alteration. Eligible interventions will target the underlying or proximate biological alteration by acting on the molecular or cellular abnormality itself, rather than acting broadly on the affected system or on downstream components.
3. Use of natural history data. There is well-characterized natural history data for the disease in the untreated population.
4. Evidence of successful target engagement or editing. There is confirmatory evidence showing that the product has successfully drugged or edited the target. This evidence may come from animal models, nonanimal models, or clinical biopsies, and, in certain cases, FDA may accept evidence of successful target editing for a subset of patients or even from the first-in-class subject dosed.
5. Demonstration of clinical improvement. There is evidence of durable improvements in clinical outcomes that is consistent with disease biology, such as prolonged periods of disease remission in relapsing conditions or consistent improvement in progressive disorders.

Obtaining FDA Approval. Makary and Prasad state that after a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, FDA will "move towards" granting marketing authorization for the product, which will allow sponsors to leverage the clinical efficacy and safety data of the platform to support marketing approval for similar personalized products in other conditions. Marketing authorization can be pursued through accelerated or traditional approval pathways, depending on the strength of the evidence in the product application.

Collecting Post-Marketing Data. The sponsor of any product approved via the PM pathway will be required to collect real-world postmarketing evidence to demonstrate durability of effect, check for off-target edits, monitor for safety signals, and study the effect of early treatment on childhood growth and development. The manner in which sponsors are expected to collect this evidence will vary based on feasibility and the product's risk-benefit profile. FDA may choose to alter product labeling, indications, or concomitant medication requirements as the safety and effectiveness data mature.

Other Applicability Considerations. Makary and Prasad state that the PM pathway will prioritize rare diseases, with a particular focus on diseases that are fatal or associated with severe disability in children. However, they also state that the PM pathway will be available for "common diseases, particularly diseases for which there are no proven alternative treatments or in which there is considerable unmet need after use of available therapy." Additionally, while the NEJM article generally describes the PM pathway through the lens of gene and cellular therapies, FDA also anticipates broader applicability to other product types, including small molecule drugs and antibodies: "[W]e see no reason that such principles will not also extend to other drugs over time."

Key Open Questions for Industry

The PM pathway represents the latest FDA initiative intended to reduce regulatory burdens by instituting greater regulatory flexibility related to the development of therapies for rare diseases. It follows the announcement of the Rare Disease Evidence Principles ("RDEP") process and the issuance of three rare-disease-focused draft guidances in September 2025. Through the RDEP process, FDA is offering clearer guidance on the types of evidence that developers of drugs for certain rare diseases can use to demonstrate substantial evidence of effectiveness by outlining specific criteria under which the agency will generally accept a single-arm trial and confirmatory evidence to meet regulatory approval standards. Similarly, a trio of recent draft guidances describe how FDA intends to utilize greater regulatory flexibility with respect to the development and post-approval studies of cell and gene therapies, particularly those intended to treat rare diseases, as explained in a recent Ropes & Gray Alert. In each case, and as appears to be the case with the PM pathway, FDA is attempting to spur innovation of novel rare disease therapies.

Nevertheless, the NEJM article is not a formal guidance document or statement of agency policy. Because the NEJM article is barely more than two pages long, significant questions remain regarding how FDA might operationalize and implement the proposed PM pathway, including:

• Alignment with Existing Statutory and Regulatory Standards. The NEJM article does not indicate whether FDA intends to implement the PM pathway using its existing statutory and regulatory authority or whether FDA believes statutory or regulatory changes would be necessary or otherwise useful to support the PM pathway. For example:
  • Under the Federal Food, Drug, and Cosmetic Act, "substantial evidence" of effectiveness—meaning at least one adequate, well-controlled clinical investigation plus confirmatory evidence—is required for FDA to approve a new drug.² The NEJM article does not address how FDA's approval of personalized therapies via the PM pathway would align with the substantial evidence requirement.
  • Similarly, although Makary and Prasad suggest that therapies approved via the PM pathway would be eligible for either full or accelerated approval depending on the strength of the evidence, they do not specifically address in the NEJM article how products developed via the PM pathway would fall within the FDA's existing standards for traditional and accelerated approvals.
• Submission Expectations for the Treatment of Initial Patients. The NEJM article does not describe the mechanism for submitting new, bespoke therapies to FDA. Makary and Prasad indicate that a product may be considered for approval under the PM pathway after successful treatment of several consecutive patients, but they do not explain how a manufacturer should obtain authorization to treat these early patients. It is unclear, for example, whether initial submissions under the PM pathway should be expanded-access INDs (like the Baby K.J. example) or if FDA will expect a different type of IND submission.
• Chemistry, Manufacturing, and Control ("CMC") Requirements. Traditionally, FDA has held cell and gene therapies to high CMC standards, requiring, for example, sponsors to furnish FDA with sufficient CMC information to assure product safety, identity, quality, purity, and strength before the agency would grant marketing authorization. However, the NEJM article does not address the CMC expectations for therapies following the PM pathway—whether for initial IND submissions or for marketing applications.

Makary and Prasad have promised that FDA will publish more information about the PM pathway in the coming weeks, which will hopefully provide further guidance for developers interested in taking advantage of the PM pathway.³

Footnotes

1. Vinay Prasad, M.D., M.P.H., and Martin A. Makary, M.D., M.P.H., FDA's New Plausible Mechanism Pathway, The New England Journal of Medicine (Nov. 12, 2025), https://www.nejm.org/doi/full/10.1056/NEJMsb2512695.

2. 21 U.S.C. § 355(d).

3. FDA Direct: Catching Up on Agency Reforms, FDA.gov (Nov. 13, 2025), https://www.fda.gov/news-events/fda-direct-podcast/fda-direct-catching-agency-reforms.

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