Comment from Robert Caudill

To Whom It May Concern, I am the parent of a child diagnosed with Alexander disease, a rare and progressive genetic leukodystrophy caused by a known mutation in the GFAP gene. I am writing to strongly support the development and implementation of the Plausible Mechanism Framework for individualized therapies. For ultra-rare diseases like Alexander disease, traditional clinical trial models are often impractical and ethically challenging. The patient population is extremely small, disease progression is often rapid and irreversible, and time is a critical factor. Waiting for large-scale randomized controlled trials may result in permanent loss of function or life. 1. Trial Design for Rare Diseases Clinical trial designs for rare diseases must be fundamentally different. Regulatory flexibility is not just helpful—it is necessary. Mechanism-based evidence, combined with strong preclinical data and early clinical signals, should be sufficient to support approval in many cases. 2. Use of Placebo The use of placebo in progressive pediatric neurodegenerative diseases should be minimized or avoided whenever possible. In conditions where decline is irreversible, assigning a child to placebo may effectively deny them their only opportunity for intervention during a critical window. 3. Outcome Measures Outcome measures should reflect meaningful clinical realities. For diseases like Alexander disease, stabilization or slowed progression is a meaningful and life-altering benefit. Preserving functions such as mobility, speech, or swallowing should be considered valid primary endpoints. The Plausible Mechanism Framework represents a hopeful and necessary shift toward patient-centered, science-driven regulation. I urge the FDA to adopt and expand this approach to ensure that children with rare genetic diseases have timely access to potentially life-changing therapies. Respectfully, Robert Caudill