FDA’s proposed plausible mechanism framework presents CMC challenges

Although the FDA is pursuing a flexible approach to chemistry, manufacturing, and controls requirements for cell and gene therapies, the agency’s efforts to remove CMC barriers are not being translated to individualized therapies for genetic conditions.

The FDA insists that regulatory flexibility must be tailored for cell and gene therapies with the intention of accommodating the unique characteristics of innovative therapies, while maintaining rigorous quality standards through appropriate control measures.

Towards that end, the agency in February 2026 published a draft guidance on a new plausible mechanism framework for the development and approval of individualized therapies that target specific genetic conditions with known biological causes, with the goal of accelerating gene and gene editing therapies for diseases affecting exceedingly small patient populations where a randomized trial would not be feasible.

The FDA’s plausible mechanism framework outlines a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data to demonstrate that a drug or biological product is safe and effective for the intended use — and that it can be manufactured to regulatory quality standards.

“These data are used to support approval or licensure of an individualized therapy for a specific indication,” states the agency’s draft guidance. “This includes a careful evaluation of the results of nonclinical and clinical data and chemistry, manufacturing, and controls (CMC) data necessary to support product quality.”

CMC and plausible mechanism framework

Given the shortened clinical investigation phase expected for individualized therapies, the FDA said in its draft guidance that CMC development should evolve concurrently with clinical development.

“Due to the limited number of subjects being treated in clinical trials to support approval, it is expected that CMC development will occur rapidly,” according to the FDA’s draft guidance. “The sequence, structures (e.g., various modifications, conjugations), stereochemistry, and other physicochemical characteristics critical to the performance of the product should be well-defined, confirmed, and controlled to ensure consistency, where applicable.”

As a result, the FDA said multiple aspects of the commercial manufacturing process should be considered when developing the manufacturing process to support the initial Investigational New Drug (IND), such as scale, validation, and commercial feasibility. 

Proof of concept for prime editing platform

In a March 31 article published in the American Journal of Human Genetics, authors from the Children’s Hospital of Philadelphia and Penn Medicine reported initial proof-of-concept studies supporting a customizable in vivo prime editing platform.

The article’s authors demonstrated that a two-part prime editing system — a lipid nanoparticle that delivers mRNA encoding the editor, plus a customized adeno-associated virus that supplies the short guide RNAs — could potentially function as a therapeutic by correcting mutations in the liver cells of infants with urea cycle disorders (UCDs).

While the article showed that the FDA’s plausible mechanism framework can help streamline non-clinical and clinical requirements for personalized gene therapies, its authors noted that CMC requirements in the framework remained challenging to meet and suggested further potential to streamline them to benefit patients with ultra-rare diseases.

Feedback from an FDA meeting

The article reported the outcome of requested feedback from the FDA via a pre-IND meeting to discuss the use of the personalized in vivo prime editing platform in an “umbrella-of-umbrellas” clinical trial, including subjects with UCDs.

“The FDA indicated that if data from subjects treated in the Phase 1/2 clinical study were to be used to support [Biologics License Applications], the CMC requirements would need to be much more stringent than would be typical for early-phase clinical trials,” the authors wrote. “Ideally, the manufacturing process and facility would be finalized before the Phase 1/2 study was initiated to avoid the need for subsequent comparability studies if the process or facility were to be changed midway through the study.”

At the same time, the article stated that it would not be necessary to manufacture identical drug product lots for process performance qualification (PPQ), but rather data from multiple individualized “variant” drug product lots could be used for PPQ if it could be demonstrated that the manufacturing process was consistent across the lots.

Nonetheless, the manufacturing facility for these Phase 1/2 PPQ lots would need to be fully current Good Manufacturing Practice (cGMP) compliant and inspection ready before producing the lots, according to the article.

“Ideally, all analytical methods used to support product quality and process control would be fully validated before the Phase 1/2 study was initiated,” the authors wrote. “Stability testing would need to be performed for all individualized drug product lots manufactured for the Phase 1/2 study, using validated assays.”

The authors concluded that based on language in the FDA’s draft guidance — which still must be finalized — and the agency’s feedback to their proposed prime editing platform for UCDs, an abbreviated pathway to regulatory approval — entailing only a single clinical trial — “appears to be dependent on a sponsor’s ability to apply the strict requirements ordinarily reserved for late-stage clinical trials to an early-stage clinical trial.”