--- title: "Gene-Edited Therapies in the EU: What EMA Asks for on Off-Target Editing" description: What EMA's guidelines ask for on off-target editing of gene-edited therapies, plus the hospital exemption, the pending pharma package and GDPR, from the primary texts. image: https://www.countagen.com/hubfs/blog-figures/Hero_EU.png --- [![Logo\_horizontal\_colored logo with black text](https://www.countagen.com/hubfs/Logo_horizontal_colored%20logo%20with%20black%20text.png)](https://www.countagen.com/) - [Technology](https://www.countagen.com/technology) - [Bioinformatics](https://www.countagen.com/bioinformatics) - [Sample Report](https://www.countagen.com/lockseq-sample-report) - [Resources](https://www.countagen.com/resources) - [FAQ](https://www.countagen.com/faq) - [About Us](https://www.countagen.com/about-us) [Request a quote](https://www.countagen.com/contact) Regulatory # Gene-Edited Therapies in the EU: What EMA Asks for on Off-Target Editing What EMA's guidelines ask for on off-target editing of gene-edited therapies, plus the hospital exemption, the pending pharma package and GDPR, from the primary texts. [Countagen Team](https://www.countagen.com/countagen-insights/author/countagen-team) Oct 15, 2026 --- The EU has no single rulebook for genome editing. Its expectations for off-target studies sit in two EMA scientific guidelines, which apply within binding EU law on advanced therapies and clinical trials. EMA has also committed to new genome-editing guidance, with drafting starting in 2026. Here is what the current texts actually say. ![Timeline of EU rules for gene-edited therapies, 2008 to 2026](https://www.countagen.com/hs-fs/hubfs/blog-figures/EUFig1_Timeline.png?width=1200&name=EUFig1_Timeline.png) ## The legal frame EMA's guidance on gene-modified cells is read together with the EU's regulation on advanced therapy medicinal products (ATMPs), Regulation (EC) No 1394/2007, which has applied since December 30, 2008 (Art. 30). Clinical trials follow the Clinical Trials Regulation (EU) No 536/2014, in application since January 31, 2022: - The application dossier includes an investigational medicinal product dossier with quality and non-clinical data (Art. 25, Annex I). - Participants don't pay for the investigational product or protocol procedures unless national law says otherwise (Art. 92). - Gene therapy trials that would modify a participant's germ line are not allowed (Art. 90). Neither regulation mentions genome editing or off-target effects. The technical detail is in EMA guidance, which is not legally binding. ## What EMA asks for: cells edited outside the body ![What EMA guidance asks for on off-target editing of genome-edited cells](https://www.countagen.com/hs-fs/hubfs/blog-figures/EUFig2_EMA_OffTarget.png?width=1200&name=EUFig2_EMA_OffTarget.png) The most detailed text is EMA's guideline on medicinal products containing genetically modified cells (Revision 1, effective June 1, 2021). It covers cells modified with genome-editing tools and names CRISPR-Cas, zinc finger nucleases and TALENs (§1–2). Its requirements relate to marketing authorization applications, but it says the principles may apply to development stages (§2). Its characterization section (§4.3) describes two steps: - **Find candidate sites.** Off-target changes "should be identified using at least one sensitive and well-characterized experimental assay" in the therapeutic cell type or a surrogate such as healthy donor cells. In silico screening with bioinformatics tools is also expected. - **Check them.** The candidate sites "should then be interrogated by deep-sequencing (or other appropriate technique) in the actual cell type to be used therapeutically", treated with the proposed protocol and nuclease expression level or dose. The same section asks for sensitivity and quality controls to be discussed, "particularly for negative results." Large deletions, chromosomal translocations and other large-scale changes should be accounted for, based on the edits verified in treated cells. Where starting material differs between batches, as with autologous cells, differences in off-target effects should be evaluated. Elsewhere in the guideline: - Off-target modifications should be addressed in process development, with a risk assessment for manufacturing (§4.2.2). - The persistence of editing tools in the cells should be evaluated. Ideally, none remain when the cells are released (§4.3.2). - The need to test each batch for on- and off-target modifications is decided case by case (§4.4). The non-clinical section (§5.3) adds that prediction may include in silico analysis, but the strategy "should also include an unbiased genome-wide evaluation of off-target activity in vitro." The sensitivity of the methods should be stated. Sponsors should also consider how species, cell state and cell type affect how predictive the data are. The guideline describes these product-class recommendations as "points for consideration rather than prescriptive guidance." ## Before first-in-human EMA's guideline for investigational ATMPs in clinical trials (EMA/CAT/22473/2025, effective July 1, 2025) applies to clinical trial applications. It covers both delivery routes: - **Ex vivo:** editing efficiency and off-target editing should be evaluated by in vitro and in silico methods. Cells should also be analyzed for large DNA-fragment inversions, deletions, duplications or chromosomal rearrangements (§4, S.3.1). - **In vivo:** in silico and in vitro analyses should evaluate possible off-target edits, especially those that could affect regulatory elements or gene sequences with a biological impact (§4, S.3.1). Off-target effects are listed under genotoxicity in the minimum non-clinical data expected before first-in-human studies (§5.6). The guideline also says that for genome editing, "the experience is too limited to provide detailed guidance" (§1). ## One authorized example When EMA's human medicines committee recommended Casgevy (exagamglogene autotemcel) for conditional marketing authorization in December 2023, it described it as "the first medicine using CRISPR/Cas9, a novel gene-editing technology." Its assessment report shows how one off-target package was built (§2.5.4.3): - **Nomination:** in silico homology searches, extended to common genetic variants from the 1000 Genomes Project, plus GUIDE-seq. - **Confirmation:** hybrid capture sequencing, which uses probes to enrich the candidate regions. The detection threshold went down to 0.2% at more than 10,000× coverage. - **Cells:** healthy-donor cells, patient cells and 7 process qualification lots. No off-target editing was confirmed. The report describes one product's data; it is not guidance. ## What the texts don't mention Full-text searches of both EMA guidelines find no mention of whole-genome sequencing, population genetic variation, amplification bias or biological replicates. Neither sets a numeric sensitivity threshold. ## What's changing The 2026 work plan of EMA's Committee for Advanced Therapies (CAT) lists a reflection paper on in vivo gene editing and a concept paper to revise the genetically modified cells guideline for cells edited outside the body, following a September 2025 workshop. The EU's pharmaceutical package is also close to adoption. The Council adopted its position on September 28, 2026, and Parliament's vote is still to come. For clinical trials with products that contain genetically modified organisms, the sponsor would submit one environmental risk assessment in the EU portal, assessed by EMA's CHMP, and the national release procedures of Directive 2001/18/EC would no longer apply (new Art. 5a of the Clinical Trials Regulation). Neither act mentions genome editing or off-target effects. ## The hospital exemption ![Clinical trials and the hospital exemption under EU law](https://www.countagen.com/hs-fs/hubfs/blog-figures/EUFig3_Trial_vs_HospitalExemption.png?width=1200&name=EUFig3_Trial_vs_HospitalExemption.png) EU law exempts an ATMP "prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital" for an individual patient (Directive 2001/83/EC, Art. 3(7)). A national authority authorizes the manufacturing. The pharmaceutical package would add notification of each approval to EMA and at least yearly reporting of use, safety and efficacy data (new Directive, Art. 3). ## Genetic data The General Data Protection Regulation (GDPR) treats genetic data, including data from analyzing a biological sample, as a special category of personal data (Art. 4(13), Art. 9). Transfers outside the EU need an adequacy decision, appropriate safeguards or a specific derogation (Arts. 44–49). Member States may add their own conditions for genetic data (Art. 9(4)). ## The net effect EMA's texts describe candidate sites found with an experimental assay plus in silico screening, then checked by deep sequencing or another appropriate technique in the cells used in patients. New guidance for both delivery routes is being drafted. If you're planning an off-target package for an EU program and want to talk through the confirmation step, [get in touch](https://www.countagen.com/contact). ### Sources - Regulation (EC) No 1394/2007 on advanced therapy medicinal products — [data.europa.eu](https://data.europa.eu/eli/reg/2007/1394/oj) - Regulation (EU) No 536/2014 on clinical trials — [data.europa.eu](https://data.europa.eu/eli/reg/2014/536/oj) - Directive 2001/83/EC, Art. 3(7) — [data.europa.eu](https://data.europa.eu/eli/dir/2001/83/oj) - EMA, Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells, EMA/CAT/GTWP/671639/2008 Rev. 1 – corr (effective June 1, 2021) — [ema.europa.eu](https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-and-clinical-aspects-medicinal-products-containing-genetically-modified-cells-revision-1_en.pdf) - EMA, Guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials, EMA/CAT/22473/2025 (effective July 1, 2025) — [ema.europa.eu](https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal-products-clinical-trials_en.pdf) - EMA, Meeting highlights from the CHMP, December 11–14, 2023 — [ema.europa.eu](https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-11-14-december-2023-0) - EMA, Casgevy public assessment report, EMA/6332/2024 — [ema.europa.eu](https://www.ema.europa.eu/en/documents/assessment-report/casgevy-epar-public-assessment-report_en.pdf) - EMA, Committee for Advanced Therapies work plan 2026, EMA/CAT/353549/2025 — [ema.europa.eu](https://www.ema.europa.eu/en/documents/work-programme/committee-advanced-therapies-cat-work-plan-2026_en.pdf) - Council of the EU, press release on the pharma package, September 28, 2026 — [consilium.europa.eu](https://www.consilium.europa.eu/en/press/press-releases/2026/09/28/pharma-package-council-adopts-new-rules-for-a-fairer-and-more-competitive-eu-pharmaceutical-sector/) - Council position at first reading: Regulation (ST 7105/26) — [data.consilium.europa.eu](https://data.consilium.europa.eu/doc/document/ST-7105-2026-INIT/en/pdf) · Directive (ST 7106/26) — [data.consilium.europa.eu](https://data.consilium.europa.eu/doc/document/ST-7106-2026-INIT/en/pdf) - Regulation (EU) 2016/679 (GDPR) — [data.europa.eu](https://data.europa.eu/eli/reg/2016/679/oj) [Regulatory](https://www.countagen.com/countagen-insights/tag/regulatory) [Off-Target Confirmation](https://www.countagen.com/countagen-insights/tag/off-target-confirmation) ## Similar posts FDA Guidance ### [Off-Target Studies for Gene-Edited Therapies: FDA, the EU and China](https://www.countagen.com/countagen-insights/fda-vs-china-cde-off-target-studies) Countagen Team Oct 15, 2026 Regulatory ### [China's New Rules for Cell and Gene Therapy: What Changed in 2026](https://www.countagen.com/countagen-insights/chinas-new-rules-for-cell-and-gene-therapy-what-changed-in-2026) Countagen Team Oct 15, 2026 FDA Guidance ### [What FDA's April 2026 Draft Guidance Means for Off-Target Confirmation](https://www.countagen.com/countagen-insights/fda-april-2026-guidance-off-target-confirmation) Countagen Team Sep 15, 2026 ### Get notified on blog articles and insights Be the first to know about new LockSeq insights and related articles. 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