Foundation Submits Public Comment to the FDA on the Plausible Mechanism Framework for Accelerating Individualized Therapy Development for Rare Diseases
April 24, 2026
On behalf of the APBD community, the APBD Research Foundation has responded to the US Food and Drug Administration's (FDA) request for public comments for its recently released draft guidance for the use of the Plausible Mechanism Framework for individualized genetic therapies.
Read the APBDRF’s Public Comments
What is the Plausible Mechanism Framework?
The FDA’s proposed Plausible Mechanism Framework provides recommendations on ways to expedite the drug development process in rare diseases. Specifically, providing for flexibility in the regulatory pathways for drugs used to treat diseases where the eligible patient population is small. The goal of this guidance is to lead to the development and approval of safe and effective individualized therapies – particularly gene and RNA-based therapies, such as gene editing and antisense oligonucleotides (ASOs).
Key factors meant to speed-up the path to treatment in rare disease include:
Allowing for flexible clinical trial designs applicable to small groups of patients, such as using natural history data as the control arm for a study (ie. no placebo group);
Supporting “all-in-one” preclinical studies that evaluate the drug’s effectiveness, safety, and biodistribution (where it gets to in the body); and
Providing for the use of previous data and “umbrella” protocols to study similar therapies that may target different genetic variants.
The APBD Research Foundation's response to the FDA draft guidance reflects our commitment to advocating for bringing safe and effective treatments to the APBD and broader GSD IV community with urgency – amplifying the voice of the entire GSD IV community. Our letter to the FDA supports the Plausible Mechanism Framework for its ability to accelerate the path to drug approval and use innovative clinical trial designs that address the challenges faced in ultra-rare diseases, like APBD and other forms of GSD IV. It also encourages the FDA to consider expanding this framework beyond gene and RNA-based therapies and provide more detailed guidance on the needed criteria for “well-characterized” natural history studies.