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Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause; Draft Guidance for Industry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, a family member affected by a rare genetic disease, supports the proposed Plausible Mechanism Framework because it addresses the unique needs of small populations with monogenic diseases. They specifically advocate for the inclusion of pre-symptomatic carriers in trials and request that patient and family community input be integrated into protocol design.

Public Responsibility in Medicine and Research (PRIM&R), a nonprofit organization, supports the draft guidance while requesting specific improvements. They advocate for clearer eligibility thresholds to prevent the framework from replacing feasible randomized controlled trials, the inclusion of pediatric assent requirements, and more detailed guidance on using natural history studies as comparators.

The Children's Hospital Association supports the FDA's draft guidance but urges the agency to incorporate specific considerations for pediatric patients, including safety, delivery protocols, and reimbursement frameworks. They advocate for partnerships with children's hospitals and the inclusion of pediatric experts in the regulatory process to ensure equitable and sustainable access to rare disease therapies.

A patient and mother of children supports the FDA's efforts to create a pathway for individualized therapies but argues that the draft guidance needs stronger requirements. She specifically calls for enforceable diversity plans in clinical trials, mandatory long-term follow-up requirements (PMRs) at the time of approval, and validated health literacy assessments to ensure meaningful informed consent.

Kyrsten Lawless, a parent and advocate for a child with alpha-mannosidosis, argues that the FDA should provide enhanced incentives and streamlined pathways for developing curative AAV gene therapies and pharmacological chaperones. She emphasizes the high clinical and economic burden of current enzyme replacement therapies and advocates for regulatory flexibility to support individualized gene therapies for rare lysosomal storage disorders.

Kyrsten Lawless, a parent and advocate for a child with alpha-mannosidosis, supports the use of the Plausible Mechanism Framework to develop individualized gene therapies for rare genetic conditions. She argues that current enzyme replacement therapies are insufficient and costly, and urges the FDA to provide enhanced incentives and streamlined pathways for curative, one-time gene therapies that can cross the blood-brain barrier.

The Cure Coalition, an organization representing patients and families, supports the FDA's draft guidance on the Plausible Mechanism Framework for individualized therapies. They advocate for strengthening the guidance by emphasizing pediatric and reproductive safety, ensuring traditional preclinical methods are not prematurely replaced by New Approach Methodologies (NAMs), and promoting transparent, collaborative implementation.

The commenter argues that gene therapy is fundamentally flawed because the immune system will recognize the introduced "good genes" as foreign neoantigens, leading to immune rejection and potentially severe autoimmunity. They contend that the FDA lacks an understanding of these basic immunological concepts and that gene therapy will be largely ineffective or harmful.

A relative of a person with a rare genetic mutation supports the proposed framework for developing individualized therapies. The commenter argues that the framework is a promising step for addressing incurable conditions where traditional clinical trials are not feasible.