FDA publishes plausible mechanism framework guidance for personalized therapies

The U.S. FDA has published draft guidance for personalized therapies that target specific genetic conditions with known biological causes, outlining the use of the agency’s plausible mechanism framework.

The framework was first discussed in a November 2025 New England Journal of Medicine article, in which FDA Commissioner Martin Makary and CBER director Vinay Prasad used the story of Baby K.J. — the infant with urea cycle disorder who was treated with the world’s first personalized CRISPR gene editing drug product — to define the plausible mechanism pathway.

The framework outlines a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data and demonstrate that the product can be manufactured to regulatory quality standards. These data are used to support approval of an individualized therapy for a specific indication.

“This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions,” said FDA Commissioner Marty Makary, MD. “It is our priority to remove barriers and exercise regulatory flexibility to encourage scientific advances and deliver more cures and meaningful treatments for patients suffering from rare diseases.”

The agency noted that while the guidance specifically discusses genome editing and RNA-based therapies (e.g., antisense oligonucleotides), the concepts may apply to other types of individualized therapies. The draft guidance is open for commentary.