The FDA has outlined a process for allowing a single application to cover multiple variants of a gene therapy. At the same time, the Centers for Medicare & Medicaid Services has revealed plans to expand the Cell and Gene Therapy Access Model to increase patient access to these products.
The FDA is full speed ahead with efforts to accelerate the development of and access to personalized gene therapies for rare diseases, issuing new draft guidance on Tuesday afternoon to help usher drug developers through the approval process for these medicines.
The draft guidance—a full court press from the Department of Health and Human Services (HHS) that includes the Centers for Medicare & Medicaid Services (CMS) in addition to FDA—seeks to provide “a clear and scientifically rigorous framework for BLA submission and postapproval management” of these therapies, Center for Biologics Evaluation and Research (CBER) Director Karim Mikhail said in a prepared statement on Tuesday. “We are helping to ensure that patients—including those with ultra-rare conditions for whom no treatment currently exists—can more efficiently access therapies that may be life-changing.”
Key to the guidance is the Individualized Feature Space (IFS), a set of pre-defined criteria describing how a gene therapy product can vary between patients—say, those whose disease is caused by a different genetic mutation—while still remaining within the scope of a single biologics license application (BLA).
“When a new patient-specific variant of the therapy falls within those boundaries and assays show that the variant has adequate safety and activity, sponsors can submit it to the BLA without needing to perform additional clinical trials,” the FDA and CMS said in the joint release.
The guidance offers clarity on how sponsors can structure a BLA capable of accommodating “multiple patient-specific product variants,” and how new variants can be efficiently added after approval to avoid additional trials.
The document also addresses other issues of concern in the gene therapy space, including manufacturing, safety testing and labeling.
Tuesday’s draft guidance follows similar initiatives, including the FDA’s Plausible Mechanism Pathway, announced by former Commissioner Marty Makary and former CBER director Vinay Prasad in November last year. The pathway was intended to expedite therapies for diseases that affect an exceedingly small patient population, for which randomized trials are not feasible.
In an article published in The New England Journal of Medicine on Nov. 13, 2025, Makary and Prasad highlighted the case of Baby KJ, a young child with an ultrarare genetic condition called CPS1 deficiency who was treated with a single-use CRISPR therapy that was produced specifically for him, as an example of the pathway’s intentions.
The latest draft guidance also comes less than two weeks after the FDA debuted its new Rare Disease Framework Initiative, intended to standardize the agency’s approach to scientific evidence and bring rare disease therapies to patients faster.
CMS also made its intentions and commitment to increasing access to the often-pricey therapies clear.
“A medical breakthrough only matters to patients if they can get it,” CMS Administrator Mehmet Oz said in Tuesday’s press release, adding that CMS is “bringing state Medicaid programs together to negotiate with drug manufacturers to help put life-changing therapies within reach.”
In January 2024, CMS introduced the Cell and Gene Therapy (CGT) Access Model, a voluntary initiative whereby CMS negotiates voluntary outcomes-based agreements on behalf of state Medicaid programs for cell and gene therapies to increase patient access to these products. The model initially focused on gene therapies for sickle cell disease. In December that year, Vertex Pharmaceuticals and bluebird bio—the developers of Casgevy and Lyfgenia, respectively—joined the program.
On Tuesday, CMS said it would take steps to broaden this model beyond sickle cell disease.
“In the coming months, CMS will release a Request for Applications (RFA) for manufacturers designed to broaden the model’s scope and enable negotiations to begin sooner after a therapy receives FDA approval or licensure, while also welcoming applications for therapies already approved or licensed,” the agency said.
The FDA’s and CMS’ most recent action also coincides with the National Organization for Rare Diseases Breakthrough Summit in Washington, D.C., which has included presentations from Mikhail and his CDER counterpart Michael Davis.
RBC Capital Markets analysts, who were attending the summit, expressed optimism about recent regulatory efforts in the rare disease space.
“Ultimately, we came away incrementally more positive on the rare disease regulatory setup, with both Mikhail and Davis striking a notably constructive tone around the newly launched Rare Disease Framework Initiative and a strong desire to harmonize regulatory standards across the two divisions in order to ultimately increase predictability for sponsors,” they wrote in a note to investors on Wednesday.
With the U.S. midterm elections less than a week away, the analysts said that multiple congressional staffers “expressed bipartisan support for clinical trial reform for rare disease.”
