Advances in individualized therapies targeting specific genetic conditions offer the promise of new treatments for rare diseases, but with so few patients, it can be extremely difficult to generate nonclinical data and near impossible to test these treatments in a standard clinical trial.
The Food and Drug Administration (FDA) has proposed guidance for using a “Plausible Mechanism Framework” as an alternative means for proving safety and efficacy of individualized and disease-targeted therapies when a large randomized controlled trial is not feasible. The Biotechnology Innovation Organization (BIO) praises FDA’s proposed guidance in written comments, while also urging improvements to make it more practical and effective.
“BIO and its members support the Agency’s intent and view this framework as an important progression in regulatory science,” says E’Lissa Flores, BIO Director, Science & Regulatory Affairs, who wrote BIO’s April 27 comment letter to the FDA. “We also believe several areas would benefit from additional clarity and operational detail to support consistent and predictable implementation.”
BIO’s recommendations for the Plausible Mechanism Framework proposal include:
- Broadening the scope to other cases: “We encourage the FDA to clarify that the framework’s applicability extends beyond individualized products and is principle‑based and modality‑agnostic, making it suitable for other therapeutic modalities and disease contexts with serious life-threatening conditions,” when appropriate, according to BIO’s comment letter.
- Providing definitions and references to existing FDA guidances: “Several key guidance concepts outlined in the framework would benefit from clearer definition or reference to existing FDA guidance,” BIO’s comments say.
- Expand flexibilities for Chemistry, Manufacturing, and Controls (CMC) expectations: “BIO members recommend that the draft guidance address feasible CMC expectations with respect to the individualized nature of these therapies and expand flexibilities when appropriate,” the comments say, “especially as current requirements for early CMC maturity are not yet as feasible for individualized therapies.”
- Using prior knowledge and leveraging Platform Technology: “The guidance would be strengthened by additional inclusion of recommendations for platform technologies and the systematic use of prior knowledge across the product lifecycle,” the comments explain.
- Fit-for-purpose post-approval safety and long-term follow-up for small population products: “We kindly advocate that the post-marketing safety monitoring and long-term follow-up expectations within the guidance reflect the realities of small patient populations and individualized products, particularly for n-of-1 therapies,” BIO’s comments say. “Traditional pharmacovigilance and confirmatory study paradigms may not be feasible in these settings.”
- Clarify framework application and provide operational “how-to” implementation direction, including with examples: “We recommend the Agency clarify how the Plausible Mechanism Framework interfaces with existing programs such as Accelerated Approval, Breakthrough, Fast-Track, RMAT, the Platform Technology Designation Program, and targeted therapy guidances to ensure coherent and predictable regulatory pathways,” BIO comments.
The comments from BIO envision further refinement of the guidance and anticipate further involvement in the process, concluding: “BIO and its members appreciate the FDA’s leadership and look forward to continued engagement as the guidance is finalized.”
