Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance for Industry

The commenter provides specific feedback on the proposed framework, advocating for the use of Activities of Daily Living (ADLs) as primary metrics and the inclusion of more diverse, impaired patient populations in trials. They also suggest clarifying guidelines for small patient populations and addressing potential inconsistencies in IRB reviews across multi-site trials.

Rejuvenation Technologies, a biotechnology company, supports the draft guidance but requests specific clarifications to ensure the Plausible Mechanism Framework includes therapies for multi-gene convergent conditions like telomere biology disorders. They argue that the current language focusing on single genetic variants might inadvertently exclude treatments that address a common downstream mechanism across multiple genes.

The American Brain Tumor Association (ABTA) supports the draft guidance as a necessary step for developing therapies for rare diseases with unmet needs. However, they request specific language changes to replace "other types" with "any types" of individualized therapies to ensure the framework is not unintentionally restrictive for various therapeutic approaches.

The N=1 Collaborative (N1C), a nonprofit consortium of clinicians, researchers, and patient advocates, supports the draft guidance as a necessary step for developing individualized therapies for rare genetic diseases. They recommend specific improvements, including making data sharing a requirement, calibrating CMC standards for small-batch manufacturing, expanding the platform concept to multiple genes, and establishing a formal process for developing clinical effectiveness standards.

Northwest Biotherapeutics, a clinical-stage biotechnology company, supports the draft guidance but requests specific language changes to broaden its scope. They argue that the framework should explicitly include cancer and cell therapies, as well as "cellular or molecular conditions," to ensure regulatory fairness across different treatment modalities.

The NIH Somatic Cell Genome Editing (SCGE) Consortium, an NIH Common Fund program, supports the proposed guidance but requests greater flexibility regarding the "well-characterized" natural history of diseases. They argue that for rare and ultra-rare diseases, the agency should accept retrospective data because prospective studies may be impossible or cost-prohibitive.

A neurologist provides feedback on the FDA's draft guidance, supporting the creation of a framework for individualized therapies. The commenter argues that the guidance should be explicitly expanded to include all types of individualized therapies (such as cell therapies) rather than being primarily focused on gene therapies.

The Cure Sanfilippo Foundation, a nonprofit patient advocacy organization, supports the proposed Plausible Mechanism Framework as a significant step forward for developing therapies for ultra-rare diseases. They request specific clarifications to ensure the framework is inclusive of various therapeutic modalities, uses "fit-for-purpose" natural history data, allows for flexible endpoints, and adopts "right-sized" manufacturing requirements for small patient populations.

The University of Wisconsin-Madison CRISPR Vision Program argues that the draft guidance lacks sufficient clarity on using New Approach Methodologies (NAMs) to establish proof-of-concept and minimum effective doses when animal models are unavailable. They propose specific, tiered standards for validating human cell-based models and dose-response characterization to reduce regulatory uncertainty in gene editing development.

flok Health, a patient-led organization for individuals with inherited disorders of protein metabolism, supports the FDA's Plausible Mechanism Framework for individualized therapies. They urge the FDA to incorporate structured real-world data as a foundational evidence stream and to leverage shared mechanisms and platform approaches to improve access for patients with ultra-rare variants.