Rare disease advocates said chemistry, manufacturing and controls requirements in the FDA’s plausible mechanism framework guidance should not resemble standards for large-scale manufacturing.
Key Takeaways
- CMC requirements in the FDA plausible mechanism guidance could limit the diseases and patient populations that could access the framework, advocates said.
- The FDA should clarify how manufacturing expectations would scale from n-of-1 to small cohorts, FOCR said.
- The N=1 Collaborative said full validation requirements should be limited to the post-approval setting.
Advocates said chemistry, manufacturing and controls expectations in the US Food and Drug Administration’s plausible mechanism framework guidance are concerning because they may not fit the small development programs for many rare diseases.
The draft guidance released in February described considerations for generating substantial evidence of effectiveness and safety of individualized therapies based on a plausible mechanism framework, and the circumstances where the data may be adequate to support approval.
Along with CMC issues, rare disease and other groups also were concerned the recommendations would limit the therapies and patient populations that potentially could use the framework. (See sidebar.)
The guidance states CMC development should evolve concurrently with clinical development. The agency expects CMC development will occur rapidly, and multiple aspects of the commercial manufacturing process should be considered when developing the manufacturing process to support the initial investigational new drug application, the guidance states.
The manufacturing process to support a new drug application or biologics license application must be appropriately validated, the guidance states. Analytical methods used for release testing in an NDA or BLA must be validated, and a potency assay is required for biological product licensure. In addition, sponsors should develop a strategy for establishing a shelf life for the intended product early in development.
The Haystack Project said products developed under a plausible mechanism framework are unlikely to be manufactured at commercial scale or in traditional, centralized production settings. Rather, they may be produced in highly specialized, small-batch, or even patient-specific contexts.
“In this respect, CMC expectations should be proportionate and fit-for-purpose, reflecting the nature of the product and its method of production, rather than directly importing standards designed for large-scale commercial manufacturing,” Haystack’s comments state.
Friends of Cancer Research requested additional clarity on CMC expectations across the full product lifecycle, particularly the transition from IND to BLA/NDA stages.
The agency should allow rolling or staged CMC submissions to reduce sponsor burden and support compressed clinical timelines, FOCR said.
The FDA also should clarify how CMC expectations scale as drug development progresses from n-of-1 applications to small cohorts, including whether approaches acceptable for n-of-1 INDs remain sufficient for platform-based expansion or whether additional validation is required at defined thresholds, FOCR said.
The N=1 Collaborative said the FDA should affirm that qualified analytical methods, rather than fully validated methods, are acceptable to support marketing approval.
“Given the constraints of small-batch manufacturing, small populations and the urgency of patient need, FDA’s approach should generally limit requirements for full validation to post-approval requirements,” the collaborative’s comments state.
The agency also should affirm that product release specifications need not meet commercial-scale standards, and that scientifically justified acceptance criteria, more comparable to specification standards for products used in investigational studies, are appropriate.