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Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance for Industry

Rejuvenation Technologies, a biotechnology company, supports the draft guidance but requests specific clarifications to ensure the Plausible Mechanism Framework includes therapies for multi-gene convergent conditions like telomere biology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 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The National Brain Tumor Society and the Society for Neuro-Oncology support the FDA's draft guidance on the Plausible Mechanism Framework as a positive step for rare disease treatment. They highlight the complexity of brain tumor biology and urge the FDA to collaborate with researchers to determine how the framework can best be applied to these complex cancers.

Sonia Vallabh, an investigator at the Broad Institute of MIT and Harvard, supports the draft guidance but urges the FDA to broaden the definition of "individualized therapies" to include drugs targeting underlying genetic causes rather than just single-patient mutations. She also suggests using more inclusive terminology like "oligonucleotide," clarifying the distinction between "genetically targeted" and "individualized" therapies, and strengthening language regarding data sharing for rare diseases.

The Academy of Managed Care Pharmacy (AMCP) supports the FDA's use of the Plausible Mechanism Framework to develop individualized therapies for ultra-rare genetic conditions. They advocate for clearer definitions of the framework's scope, standardized protocols for real-world evidence (RWE) collection, and increased transparency regarding post-marketing evidence to support coverage and reimbursement decisions.

The Biotechnology Innovation Organization (BIO) supports the FDA's proposal to create a Plausible Mechanism Framework for individualized therapies, viewing it as a necessary evolution in regulatory science. They request additional clarity on operational details, including broader scope for modalities, clearer definitions, expanded CMC flexibilities, and better integration with existing regulatory pathways.

The ALS Network, an organization serving people with ALS and their families, supports the FDA's draft guidance on the Plausible Mechanism Framework for individualized therapies. They argue that the framework should specifically include mutation-defined subsets of ALS while maintaining rigorous standards for biomarker validity, clinical evidence, safety monitoring, and confirmatory follow-up.

The Pediatric Inclusion Alliance supports the draft guidance but urges the FDA to provide greater clarity on definitions like "individualized" and "well-characterized." They specifically advocate for more explicit language and flexibility regarding the early inclusion of children in clinical trials for rare diseases.

Certara, a pharmaceutical services company, supports the proposed guidance but requests specific clarifications and additions to make it more actionable for sponsors. They advocate for defining tiered evidentiary frameworks, clarifying statistical approaches for small populations, and explicitly recognizing various modeling techniques (like PBPK and QSP) as valid mechanistic data.

The National Organization for Rare Disorders (NORD) supports the FDA's interest in developing a Plausible Mechanism Framework for rare disease therapies but requests specific revisions to terminology, scope, and clarity on existing tools. They advocate for clarifying that the framework applies to non-genetic medicines, removing the term "individualized" to avoid misleading implications, and establishing a holistic framework for manufacturing and commercialization.