Genome editing products at the FDA: A quick primer

• Genome editing technology is the result of many years of scientific study and clinical research. But not until recently has a genome editing product successfully gone through regulatory review in the U.S. The FDA’s 2023 OK of a CRISPR-based therapy for sickle cell disease was the first – and is still the only – approval of a genome editing product, which the agency views as a subtype of gene therapy. So, while the FDA has ample experience with cell and gene therapy products that work by means other than direct DNA editing, its familiarity with reviewing genome editing treatments remains limited.
• The FDA has set out comprehensive recommendations for developing genome editing products, however. Guidance that the FDA finalized in 2024 outlines the agency’s views on manufacturing such products, as well as designing nonclinical and clinical studies. As defined by the FDA in the guidance, human genome editing is “a process by which DNA sequences are added, deleted, altered or replaced at specific location(s) in the genome of human somatic cells, ex vivo or in vivo, using nuclease-dependent or nuclease-independent GE technologies.” Examples of nuclease-dependent technologies include CRISPR, but also zinc finger-based and other older means of editing. Researchers and biotechnology firms have more recently advanced techniques like base and prime editing that don’t break both strands of DNA to introduce their intended genomic change. [Read AgencyIQ’s analysis of the FDA’s 2024 guidance here.] The recommendations are supported by dozens of other guidance documents that pertain to cell and gene therapy products more broadly.
• Off-target editing remains a safety concern for genome editing therapies. While such products are designed to make precise changes to genes involved in disease, the way they work carries risks of inadvertent changes elsewhere in the genome, which in theory could later lead to serious health consequences, such as cancer. Manufacturing is another hurdle. Producing GE therapies, which can involve cells, nucleic acids, viruses or lipid nanoparticles, is substantially more complex than making traditional pharmaceutical and biologic medicines. Product consistency and comparability remain just as vital, but the standard methods for demonstrating that at commercial scale aren’t always suitable to genome editing products. The FDA issued guidance on cell and gene therapy manufacturing in 2023; held a town hall in October 2025 on manufacturing, inspections and post-licensure changes for gene therapy; and in May 2026 codified the flexibilities it offers in Level 2 guidance.
• The FDA is exploring further ways to help advance genome editing products, motivated by a fast-advancing pipeline and Baby KJ’s landmark 2025 treatment with a bespoke editing therapy. The KJ case in particular pushed agency leaders to develop a “plausible mechanism” pathway to facilitate development and approval of personalized treatments for ultrarare diseases. Draft guidance issued by the FDA in February 2026 focused on genome editing products (along with antisense oligonucleotides, another modality that’s proven useful for personalized therapy.) The document, which could be revised following substantial industry feedback, envisions a framework whereby sponsors could secure approval of a genome editing product and then, with evidence of a plausible mechanism of action, adapt it to treat patients with related mutations that weren’t studied in the clinical trial originally used to support licensure. [Read AgencyIQ’s analysis of the draft guidance here.]

Guidance on ‘prior knowledge’ could aid developers

• The FDA on June 2, 2026, unveiled much-anticipated draft guidance describing how developers of genome editing products can appropriately use existing scientific knowledge in their submissions. The document, titled “Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing,” fulfills a commitment the FDA made in its most recent Prescription Drug User Fee Act agreement with industry. While the draft guidance focuses on genome editing products, the FDA noted that its recommendations, if finalized, could apply to other cell and gene therapies, too. [Read AgencyIQ’s full analysis here.]
• The FDA used the draft guidance to define terms that could otherwise be open to interpretation. Prior knowledge, it wrote, can refer to either “public knowledge,” which describes generally accepted medical or scientific information based on long-standing principles, or “platform knowledge,” which refers to the information accumulated “from developing and manufacturing of similar products and processes,” the guidance explains. Platform knowledge can be proprietary to a specific company or widely available. Platforms, in this context, are “well-understood and reproducible technology(s) applied to the development of a GE product that consists of the same or highly similar features across development programs.” The draft guidance also specifies that the term “leveraged knowledge,” whether public or private, means prior knowledge that can be used to “fully or partially alleviate the need to generate new information/data.”
• The draft guidance provides recommendations specific to use of prior chemistry, manufacturing and controls; nonclinical; and clinical knowledge. Different factors may affect the “scientific soundness” of reusing existing knowledge in each domain, the FDA indicated. For leveraged CMC knowledge, the agency explained that the similarities in the molecular structure of a product and its manufacturing process could influence the soundness of leveraging the prior knowledge. Similarities in product, formulation and therapeutic mechanism could correspondingly change the soundness of repurposing existing nonclinical data. For clinical data, the sameness of the disease, trial phase and regulatory purpose might affect the FDA’s assessment of the soundness of leveraging prior knowledge.
• The draft guidance describes four ways in which a sponsor might repurpose prior clinical data. Sponsors can leverage data for trial design, or to inform trial conduct and analysis; they might use data from natural history studies and real-world evidence; or they might turn to existing data to inform long-term follow-up studies. In all cases, sponsors should “consider how the characteristics of the platform technology may impact the clinical evaluation of the product.” The agency’s advice is most specific in cases when a sponsor might use prior data for trial design or conduct and analysis. In designing a study, a sponsor could rely on past results to select dose-limiting toxicity definitions or duration of monitoring, for example. Prior clinical pharmacology work can also inform how a sponsor assesses biodistribution or immunogenicity. When conducting a study, sponsors can use existing knowledge can reduce the data collected for purposes of establishing safety, efficacy, pharmacokinetics or drug-drug interactions “as appropriate based on whether there are expected clinical differences.”

Stakeholders seek broadening of guidance to modalities beyond genome editing

• The FDA received substantive feedback on its draft guidance for leveraging prior knowledge. Thirty groups and individuals commented, including major medical centers such as City of Hope and University of Pennsylvania Health System, large pharmaceutical companies such as AstraZeneca, biotechnology firms such as Tessera Therapeutics, and trade groups including PhRMA and BIO.
• Stakeholders supported the FDA’s efforts to support greater use of prior knowledge, describing the guidance as both needed and useful. “We believe this guidance represents an important step toward reducing unnecessary duplication of data generation, increasing regulatory efficiency, and facilitating timely patient access to innovative cell and gene therapies,” wrote BIO. However, many urged the agency to more explicitly broaden the guidance beyond genome editing products and to make clear how it connects with related regulatory frameworks, such as the plausible mechanism guidance. Others sought additional examples, case studies and templates that could help them evaluate when leveraging is appropriate. Stakeholders were specifically interested in risk-based frameworks that could inform their assessment of whether products or their components are sufficiently similar to permit leveraging. And some asked the FDA to clarify whether prior knowledge could be leveraged across an individual product’s life cycle, rather than across separate products.
• While the draft guidance indicates that its recommendations could apply widely, stakeholders wanted more specific assurance that prior knowledge could be leveraged across types of cell and gene therapy that don’t incorporate genome editing. “The guidance would hold greater value, however, if it applied more broadly across cell and gene therapy modalities,” wrote the American Society of Gene and Cell Therapy. “Limiting the guidance to one technology reduces the potential value of the framework to the broader CGT field and could lead to the need for additional modality-specific guidance documents addressing the same underlying regulatory principles.” Flagship Pioneering, a venture firm that has backed dozens of biotechnology companies, made a similar argument, noting that broadening the guidance’s scope would help ensure it stays relevant as new cell and gene therapy modalities are developed. Several groups, such as the Pediatric Inclusion Alliance, noted that the section of the PDUFA VII commitment letter that tasked the FDA with developing this guidance references cell and gene therapy broadly, rather than genome editing specifically.
• Stakeholders also asked the FDA to clarify the relationship between the draft guidance and its prior recommendations on the plausible mechanism framework and the platform technology designation. In comments and press statements, the FDA has, in fact, linked its leveraging prior knowledge and plausible mechanism guidances. The prior knowledge guidance provides “the scientific tools and data-sharing strategies that allow sponsors to efficiently establish the evidentiary foundation” required by the plausible mechanism approach, the agency said in a June 2 statement. By contrast, the FDA distinguished its use of “platform knowledge” in this new draft guidance from its platform technology designation, which it said is not required to leverage prior knowledge. “Consistency of principle across these guidances would enhance their combined value, affording developers regulatory predictability across diverse programs and stages of development,” wrote Flagship. BIO and PhRMA, meanwhile, asked the FDA to explain how platform knowledge and platform technologies differ, given the similarity in description between the two. “The use of highly similar terminology for potentially different concepts risks creating confusion regarding the circumstances under which sponsors may leverage prior knowledge and the benefits associated with each framework,” wrote PhRMA.
• The draft guidance recommends that sponsors assess similarities between products and processes when assessing the scientific soundness of leveraging prior knowledge. Stakeholders sought more information on how they should make such assessments, however. Tessera Therapeutics, a biotech developing a therapeutic editing method it describes as “gene writing,” asked the FDA to “provide a structured, risk-based framework for evaluating whether products, components, processes, or methods are sufficiently similar to support leveraging.” PhRMA proposed much the same, so sponsors could determine “when prior knowledge is sufficient to support full reliance, when targeted bridging data should be generated, and when de novo data generation remains necessary.” AstraZeneca, whose comments were authored by former FDA cell and gene therapy regulator LOLA FASHOYIN-AJE, encouraged the FDA add a “brief set of minimum considerations for establishing platform similarity.”
• Sponsors should also be permitted to base their assessment of similarity within specific product contexts, or between product components, a few stakeholders recommended. “Similarity assessments should be considered in the context of the specific inference being supported, rather than framed as a binary determination of whether two products are broadly similar or dissimilar,” wrote Friends of Cancer Research. As an example, Friends noted that two products may differ enough to limit leveraging on dependent attributes, such as potency, but remain sufficiently similar to leverage analytical methods or manufacturing controls. City of Hope, a cancer treatment and research organization based in California, encouraged the FDA to make the guidance modular, allowing prior knowledge leveraging across well-characterized attributes rather than entire products. “The relevant question should not always be whether two products are globally ‘the same’” or ‘similar enough,’ but whether the specific prior knowledge being relied upon remains scientifically applicable to the unchanged components, processes, or product attributes,” City of Hope wrote.
• While the guidance outlines how sponsors can leverage prior knowledge between related products, it has comparatively less to say on leveraging throughout a single product’s life cycle. Doing so “may be possible,” the FDA wrote, “as product specific experience and knowledge in the field is gained.” Numerous stakeholders asked the FDA for further clarity on this point. “BIO believes the final guidance would be strengthened by explicitly discussing how prior knowledge may be applied throughout the entire product lifecycle, including post-approval as it currently focuses primarily on product development,” wrote the trade group. Post-approval leveraging could be especially useful on the manufacturing front, added PhRMA, such as “to support manufacturing changes, comparability assessments, updated release criteria and lot release specifications, process optimization, scale-up, technology transfers, and site changes.” ASGCT, the Alliance of Regenerative Medicine and the Personalized Medicine Coalition similarly sought fuller descriptions of how prior knowledge could be used across a product’s life cycle.
• Several stakeholders used their input as opportunity to petition the FDA to change its long-standing rules limiting the use of drug master files, or DMFs, within Biologics License Applications. Sponsors are not currently allowed to reference in BLAs “drug substance, drug substance intermediate, or drug product information contained in a master file” – a stance the agency affirmed in the draft guidance. ASGCT, PhRMA and the Alliance for mRNA Medicines all asked the FDA to reconsider its DMF restrictions for BLAs. “Requiring third-party platform information to be provided directly in each BLA limits the practical ability to leverage proprietary knowledge throughout the product lifecycle and may result in duplicative submissions and regulatory review,” wrote ASGCT. City of Hope, meanwhile, proposed that the FDA set up a different kind of master file, through which different investigators within the same center could cross-reference “institutionally controlled prior knowledge.” And the Cystic Fibrosis Foundation proposed a mechanism “akin to DMFs” that would permit non-industry stakeholders to “submit leverageable technical and scientific data for use by multiple sponsors.”

Analysis

• The collective feedback shows that stakeholders view this guidance as a powerful tool to aid development. Leveraging prior knowledge offers a path for developers to spend less time and money collecting duplicative data that the FDA needs to similarly expend time and staff resources to review. This could be especially meaningful in manufacturing, where cell and gene therapy development time and again gets hung up. “Applied correctly, these principles would meaningfully reduce the time and cost of bringing new medicines forward,” wrote Flagship, which helped build the cell and gene therapy developers Tessera, Editas Medicine and Sana Biotechnology, along with dozens of other biotechs. The shared feedback urging the FDA to broaden the scope of the guidance similarly indicates the potential that stakeholders see for efficiency gains from prior knowledge leveraging.
• Stakeholders appear to be largely on the same page in their feedback. Agreement between groups that share members isn’t entirely unexpected, but the level of concordance is striking. No stakeholder raised major objections to the general direction or purpose behind the guidance, while many of those commenting sought to push the FDA in the same direction. Stakeholders were generally aligned on asking the FDA to broaden the guidance to cover other modalities, for instance, as they were in asking for risk-based assessment frameworks, more detail on leveraging across product life cycles and more flexibility in use of drug master files. This was true of drugmakers as well as trade and patient associations. The Cure Coalition, an advocacy group that says it advocates for U.S. biomedical research, struck the most cautious note, writing that prior knowledge should be used only as a tool, rather than a substitute for adequate evidence.
• The FDA’s challenge is drawing appropriate boundaries around leveraging of prior knowledge. While the agency acknowledged the potential for its draft guidance to apply beyond human genome editing, it noted that “additional considerations may also apply to these related product types, based on the specific product and manufacturing process, that are beyond those recommended in this guidance.” Stakeholders want the FDA to go further and explicitly extend its leveraging recommendations to a cell and gene therapy field that’s ever expanding to new modalities. The agency’s decision to draw the guidance rather tightly around genome editing – even as the relevant PDUFA VII commitment referenced cell and gene therapy overall – may reflect caution in opening up opportunities for data reuse across widely disparate product types. The FDA faces a similar challenge in finalizing its plausible mechanism guidance, which focused on gene editing and antisense oligonucleotides, but also drew comments urging modality-agnostic revisions. [Read AgencyIQ’s full analysis of comments on that document here.] A few commenters recommended that the FDA ensure the leveraging prior knowledge guidance directly support or reference the plausible mechanism framework, which could mean expanding it to include antisense oligonucleotides.
• Genome editing’s rapid advances could pressure any regulatory architecture the FDA sets up. The draft guidance uses a definition of human genome editing that’s circumscribed to somatic cells but applicable to both nuclease-dependent and nuclease-independent technologies. Still, the FDA received comments seeking clarification of whether its recommendations would apply to newer editing techniques, such as multiplex editing. The guidance is “largely structured around single gRNA and single-locus comparisons,” wrote Breakthrough T1D. “We recommend FDA clarify how comparability, off-target, and genomic integrity leveraging determinations should be made when a product edits multiple loci simultaneously.”
• Comments indicate there’s confusion about the platform technology designation. Created through the Consolidated Appropriations Act, 2023, the designation is meant to aid development of multifunctional platforms where different drug products are made, at least in part, using shared or parallel technology. The FDA issued draft guidance outlining its thinking in May 2024 but to AgencyIQ’s knowledge has only designated two platform technologies since – one of which it later withdrew. [Read AgencyIQ’s analysis of the program here.] Platform knowledge, as defined in the draft guidance on leveraging prior knowledge, refers to “well-understood and reproducible technology,” which also happens to be the language used to describe a platform technology in the statute establishing the designation. Yet the draft guidance on leveraging prior knowledge disclaims any direct connection. “BIO recommends that FDA more clearly distinguish these concepts through consistently applied terminology and definitions,” wrote the trade group. PHILIP KURS, an associate director of policy at Center for Biologics Evaluation and Research, previously gave some hint as to why at the Food & Drug Law Institute’s annual conference in May. “We spent a lot of time on the platform technology designation program guidance, but we were limited in that guidance with the statutory parameters of how the program worked, whereas we have more flexibility in this leveraging prior knowledge guidance to cover other scenarios where we think leveraging prior knowledge can be helpful.”
• What’s next? The PDUFA VII commitment letter tasks the FDA to “work towards the goal of publishing final guidance within 18 months after the close of the comment period” on the draft, though the substantive feedback could mean the FDA pursues revisions rather than finalization.

To contact the author of this item, please email Ned Pagliarulo ( npagliarulo@agencyiq.com).
To contact the editor of this item, please email Jason Wermers ( jwermers@agencyiq.com).

Key documents and dates

• Draft guidance: Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing (published June 2, 2026)
• Docket: FDA-2026-D-1257 (comment period closed Sept. 1, 2026)

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