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Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance for Industry

Flagship Pioneering, a venture creation and innovation firm, supports the FDA's Plausible Mechanism framework as a necessary step toward modernizing regulatory approaches for individualized therapies. They argue for expanding the framework's scope to include more modalities and patient populations, while requesting greater clarity on its relationship to existing pathways and operational implementation.

North Star ALS, a nonprofit organization representing families affected by ALS, strongly supports the finalization of the FDA's draft guidance on the plausible mechanism framework. They argue that this framework is essential for developing sustainable, individualized therapies for ultra-rare genetic mutations and request that the FDA clarify its eligibility for biomarker-defined subgroups of sporadic ALS.

The brain tumor community supports the Plausible Mechanism Framework but argues that the draft guidance is too narrow and needs to explicitly include molecularly defined subsets of common cancers and specific modalities like personalized cancer vaccines. They urge the FDA to clarify that these small, biologically distinct populations with well-understood drivers should be eligible for the framework to ensure patients with high unmet needs are not excluded.