Former officials propose changes to FDA’s plausible mechanism pathway

Two former US Food and Drug Administration (FDA) officials have commented on and proposed changes to the agency’s recent draft guidance on the development of a plausible mechanism framework for individualized therapies to treat rare diseases.

FDA released its draft guidance in February, which outlines a potential pathway for the agency to authorize the use of individualized drugs and biologics for specific genetic conditions that have known biological causes (RELATED: FDA proposes plausible mechanism pathway for ultra-rare disease therapies, Regulatory Focus 23 February 2026).

Writing in JAMA Health Forum, former FDA Commissioner Scott Gottlieb, and Maarika Kimbrell, the co-founder and former director of the Office of New Drug Policy for FDA’s Center for Drug Evaluation and Research (CDER), said the draft guidance builds on previous efforts by FDA to regulate treatments for rare, inherited conditions.

“The new policy acknowledges that biology is personal and that technology now allows medicine to be personal as well. The FDA aims to clear a path for patients (often children) with vexing genetic disorders that have long stood beyond the reach of conventional drug development,” Gottlieb and Kimbrell said. “The agency can build on this draft guidance as it reviews public comments and moves toward finalizing the policy later this year, turning a forward-looking framework into durable reforms that keep pace with advances in science.”

With the advent of new genomics and platform technologies that can shorten the development time of individualized genetic therapies, “regulatory timelines must keep pace with that opportunity, especially given the rapid progression of many genetic disorders,” they noted.

“The FDA faces a dual imperative: to provide a forward-looking regulatory framework that enables these innovations and to construct pathways that (without compromising the FDA’s evidentiary standards) can match the speed at which these therapies are now being conceived and constructed,” the authors said.

Expanding the draft guidance

Gottlieb and Kimbrell noted that the new pathway would give FDA the authority to approve a core genetic therapeutic platform that is tied to an anchor like a viral vector or oligonucleotide with the flexibility of allowing variance in the genetic therapy on a patient-to-patient basis.

“This framework addresses disorders in which distinct variations disrupt the same gene to produce a common phenotype. The policy recognizes that modern drugs can correct those errors for individual patients based on their unique genetic perturbations without regulators starting from scratch for each patient,” they said.

However, the agency should address whether these genetic variants would be bundled into a single approval or considered separate medicines. “Greater clarity, especially about limits on variables like sequence length, structural configuration, and other design features, would more clearly define the development pathway for these therapies,” Gottlieb and Kimbrell wrote. “By outlining those boundaries, regulators can show scientists where adaptation is permitted and where it begins to alter the identity of the product. Such definitions would help make the pathway more accessible.”

The draft guidance also is flexible in that FDA is considering allowing for extrapolation of efficacy and safety data across products with differing genetic variants. Gottlieb and Kimbrell noted FDA does this when assessing evidence across populations and formulations, but “the question becomes more critical here when clinical data may encompass a small group of patients—or even a single child.”

“The final guidance should specify evidentiary criteria for the shared molecular mechanism, comparable vector biology, or overlapping patient phenotype that a sponsor must satisfy to justify extrapolating safety and efficacy data from one variant to another,” they wrote.

Other considerations, such as chemistry, manufacturing, and controls, can be standardized regardless of variation of genetic payload, the authors said. However, it is unclear whether the same level of process validation, comparability data, and release testing will be required for a therapy in a single patient as compared to a therapy for more than one patient. Gottlieb and Kimbrell said there must be a balance between meeting safety, quality, and purity expectations while also giving manufacturers a “practical roadmap for manufacturing flexibility.”

“The efficiency of this framework depends on the FDA continuing to refine its requirements for platform approval by broadening the established scope of permissible personalization,” the authors said. “These steps will build on the agency’s recent efforts to enable more children to benefit from the molecular tools now within reach.”

JAMA Health Forum Gottlieb et al.