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Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance for Industry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.

UCB, Inc., a global biopharmaceutical company, supports the draft guidance and provides specific recommendations to improve clarity and scope. They suggest expanding the scope to include other RNA-based therapies, refining language on nonclinical data and biomarkers, and clarifying requirements for patient diagnosis and master protocols.

A parent of a woman with spinocerebellar Ataxia type 3 expresses support for the proposed guidance to accelerate scientific research and individualized therapies. The commenter argues that patients with rare genetic diseases need fewer regulatory hurdles and more funding to develop life-altering treatments.

Rejuvenation Technologies, a biotechnology company, supports the draft guidance but requests specific clarifications to ensure the Plausible Mechanism Framework includes therapies for multi-gene convergent conditions like telomere biology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The American Brain Tumor Association (ABTA) supports the draft guidance as a necessary step for developing therapies for rare diseases with unmet needs.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The California Institute for Regenerative Medicine (CIRM), a state agency, supports the draft guidance as a positive regulatory innovation for accelerating the development of genetic medicines for rare diseases. They advocate for specific refinements, including clearer eligibility criteria, flexibility in observational periods for rapidly progressing diseases, and the creation of a unique regulatory designation to ensure consistent FDA interaction.

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.

DEE-P Connections, a caregiver-led collaborative organization representing families affected by Developmental and Epileptic Encephalopathy (DEE), strongly supports the FDA's Plausible Mechanism Framework. They argue that the framework should be improved to better incorporate real-world data, mandate meaningful patient engagement, utilize flexible trial designs, and ensure the use of fit-for-purpose outcome measures for medically fragile populations.