After teasing a new regulatory process for personalized genetic medicines at the end of last year, the FDA today unveiled draft guidance for an approval pathway that could see custom CRISPR therapies, like the one that treated critically ill baby KJ last year, formally embraced by the agency.
For now, the new pathway focuses on genome editing and RNA-based methods—like antisense oligonucleotides—that target the underlying cause of a rare disease, the FDA said in a Feb. 23 release.
Agency leaders Marty Makary, M.D., the FDA commissioner, and Vinay Prasad, M.D., the director of the Center for Biologics Evaluation and Research (CBER), first unveiled the pathway, called the “plausible mechanism” framework, in a November publication in the New England Journal of Medicine.
The new path aims to remove barriers for bespoke medicines designed for patients with rare diseases, potentially allowing data in a few patients to support approvals in broader populations by targeting specific genetic, cellular or molecular abnormalities, according to the FDA release. In a statement, Prasad called the new approach a “revolutionary advance in regulatory science.”
“Individualized medicine is no longer theoretical,” Robert F. Kennedy, Jr., head of the Department of Health and Human Services, said in a Feb. 23 press conference. “A disease with 100 distinct mutations in the same gene will no longer require 100 clinical trials. When biology is clear and the science is sound, we will evaluate therapies based upon strong evidence and not arbitrary barriers.”
Drug developers can secure approvals by meeting at least four criteria, according to the draft document. The underlying biological cause of the disease must be identified, and the therapy must be proven to target that root mechanism or “proximate pathogenic biological alterations” with confirmed successful target drugging or editing. Sponsors may leverage “well-characterized natural history data” in untreated patients, which may serve as an external control “if it is adequate to allow for the treatment effect to be reasonably distinguished.”
The FDA also recommends that clinical trials should be designed to demonstrate clinical benefits, such as improvement in symptoms, stabilization or slowing of disease progression, or decreases in episodic serious disease-related events.
To support traditional approvals of these medicines, alongside weighing evidence of improvement in clinical outcomes or disease course, the FDA appears open to accepting data from biomarkers “if they are established to predict clinical benefit.”
Without going into details, the agency said it will mandate that clinical results “be robust to exclude chance findings that may incorrectly suggest effectiveness,” as it recognizes that clinical trials in rare disease settings tend to be small.
When first outlining the pathway in November, Makary and Prasad highlighted baby KJ’s groundbreaking treatment as an example of a therapy that could go through the new regulatory approach. KJ’s bespoke CRISPR therapy targeted a genetic mutation called Q335X, which was a significant cause of his carbamoyl phosphate synthetase 1 (CPS1) deficiency. CPS1 deficiency has a “well-characterized natural history,” the regulators noted, and KJ’s care team also demonstrated that the custom treatment successfully edited 42% of liver cells in mice.
Following a product’s approval under the new pathway, the FDA will continue to gather data post-market to ensure safety, according to the draft guidance.
If follow-up studies show a treatment is not as safe or effective as previously thought, the FDA may withdraw the product from the market, a senior FDA official said in a Feb. 23 call with journalists in advance of the press conference. The agency asked that the official not be named.
“We need to take each of these on a case-by-case basis,” the official said. “We hope that this is actually going to result in numerous treatments for [ultra-rare] diseases that otherwise would not have had an effective treatment.”
“We anticipate that we’re going to get a flood of applications for treatments of rare diseases,” the official added, noting that the team behind KJ’s treatment has been working to unify multiple potential treatments for different genetic diseases, all using a common mechanism, under one investigational new drug application.
Speaking at the press conference, the leaders of KJ’s care team highlighted the work they are doing to bring his unique treatment to more patients while also heralding the potential of the plausible mechanism pathway.
“We’ve turned this therapy into a whole platform,” Kiran Musunuru, M.D., Ph.D., co-founder of Verve Therapeutics and a cardiologist at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania, said during the conference. The team plans to “eventually launch a single clinical trial for a whole set of liver-centered diseases, the urea cycle disorders,” which includes KJ’s disease, CPS1 deficiency.
Despite his past involvement in outlining the plausible mechanism framework and oversight of CBER, which would handle the majority of medicines submitted for approval through the pathway, Prasad was not present at today’s press event. When asked about his absence, a spokesperson for the Department of Health and Human Services cited a “scheduling conflict” due to Prasad being “out west,” a possible reference to his home in San Francisco.
Health leaders under the second Trump administration have long expressed a desire to cut red tape for cell and gene therapies. But the reality for the developers of these cutting-edge medicines has been harsh. The FDA recently told uniQure that the biotech’s gene therapy for Huntington’s disease no longer had sufficient evidence to support its approval, even though the candidate addresses the root biological cause of the rare disease.
And earlier this month, Regenxbio’s gene therapy for Hunter syndrome was shot down by the FDA over concerns about the company’s use of a natural history control arm and a well-established biomarker as a surrogate endpoint, both of which the agency says are acceptable under the new plausible mechanism framework.
Asked about this discrepancy, the senior FDA official on this morning’s press call said she could not provide specifics about any rejection decisions, as they fall under CBER’s purview and not her own center. She did specify that the agency is not changing “the standards for evidence” with the new pathway and reiterated that the approvals under the plausible mechanism framework will have a “high bar.”
Rebecca Ahrens-Nicklas, M.D., Ph.D., also of CHOP and Penn and the other leader of KJ’s care, said that “clear, pragmatic, consistent regulatory guidance is essential” for the development of new rare disease therapies.
“I hope that we can all proceed with radical transparency and share all that we learn, both the triumphs and the struggles, as we build this field of interventional genetics,” Ahrens-Nicklas said.
During the press conference, an advocate for the rare mitochondrial disorder pyruvate dehydrogenase complex deficiency (PDCD), which has no approved treatments, asked how the new pathway relates to products currently in the regulatory process. An oral candidate for PDCD from Saol Therapeutics was rejected by the FDA in September 2025.
“I can’t speak specifically to that application,” Tracy Beth Høeg, M.D., Ph.D., the acting director of the FDA’s Center for Drug Evaluation and Research, said in reply. The goal of the new pathway is to “be able to approve things more rapidly and in a more orderly manner,” she said, adding that “specific issues with applications we hope that we can also address in a timely manner.”
The new pathway could accelerate approvals of bespoke gene therapies or enable new authorizations that weren’t previously possible. Its rollout comes amid growing concerns that the U.S. is ceding dominance in the field to China, which has been continuously streamlining its regulations to expedite review of innovative trials and drugs. By allowing a plausible mechanism pathway, the FDA is signaling an attempt to prevent early gene therapy innovation from shifting permanently to Beijing.
“We definitely would like the United States to lead in terms of innovation in the rare disease and the non-rare disease space. And we hope that this is going to contribute to that happening,” the senior FDA official said.
“I don’t think that this one guidance is sufficient for us to move ahead of China, and I think that there are many different changes that need to be made,” she added.
https://www.fiercebiotech.com/biotech/fda-illuminates-new-approval-pathway-bespoke-gene-therapies
