The framework, first introduced by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research head Vinay Prasad in November, was criticized for lacking detailed guidance. Agency leaders elucidated on the pathway for personalized medicines on Monday.
In advance of a bipartisan Senate hearing scheduled for Thursday focused on the authorization process for rare disease therapies, the FDA has proposed a regulatory path for individualized therapies like the one that famously helped Baby KJ this summer.
On Monday, the agency published draft guidance for personalized genetic medicines, setting out a route to market for bespoke treatments that address unmet medical needs.
“This framework aligns regulation with biology,” Health Secretary Robert F. Kennedy Jr. said during a press conference to announce the guidance. “For ultra-rare conditions, randomized controlled trials are often . . . just not feasible. Under the framework that we’re announcing today, one well-controlled clinical investigation supported by confirmatory evidence can support approval.”
In a November article published in The New England Journal of Medicine introducing the Plausible Mechanism Pathway, FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research Director Vinay Prasad cited the case of Baby KJ, who received a personalized CRISPR therapy last year, as an example of the type of care they want to facilitate through the pathway.
The concept could accelerate the development of gene therapies and gene-editing treatments, William Blair analysts said in a note when Makary and Prasad first disclosed the model. However, the analysts also noted a lack of detail about the application of the pathway.
The FDA has previously provided general guidance for sponsors developing targeted treatments. However, that guidance did not cover individualized therapies where the clinical evidence is more limited, according to the draft guidance.
The guidance focuses on genome editing and RNA-based treatments for rare diseases, but the FDA said the framework could also apply to other types of individualized therapies. In the FDA’s definition, individualized therapies target the “specific pathophysiologic abnormality serving as the root cause of a disease,” such as a genetic variant.
Identifying the underlying cause of a disease and developing a drug that addresses it are the first steps in the framework. Beyond that, the FDA recommends that companies rely on a well-characterized natural history of the disease in an untreated population as a control and show improvements in clinical outcomes. In addition, investigators should confirm the target was engaged successfully. The draft features detailed advice on how to conduct preclinical and clinical tests.
Harpreet Singh, chief medical officer at the global clinical research organization Precision for Medicine, noted that the guidance came out “very quickly for even a draft guidance.”
“It doesn’t really expand much on what the original [NEJM] article talked about, but . . . I think that’s most guidances,” Singh, who previously served as a division director of Oncology at the FDA, told BioSpace. She added that, as this is a draft guidance, “it’s on industry to respond to this and ask for more clarity.”
Singh also noted the absence of guidance for cancer indications.
“We are not seeing any nod or mention to any of the oncologic diseases, and I do think that this guidance certainly spans oncology,” she said, adding that it would be interesting to see who from CDER—which regulates most cancer drugs—contributed to the guidance.
Several companies have shown interest in leveraging the framework. Menlo Ventures named the FDA pathway as a development underpinning its belief in Aurora Therapeutics, a biotech launched recently by CRISPR co-inventor Jennifer Doudna and Berkeley Professor Fyodor Urnova, a collaborator on Baby KJ’s treatment. Menlo invested $16 million in Aurora to support efforts to replicate the Baby KJ success story.
Aurora is initially targeting some of the hundreds of gene variants in people with phenylketonuria (PKU). By grouping variants, the biotech could develop treatments for causes of PKU that are too rare to viably address under existing paths to market.
Editor’s note: Heather McKenzie contributed reporting to this story.
