The status of the Food and Drug Administration's plausible mechanism pathway for individualized therapies is uncertain following the recent departures of Center for Biologics Evaluation and Research Director Vinay Prasad and Commissioner Marty Makary, according to a June 8 report. The pathway, first introduced in November 2025, was discussed at an FDA workshop last month intended to clarify its implementation.
Stacey Frisk, then executive director of the Rare Disease Company Coalition, said prior to her departure on May 15 that she anticipated delays while permanent leadership is sought. Saol Therapeutics CEO Dave Penake said he remains concerned about delivering therapies for children with rare diseases like pyruvate dehydrogenase complex deficiency but emphasized focusing on supporting science amid organizational changes. “Organizations change, and so what we have control over is doing the best we can to support the science and kind of move the ball forward each day,” Penake said.
The plausible mechanism pathway has been both welcomed and questioned since its publication by Makary and Prasad in The New England Journal of Medicine. Anna Kwilas, Gene Therapy CMC branch chief at the FDA, clarified during the May 4 workshop that it is a framework using existing approval pathways rather than a new approval process itself. She also stated that it focuses on genome editing and RNA-based therapies but may apply more broadly.
Despite draft guidance issued in February around this framework, experts say there remains ambiguity about which products qualify. Penake said he believes there should be enough definition for stakeholders to attempt use without excluding important technologies: “They have clarity of intent. I think the spirit of the program is great,” he said. “The devil’s in the details.”
A key challenge highlighted at the workshop was how evidence from external controls—such as real-world data or historical controls—should be used when traditional randomized trials are not feasible due to small patient populations. Linda Marbán, CEO of Capricor Therapeutics, noted confusion among review staff regarding this flexibility despite supportive agency guidance.
Deanna Portero from Orphan Therapeutics Accelerator identified further disconnects between FDA expectations for clinical trial manufacturing standards and available resources among academic developers. She called clarification on these requirements “an obvious and critical disconnect,” but acknowledged that recent workshops provided helpful context about qualification criteria under this framework.
