FDA issues draft guidance on individualized gene editing products to fill ‘critical gap’
The US Food and Drug Administration (FDA) on Tuesday issued draft guidance laying out its proposed regulatory approach to overseeing individualized gene editing (GE) products, including those that feature multiple product variants developed under a single investigational new drug application (IND).
The guidance discusses both biologics license application (BLA) submissions for individualized GE products, as well as managing postapproval change management for such products.
The guidance addresses a "critical gap" in FDA's regulatory framework for GE products and outlines a “logical next step” for submitting a single BLA for products aimed at correcting multiple pathogenic variants within a gene, said Andrew Byrnes, director of the Division of Gene Therapy 1 within the Center for Biologics Evaluation and Research (CBER), during a webinar about the guidance on Tuesday.
Byrnes said that currently, each individualized product variant is treated as a separate product needing a separate BLA. This approach involves distinct development processes, separate clinical studies and separate BLAs for each patient. However, he said that this approach is “infeasible” and “not necessary.”
The approach laid out in the draft guidance “creates a way to develop and submit multiple variants of a GE product in one BLA,” said Byrnes. This way, sponsors “can also continue to add new product variants to the BLA after approval, to address additional patient-specific gene variants.”
The guidance addresses manufacturing process and control strategy, potency and safety evaluation of product variants, manufacturing process validation, labeling and indication statements, and drug naming.
The guidance defines GE as a “process by which DNA sequences are added, deleted, altered or replaced at specified location(s) in the genome of human somatic cells, ex vivo or in vivo, using nuclease-dependent or nuclease-independent GE technologies. GE is a type of gene therapy that relies on GE components to edit DNA.”
The scope of this guidance is limited to individualized GE products that aim to prevent, treat, or cure a monogenic disease or condition. FDA further notes the disease or condition mut be caused by known pathogenic gene variants and the products included under the BLA should be designed to achieve the same editing outcome.
Jacob Bitterman, lead biologist in the Division of Gene Therapy 1, said the guidance introduces the concept of the “individualized feature space” (IFS) for these products. He said the IFS “defines the allowable limits of variation for the GE components across all product variants.”
The guidance cites the example of a GE product whose only variable feature is a gRNA spacer sequence. In this case, “the IFS should describe which types of spacer sequences are allowable in the BLA – such as any spacer sequence that targets a defined class of pathogenic gene variants in a specified gene and results in the same editing outcome (e.g., correcting the gene so that it encodes the wild-type protein).”
Furthermore, the guidance notes that a new product variant should be considered a manufacturing change rather than a new product, as long as the variable features of the product variant’s GE components fall within the established IFS; and the resulting product variant is predicted to have “adequate safety and activity based on clinical and/or in vitro data.”
FDA encourages sponsors to develop the IFS prospectively during their clinical development programs. This ensures that clinical studies are designed to generate data that will support the proposed boundaries of the IFS. The clinical studies required to support a proposed IFS will be highly specific to each case. Applicants must provide a “robust scientific rationale” to justify the proposed IFS boundaries.
Byrnes said the document builds upon other foundational guidance in this area, including draft guidance on human gene therapy products that incorporate human gene editing, issued in January 2024; guidance on the plausible mechanism framework for individualized therapies, released in draft form in February 2026; draft guidance on safety assessments utilizing next-generation sequencing, published as a draft in April 2026; and draft guidance on leveraging prior knowledge across genome editing programs, issued in June 2026.
