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# ‘Plausible Mechanism’ Drug Pathway Raises Process Concerns
- URL: https://www.fdaweb.com/plausible-mechanism-drug-pathway-raises-process-concerns/
- Published: 2026-01-26T12:00:00.000Z
- Updated: 2026-09-14T15:31:34.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5160541

A newly announced FDA pathway allowing drug approvals based on a “plausible mechanism of action” could accelerate the development of highly individualized treatments for rare genetic diseases, but health policy experts are warning that the approach raises unresolved legal, scientific, and transparency concerns. The pathway for approving certain bespoke, personalized therapies was described by FDA commissioner **Marty Makary** and CBER director **Vinay Prasad** in a recent *New England Journal of Medicine* [article](https://www.nejm.org/doi/full/10.1056/NEJMsb2512695?ref=fdaweb.com). 

In a new *Health Affairs Forefront* [analysis](https://www.healthaffairs.org/content/forefront/promise-and-perils-fda-s-new-plausible-mechanism-pathway-part-1?ref=fdaweb.com), a group of legal, medical, and bioethics scholars said the pathway has the potential to remove a major regulatory barrier to personalized gene and RNA-based therapies. At the same time, the authors cautioned that the agency announced the policy without public input and has yet to define clear boundaries for its use.

The policy discussion follows the widely publicized case of “Baby KJ,” an infant born with a rare and typically fatal urea cycle disorder who, in early 2025, became the first patient to receive a personalized gene-editing therapy designed specifically for his unique genetic mutation. The child’s recovery has been cited by FDA leadership as an example of the promise of individualized therapeutics.

Makary and Prasad described the pathway as a route to marketing authorization when traditional randomized clinical trials are not feasible, particularly for ultra-rare genetic conditions. Under the approach, FDA could grant approval based on strong biological understanding of a disease, evidence that a therapy successfully targets the underlying mechanism, and consistent clinical improvement across a small number of patients — even if large controlled trials are impossible.

The *Health Affairs* authors said the pathway represents a significant departure from FDA’s traditional evidentiary framework, especially because Makary and Prasad indicated it could apply not only to rare diseases and gene therapies, but also to more common conditions.

The authors argue that FDA’s rollout of the policy departed from standard administrative practice. Major regulatory changes, they note, are typically developed through draft guidance and public comment—a process that allows patients, clinicians, manufacturers, and insurers to weigh in.

They also warn that the lack of explicit eligibility criteria could allow the pathway to be applied too broadly, potentially lowering evidentiary standards beyond rare, well-understood genetic diseases.

Before FDA implements the pathway, the authors recommend that the agency issue draft guidance, clarify how much evidence will be required, and narrowly define when approvals based on “plausible mechanism” are appropriate.

The authors said they will address those unresolved questions — including legal risks and potential impacts on drug safety and effectiveness — in a second installment of their analysis.