Genetically Modified Organisms-Based Advanced Therapy Medicinal Products

Introduction

The development of Advanced Therapy Medicinal Products (ATMPs) based on Genetically Modified Organisms (GMOs) raises complexity and regulatory issues from the Research & Development phase, especially at the stage of clinical trials. Two of them are particularly important. On the one hand, two different sets of European Union (EU) legislation have to be implemented: the legislation on GMOs and/or on Genetically Modified Micro-organism (GMM), and the legislation on clinical trials. On the other hand, there are discrepancies across the EU as regards as the application of modified organisms’ rules: implementation of the GMOs deliberate release and/or the GMM contained use frameworks differently in national Member States.

These issues are increased as EU modified organisms’ rules have been adopted for plants and not appropriately for human cells. In addition, the clinical trials regulation is not addressing specifically the environmental aspects notably regarding the Clinical Trials Information System (CTIS).

Nevertheless, several Member States have endorsed common positions to facilitate the conduct of clinical trials of ATMPs containing or consisting of GMOs. This is based on a Questions & answers document, Good Practice documents and common application forms published on the European Commission’s website. In that context, the assessment of GMO-related aspects regarding clinical trials with Adeno-Associated Virus (AAV) clinical vectors, with human cells genetically modified by means of viral vectors, and the evaluation of shedding from oncolytic viruses have been targeted. Moreover, a repository of national regulatory requirements for medicinal products containing GMOs has been established.

While these supporting works have been developed on a voluntary cooperation basis from Member States, the new framework for clinical trials that came into application in 2022 does not resolve the problem and has failed in providing a practical and efficient solution for GMO-ATMPs. There is no functionality for national GMO submissions via the CTIS, and the coordinated authorisation of clinical trials and Environmental Risk Assessment (ERA) that was available in some Member States has become futile. Stakeholders are thus calling for simplification of GMO requirements for investigational medicinal products in clinical trials.

However, ongoing changes in EU law provide opportunities to facilitate the development of ATMPs containing or consisting of GMOs in solving these issues at the EU legislative level. First, the current revision of the EU pharmaceutical legislation proposes to transfer the ERA evaluation to the European Medicines Agency (EMA) via the Committee for Medicinal Products for Human Use (CHMP). Second, the more recent proposal for a European Biotech Act proposes that certain categories of advanced investigational therapy medicinal products that consist or contain GMOs which present no or negligible risks to human health and the environment, should be exempted from the requirement to submit an environmental risk assessment as well as from the GMO related requirements of the regulation on clinical trials (Regulation (EU) No 536/2014) regarding manufacturing and import.

Moreover, it should be highlighted that for medicines based on modified organisms (GMOs or GMMs) to be made accessible via early or compassionate use schemes as well as for exempted ATMPs, national rules implementing the EU modified organisms’ legislations are applicable. The potential regulatory issues are particular to each Member State and depend on their combination of national rules relating to early or compassionate use or exempted ATMPs, and to GMOs.

Regarding Marketing Authorisation of GMO-based ATMPs by the EC, several ATMPs that are based on or contain GMOs have been authorised by the European Commission (EC). According to the EMA Committee for Advanced Therapies quarterly highlights and approved ATMPs as of 23 May 2025, examples include gene therapy and cell therapy products such as ‘Glybera’, ‘Strimvelis’, ‘Zalmoxis’, and ‘Imlygic’, all of which involve genetically modified cells or viral vectors. The EU’s regulatory framework for ATMPs, established by Regulation (EC) No 1394/2007, has enabled the approval of these innovative therapies.

As of end of July 2025, ‘Vyjuvek’ (beremagene geperpavec) remains the most recently approved GMO-based ATMP by the EC on 23 April 2025. This medicine is a combined ATMP, intended for patients with dystrophic epidermolysis bullosa. It was designated ‘Orphan medicine’ (a medicine used in rare diseases) and was granted eligibility to the EMA Priority Medicines (PRIME) scheme during its development. More information on Vijuvek’s EMA authorisation here and here.

Another GMO-based ATMP, Aucatzyl (obecabtagene autoleucel), received in May 2025 a positive opinion from the CHMP of a conditional marketing authorisation, and the formal marketing authorisation has been granted by the EC on 17 July 2025. More information on Aucatzyl’s EMA authorisation here.

Main Actors

‘user’ means any natural or legal person responsible for the contained use of GMMs (Article 2(e) of Directive 2009/41/EC)

‘notifier’ means the person submitting the notification; (Article 2 (6) of Directive 2001/18/EC)

National Competent Authority (NCA) is an authority related to state’s power (such as a ministry or an agency for example) in charge of authorising and controlling establishments or other bodies, their activities and products. In the context of GMO-based ATMPs, (and under Directive 2001/18/EC and Directive 2009/41/EC), NCAs are in charge of the following: 

  • Evaluation of Risk Assessment: evaluation of ERA submitted by the user or notifier, ensuring that GMO use does not adversely affect human health or the environment  (Article 4 of Directive 2009/41/EC and Article 6 of Directive 2001/18/EC);
  • Authorisation or written consent of the contained use or deliberate release of GMOs based on scientific and regulatory criteria;
  • Ensuring compliance with EU directives (including through inspections), especially safety measures (Article 16 of Directive 2009/41/EC and Article 4.5 of Directive 2001/18/EC);
  • Coordination with EU bodies as the national contact point for communication with the EC, the EMA, and other Member States.

Environmental Authorities are responsible for assessing and managing the potential environmental risks posed by the contained use or deliberate release of GMOs in GMO-based ATMPs. Under Directive 2001/18/EC (Article 4.4 and 6) and Directive 2009/41/EC (Article 4), these authorities evaluate ERAs submitted by developers or users to prevent adverse effects on environment and human health. They oversee monitoring plans, risk management measures, and post-release surveillance to ensure ecological safety. Coordination with NCA or EMA ensures comprehensive oversight of GMO-based ATMPs, balancing innovation with environmental protection.

Manufacturer: The legal entity manufacturing GMO-based ATMPs responsible for the development, and production of the medicines. This entity undertakes the genetic engineering processes required to create GMOs or cells, ensuring that the GMO-based ATMP meets stringent quality, safety, and efficacy standards, complying with EU quality GMP for ATMPs and European pharmacopeia. The manufacturer must prepare comprehensive dossiers for regulatory submissions, including detailed information on manufacturing processes, risk assessments, and environmental safety. 

More information on Manufacturing Authorisation of ATMPs | EuroGCT

Sponsor: The legal entity who takes responsibility for the initiation, management and financing of a clinical trial involving GMO-based ATMPs. It is in relation to and cooperates with the manufacturer to ensure that the manufacturing sites, manufacturing processes and quality control comply with GMP for investigational ATMPs and the European Pharmacopeia. The sponsor’s role in clinical trials involving GMO-based ATMPs extends beyond traditional pharmaceutical oversight to encompass environmental risk governance and multi-layered regulatory coordination.

See also Clinical trials | EuroGCT

Ethics Committees: Ethics Committees’ role is to verify that the research protocol of the clinical trials complies with all ethics principles. Ethics Committees are independent national or local bodies established by Member States in accordance with their national law and empowered to give opinions for the NCAs to authorise or not the start of clinical trials. In the context of clinical trials of GMO-based ATMPs, Ethics Committees face additional complexities related to the risks associated with GMOs, including potential long-term effects and environmental considerations.

See also Clinical trials | EuroGCT

Definitions

‘micro-organism’: “any microbiological entity, cellular or non-cellular, capable of replication or of transferring genetic material, including viruses, viroids, and animal and plant cells in culture”. (Article 2(a) of Directive 2009/41/EC)

‘genetically modified micro-organism’ (GMM): “a micro-organism in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination; within the terms of this definition:

  1. genetic modification occurs at least through the use of the techniques listed in Annex I, Part A;
  2. the techniques listed in Annex I, Part B, are not considered to result in genetic modification”. (Article 2(b) of Directive 2009/41/EC)

‘contained use’: “any activity in which micro-organisms are genetically modified or in which such GMMs are cultured, stored, transported, destroyed, disposed of or used in any other way, and for which specific containment measures are used to limit their contact with, and to provide a high level of safety for, the general population and the environment”. (Article 2(c) of Directive 2009/41/EC)

‘organism’: “any biological entity capable of replication or of transferring genetic material”. (Article 2 (1) of Directive 2001/18/EC)

‘genetically modified organism (GMO)’: “an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination;

Within the terms of this definition:

(a) genetic modification occurs at least through the use of the techniques listed in Annex I A, part 1;

(b) the techniques listed in Annex I A, part 2, are not considered to result in genetic modification”. (Article 2 (2) of Directive 2001/18/EC)

‘deliberate release’: “any intentional introduction into the environment of a GMO or a combination of GMOs for which no specific containment measures are used to limit their contact with and to provide a high level of safety for the general population and the environment”. (Article 2 (3) of Directive 2001/18/EC)

‘placing on the market’: “means making available to third parties, whether in return for payment or free of charge;

The following operations shall not be regarded as placing on the market:

  • making available genetically modified microorganisms for activities regulated under Council Directive 90/219/EEC of 23 April 1990 on the contained use of genetically modified microorganisms ( 1 ) including culture collections,
  • making available GMOs other than microorganisms referred to in the first indent, to be used exclusively for activities where appropriate stringent containment measures are used to limit their contact with and to provide a high level of safety for the general population and the environment, the measures should be based on the same principles of containment as laid down in Directive 90/219/EEC,
  • making available GMOs to be used exclusively for deliberate releases complying with the requirements laid down in part B of this Directive”. (Article 2 (4) of Directive 2001/18/EC)

‘notification’: “the submission of the information required under this Directive to the competent authority of a Member State”. (Article 2 (5) of Directive 2001/18/EC)

‘product’: “a preparation consisting of, or containing, a GMO or a combination of GMOs, which is placed on the market”. (Article 2 (7) of Directive 2001/18/EC)

‘environmental risk assessment’: “the evaluation of risks to human health and the environment, whether direct or indirect, immediate or delayed, which the deliberate release or the placing on the market of GMOs may pose and carried out in accordance with Annex II.” (Article 2 (8) of Directive 2001/18/EC)

ERA is currently mandatory for a marketing authorisation application for ATMPs in the EU but this may change for certain ATMPs with the future European Biotech Act. The ERA ensures any potential risk to public health, third parties, or the environment is systematically identified, evaluated, and managed before GMO-based ATMPs can be developed or placed on the EU market.

Summary Notification and Information Form (SNIF): The SNIF form is a standardised summary that provides essential information about the deliberate release of GMOs in clinical trials. Its main function is to facilitate the sharing of information across all EU Member States and to ensure public transparency regarding environmental risks associated with medicinal products containing GMOs.

Challenges

1. GMOs-based ATMPs may raise environmental risks

They are mainly subject to an ERA procedure under Directive 2001/18/EC and 2009/41/EC. However, requirements of these directives do not take into account the specificities of medicinal products as they were adopted mainly for plants. This issue is increased at the clinical trials stage where compliance with these directives have been considered both complex and time-consuming regarding the ERA procedure and the authorization of clinical trials by NCAs. It is even more increased regarding multi-centres clinical trials conducted in several EU Member States. Indeed, sponsors of these clinical trials need to submit multiple requests for authorisation: authorisation prior to the start of a clinical trial and prior consent or notification for deliberate release into the environment or contained use of GMOs. These procedures depend often on different NCAs in one Member State and they need to be followed in the different Member States where the multi-centres clinical trials are conducted.

Moreover, there are discrepancies across the EU as regards as the application of GMO directives: “some Member States apply Directive 2001/18/EC, others apply Directive 2009/41/EC and there are Member States that apply either Directive 2009/41/EC or Directive 2001/18/EC depending on the specific circumstances of a clinical trial”.

(Recital 146 of Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006) – the Proposed Regulation - 

In the EU, an ERA is currently a mandatory part of both clinical trial and marketing authorisation applications for GMO-based ATMPs. The ERA systematically evaluates potential risks to human health and the environment from the use, handling, and disposal of GMO-based ATMPs, including the possibility of gene transfer, environmental shedding, or unintended exposure.

Under normal circumstances, the use of GMOs, including genetically modified viral vectors often used in vaccines, is subject to strict regulatory requirements under Directive 2001/18/EC and Directive 2009/41/EC. These include complex risk assessments and lengthy authorisation procedures, which could significantly delay clinical research, and in fine, patient access to medicines.

2. In 2020, the EU adopted a temporary derogation from its existing legislation on GMOs to facilitate the development and testing of COVID-19 treatments and vaccines in clinical trials

This measure was introduced in response to the urgent public health crisis caused by the COVID-19 pandemic, which required the rapid deployment of innovative vaccines and biomedical products. Recognising the need for speed and flexibility in a public health emergency, the European Parliament and the Council adopted Regulation (EU) 2020/1043 on 15 July 2020. This regulation introduced a temporary exemption from certain provisions of GMO legislation for clinical trials involving COVID-19 treatments or vaccines, while maintaining appropriate environmental and safety standards. The derogation provided that most operations related to the conduct of clinical trials will not require a prior ERA or consent. These operations include packaging and labelling, storage, transport, destruction, disposal, distribution, supply, administration or use of investigational medicinal products for human use containing or consisting of GMOs intended to treat or prevent COVID-19. The aim was to accelerate the approval process for clinical trials without compromising participant safety. This derogation demonstrates a willingness from the EU to balance public health imperatives with environmental protection and scientific caution.

The regulation explicitly states in Recital 17 that the derogation is temporary and "should be limited to clinical trials […] intended to treat or prevent COVID-19" and applies "for the duration of the COVID-19 pandemic or as long as COVID-19 is a public health emergency". On 5 May 2023, the World Health Organization officially declared the end of the COVID-19 public health emergency of international concern, and on 6 March 2024 the EC published a Notice stating that the conditions for the application of Regulation (EU) 2020/1043 were no longer fulfilled.

3. Medicinal products available for compassionate use and urgent situations

As mentioned in the above section, this regulatory approach acknowledges that in exceptional cases such as a pandemic like COVID-19 or life-threatening condition with no alternative treatment, accelerated access to innovative medicinal products may be critical.

Medicinal products containing or consisting of GMOs, under Directive 2001/18/EC and Directive 2009/41/EC require an ERA evaluation, a formal consent procedure, and a clinical trial authorisation before any such product can be authorised for clinical use or trial deployment. Thus, when medicinal products based on GMOs or GMMs are made available to patients through early access mechanisms like early or compassionate use programs, or as exempted ATMPs, they still must comply with the national laws that implement the EU’s GMO regulations in each country. As each EU Member State implements the overarching EU GMO rules through its own national regulations access to these medicinal products remains subject to national approval processes for environmental and health risks, notifications to NCAs, and potentially divergent requirements across countries, which can cause delays or differences in access among EU Member States.

To avoid these discrepancies, recital 54 of the Proposed Regulation of the EU pharmaceutical legislation reform explains that in exceptional and urgent situations, such as public health emergencies or compassionate use, Member States may temporarily authorise the use and supply of medicinal products containing or consisting of GMOs without requiring an ERA or consent under Directive 2001/18/EC or Directive 2009/41/EC. It notes that, in these cases, appropriate measures should still be taken to minimise environmental risks.

This principle is set out in the Article 7 of the Proposed Regulation which provides that Member States may allow the use and supply of unauthorised GMO medicines in response to individual patient needs, public health emergencies, or under compassionate use programmes, without the ERA being a prerequisite. In such cases, Member States must implement measures to “minimise foreseeable negative environmental impacts” resulting from the intended or unintended release of the GMO medicine. These measures, in line with the precautionary principle, may include ensuring the proper containment of GMOs during clinical use, establishing protocols to prevent unintentional environmental release, training personnel, and implementing post-use monitoring systems where applicable.

This balanced approach is based on complementary principles of EU law: the principle of proportionality, which allows regulatory requirements to be adjusted to the urgency and gravity of the public health threat, and the precautionary principle, which safeguards against environmental harm when scientific uncertainty remains. Together, they allow for a calibrated approach that balances the need for expedited access to health technologies with the protection of biodiversity and ecological systems.

4. Discrepancies between Member States in the implementation of EU GMO regulatory framework

These discrepancies constitute a significant obstacle to the development and placing on the market of GMO-based ATMPs in the EU. Although the existence of Directive 2001/18/EC on the deliberate release of GMOs and Directive 2009/41/EC on their contained use, the transposition of these directives into national law has led to substantial differences in administrative procedures, timelines, and requirements among Member States.

This fragmentation has serious implications for multinational clinical trials, which are often essential for generating robust clinical evidence and securing the marketing authorisation application. Indeed, sponsors of GMO-based ATMPs must frequently submit separate applications for ERAs to multiple NCAs, each with their own national procedures, documentation standards, and review timelines. This can create regulatory duplication and additional delays but also increases the administrative burden and cost of compliance for GMO-based ATMPs developer, particularly for small and medium-sized enterprises (SMEs) with limited resources.

For instance, differences in the classification of use of clinical trials with GMO-based ATMPs (deliberate release or contained use), and/or the involvement of environmental agencies when assessing GMO-based clinical trials, while others delegate the procedure solely to health authorities. Additionally, requirements for documentation and the format of ERA reports may vary significantly, forcing sponsors to adapt their submissions for each jurisdiction.

These discrepancies in the implementation of EU-GMO requirements are also evidenced by the absence of a centralised procedure for ERA authorisation at the EU level. While the EMA plays a key role in evaluating the quality, safety, and efficacy of ATMPs under the centralised marketing authorisation procedure, it has no authority over GMO-specific assessments, which remains under the responsibility of NCAs. (Please refer here for additional information on Member State’s policy)

5. Complex and costly Good Manufacturing Practice (GMP) Compliance for GMO-Based ATMPs:

A central regulatory challenge in the development of ATMPs, particularly those incorporating GMOs, is the strict requirement to comply with GMP standards. GMP compliance is essential to ensure product quality, safety, and consistency, imposing significant scientific, technical, and financial requirements on developers.

Under Regulation (EC) No 1394/2007 on ATMPs and Directive (EU) 2017/1572 laying down GMP requirements for medicinal products, all ATMPs must be manufactured in facilities that are authorised and regularly inspected by NCAs. This obligation applies equally to investigational ATMPs used in clinical trials, which must also meet GMP standards set by EU guidelines, including the EudraLex Volume 4, Part IV specific to ATMPs.

See also Manufacturing Authorisation of ATMPs | EuroGCT and Good Manufacturing Practice for ATMPs | EuroGCT

Regarding ATMPs containing or consisting of a GMO, they must comply with the same overarching EU GMP framework established for ATMPs. However, GMO-based ATMPs may require additional biosafety and containment measures as part of the risk-based GMP approach, reflecting the specific risks associated with GMOs.

Manufacturing sites must also comply with environmental protection laws, particularly Directive 2009/41/EC on the contained use of GMOs for GMO handling. This creates a twofold compliance obligation: one based on medicinal product regulation and another on environmental biosafety law, managed by different NCAs. These dual layered obligations result in increased production costs, extended timelines for patient access, and a high technical entry threshold, in particular for SMEs and academic research centers developing ATMPs in the establishment or access to a suitable facility both GMP certified and GMO compliant.

In addition, the lack of harmonisation in the interpretation and enforcement of GMP standards for GMO-based ATMPs across EU Member States adds further uncertainty. Indeed, despite the EMA and the Committee for Advanced Therapies’ guidance, NCAs retain discretion in inspections and approvals. This can result in variations in practice and delays in clinical trial or market access.

Thus, even if there is no separate GMP standard for GMO-based ATMPs, the practical application of GMP may be more complex, in particulars for SMEs, due to the unique risks raised by GMOs.

6. Logistical challenges in clinical trials and Product Distribution for GMO-Based ATMPs

The development and deployment of ATMPs containing or consisting of GMOs are also constrained by highly complex logistical challenges. These obstacles arise from the characteristics of ATMPs such as unique patient manufacturing, strict storage conditions and short shelf lives due to the use of living materials, which are further increased by GMO specific requirements relating to biosafety, traceability, and environmental containment.

ATMPs like autologous gene therapies or cell-based products, require individualised manufacturing for each patient. This involves the collection of cells or tissues from the patient, transport to a specialised GMP certified facility, which may be located in a different country, genetic modification often using viral vectors classified as GMOs, and subsequent re-transport of the medicine for administration to a patient. Each of these steps must occur under precisely controlled quality conditions.

When the medicine involves GMOs, additional biosafety constraints apply. The transport and storage must comply not only with pharmaceutical regulations but also with GMO handling laws derived from Directive 2009/41/EC or Directive 2001/18/EC, depending on whether the use is considered contained or deliberate. In this case, specific permits have to be obtained, packaging has to meet biohazard containment standards, and local environmental authorities must be notified or consulted.

This complexity significantly delays the initiation of clinical trials, particularly in multicenters, multinational studies, as sponsors must navigate differing national interpretations and implementation procedures of GMO related laws.

The distribution of the medicine is also affected as GMO-based ATMPs are rarely stored in standard pharmaceutical distribution centers. They often require direct shipment from manufacturer to hospital, under conditions that comply with both pharmaceutical and biosafety regulations.

The traceability and pharmacovigilance systems required for GMO-based ATMPs must accommodate not only patient-specific identifiers but also environmental monitoring data in some cases. It results in complex logistics not only in the physical handling of the medicine but also in data management, risk communication, and follow-up protocols.

Also, the presence of GMOs in ATMPs introduces additional regulatory layers for transport, unlike most conventional medicines. While most authorised medicines are exempt from dangerous goods transport rules, GMMs and GMO-based ATMPs may be regulated because the transport of GMOs and GMMs is specifically addressed in international and EU dangerous goods frameworks, such as European Agreement concerning the International Carriage of Dangerous Goods by Road (ADR) and Directive 2008/68/EC.

Each shipment must be assessed against dangerous goods criteria to determine if special packaging, labelling, and transport measures are required. This is because GMO products and related biological materials may pose risks to humans, animals, or the environment, triggering regulatory controls.

Therefore, even authorised GMO-based medicines and patient samples may need to comply with these additional transport requirements. This adds complexity and administrative steps compared to conventional authorised medicines.

Therefore, the logistical challenges inherent to GMO-based ATMPs imply multidisciplinary coordination between clinical teams, manufacturers, logistics and transports providers, biosafety officers, and regulatory authorities, which could imply a significant hurdle to both clinical development and patient access.

Opportunities and incentives

While each Member State has its own specific requirements, leading to significant variation and delays in clinical trial approvals, there have been concerted efforts to harmonise and facilitate the process across the EU. These efforts include:

  1. EMA Questions & Answers on GMO-based ATMPs: this document explains and clarifies how EU legislation on GMOs applies to ATMPs, especially for clinical trials. Its main use is to help developers, regulators and other stakeholders navigate the complex and fragmented regulatory landscape for GMO-based ATMPs across different Member States.
  2. EC Repository of National Requirements: The EC has created an online repository detailing national regulatory requirements for medicinal products containing GMOs, providing sponsors with clearer information and supporting more uniform application processes. This resource, providing easy access to the diverse regulatory requirements that exist across EU Member States for medicines, improves transparency, facilitates cross-border GMO-based ATMP development, and enhances patient access by helping stakeholders easily compare and comply with varying national rules throughout the EU. The country fiches in the document provide an overview of national regulatory requirements (EU countries and Norway). More information on Genetically Modified Organism (GMO) aspects for investigational medicinal products.
  3. Several Member States have endorsed common positions and engaged in coordinated actions aiming at streamlining the regulatory pathway for GMO-based ATMPs. It includes good practice documents and common forms on specific topics.

            3.1. In-vivo gene therapy:

            3.2 Genetically modified human cells:

  • Good Practice on the assessment of GMO-related aspects in the context of clinical trials with human cells genetically modified – 11/2021 - The guidance has been jointly developed by the EC and the competent authorities of the Member States responsible for the implementation of the legislation on clinical trials and of the GMO legislation. It has been endorsed by Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Portugal, Romania, Spain, Sweden and Norway.
  • Common Application form for clinical research with human cells genetically modified - This document has been endorsed by the NCAs in Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Portugal, Romania, Spain, Sweden and Norway.

            3.3. Evaluation of shedding of oncolytic viruses:

  • Oncolytic viruses: Considerations for the evaluation of Shedding – This document outlines the principles and practical requirements for assessing whether and how oncolytic viruses are released from treated patients into the environment. Its main use is to guide sponsors and regulators on how to systematically study, detect, and interpret shedding of oncolytic viruses as part of the ERA. The document has been endorsed by the NCAs of the following Member States: Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Portugal, Romania, Slovenia, Spain, Sweden and Norway.

Even if these common positions and collaborative measures do not yet fully harmonise GMO requirements across the EU, they represent significant steps toward reducing discrepancies, streamlining approvals, and facilitating multinational clinical trials of ATMPs containing or consisting of GMOs.

Although specific GMO requirements for ATMPs still vary by Member State, coordinated EU-level initiatives and the endorsement of common positions by several countries are gradually improving the regulatory landscape and facilitating the conduct of clinical trials across the EU.

  1. Reform of the EU Pharmaceutical legislation:

    The proposed new medicines Regulation and medicines Directive address the long-standing issues arising from the dual obligation to comply with both the GMO legislation and the medicinal products legislation for GMO-based ATMPs.

    Key proposals are as follows:

            4.1 Clinical trials of GMO-based ATMP:

Article 177 of the Proposed Regulation provides amendments to Regulation (EU) No. 536/2014 on clinical trials inserting a new Article 5a ‘Environmental risk assessment for investigational medicinal products for human use containing or consisting of genetically modified organism’:

  • 5a.1: The EC proposal calls for the integration of the GMO authorisation process into the CTIS for clinical trials involving GMO-based medicinal products: “Where the application according to Article 5 of this Regulation concerns clinical trials with investigational medicinal products for human use containing or consisting of genetically modified organisms (GMOs) […] the sponsor shall submit an environmental ERA in the EU portal (CTIS) as part of the application”.
  • 5a.3: Exemption of clinical trials of GMO medicines from the scope of the deliberate release Directive 2001/18/EC requirements. This means sponsors would no longer need to apply for and secure a separate authorisation for the deliberate release of GMOs for clinical trial purposes, which has been a major source of regulatory complexity and delay. “Articles 6 to 11 of Directive 2001/18/EC shall not apply to investigational medicinal products for human use containing or consisting of genetically modified organisms”.
  • 5a.4: Harmonisation of ERA requirement: instead of the current fragmented system, the proposals require that a sponsor submits an ERA with any clinical trial application for a GMO medicine. The ERA’s assessment will be conducted by the CHMP, ensuring that experts in human medicines, and not environmental authorities, assess the risks and more standardised and harmonised review steps in the future. “The Committee for Medicinal Products for Human Use (CHMP) referred to in Article 148 (revised Regulation No (EC) 726/2004) shall assess the ERA referred to in paragraph 1 in the form of a scientific opinion”.

            4.2 Centralised marketing authorisation of GMO-based ATMP

  • Article 7.1 of the Proposal for a regulation provides that marketing authorisation application of GMO- based medicines shall be accompanied by an ERA.
  • Article 8 of the Proposal for a regulation provides elements on the content of the ERA
  • Article 9 of the Proposal for a regulation describes the procedure for the environmental risk assessment for medicinal products containing or consisting of genetically modified organisms. ERA shall be submitted by the applicant to the EMA, and the CHMP will assess it. Article 9.2  also precises that the CHMP may consult national authorities for first-in-class products or when novel questions arise only, reducing unnecessary duplication and delays: “In case of first-in-class medicinal products or when a novel question is raised during the assessment of the submitted environmental risk assessment, the Committee for Medicinal Products for Human Use, or the rapporteur, shall, as necessary, carry out consultations with bodies Member States have set up in accordance with Directive 2001/18/EC”.
  • Article 7.3 of the Proposal for a regulation provides an exemption from Articles 13 to 24 of Directive 2001/18/EC.
  • Article 7.4 of the Proposal for a regulation provides an exemption from Articles 6 to 11 of Directive 2001/18/ECas well as Articles 4 to 13 of Directive 2009/41/EC regarding the supply and clinical use, including the packaging and labelling, distribution, storage, transport, preparation for administration, administration, destruction or disposal of GMO-based medicines. However, these articles apply to the manufacture of GMO-based medicines when they are prepared to fulfil special needs, or made available for compassionate use, or when Member States have temporarily authorise the use and distribution of an unauthorised GMO-based medicines.

           4.3 New definition for gene therapy medicinal products

  • Article 4.29 of the Proposal for a directive provides a new definition of gene therapy medicinal products which is included GMO-based medicines, especially gene-editing based medicines, more broadly.

    “‘gene therapy medicinal product’ means a medicinal product, except vaccines against infectious diseases, that contains or consists of:

    (a)a substance or a combination of substances intended to edit the host genome in a sequence-specific manner or that contain or consists of cells subjected to such modification; or

    (b)a recombinant or synthetic nucleic acid used in or administered to human beings with a view to regulating, replacing or adding a genetic sequence that mediates its effect by transcription or translation of the transferred genetic materials or that contain or consists of cells subjected to these modifications”.

  1. Proposal for a new European Biotech Act:

The proposal for a new European Biotech Act is also proposing changes regarding clinical trials of GMO-based ATMP.

Article 57.2 inserts a new article 4a in Regulation (EC) No 1394/2007 on ATMP in order to exempt from the requirement to submit an ERA, certain categories of advanced investigational therapy medicinal products that consist or contain GMOs which present no or negligible risks to human health and the environment. However, sponsors of clinical trials should, as part of the clinical trial application, submit a declaration explaining why the investigational ATMP concerned falls into one or more of the specific categories of products presenting no or negligible risks to human health and the environment. This declaration will be verified by the CHMP at the EMA.

These types of investigational ATMP are also exempted from the GMO related requirements of the regulation on clinical trials (Regulation (EU) No 536/2014) regarding manufacturing and import of GMO-based investigational ATMP.

Practical steps

  1. E-Submission Food Chain (ESFC) platform is a web-based application developed by the EC to streamline and centralise the submission, management, and tracking of applications for regulated products in the food chain within the EU. It is used by applicants to submit dossiers for obtaining EU authorisations, renewals, or modifications related to various food and feed products. The ESFC platform covers a wide range of regulated product areas, including GMOs.

    Since October 1, 2022, the ESFC platform is mandatory for submitting Summary Notification Information Format (SNIF) documents for clinical trials involving medicinal products composed of or containing GMOs, as required under Directive 2001/18 EC. The SNIF form is a standardised summary that provides essential information about the deliberate release of GMOs in clinical trials. Its main function is to facilitate the sharing of information across all EU Member States and to ensure public transparency regarding environmental risks associated with medicinal products containing GMOs.

    Before October 2022, SNIF forms were submitted together with the GMO application to the NCA in each Member State. Now, the SNIF must be submitted directly to the EC through the ESFC platform, while the rest of the GMO application is still sent to the NCA.

    The implementation of the ESFC platform implies for the sponsors:

  • Parallel processes: as submission of the SNIF through the ESFC platform is now a separate process from the submission of the main GMO application to NCAs, the order and requirements for these submissions can vary between Member States. For example, in Germany, proof of SNIF submission via ESFC must be included in the GMO application, while in Spain, the SNIF is first submitted nationally and then via ESFC after approval by the Ministry of Agriculture, Food and Fisheries.
  • Platform specific requirements: the SNIF form must be completed directly within the ESFC platform; it cannot be prepared offline and uploaded. This adds a layer of complexity for sponsors conducting multinational trials, who must now manage submissions in both the ESFC and national systems.
  • Change in responsibilities: any amendments to the clinical trial application affecting the SNIF must be managed through the ESFC platform, rather than by NCA.

More information on the ESFC platform here and there.

  1. CTIS & GMO-based medicines clinical trials: While under Regulation (EU) No. 536/2014, the CTIS is the entry single point for centralised submission, assessment, and management of clinical trial applications across the EU and European Economic Area, there is no specified procedure, nor structure for submission of a GMO application via CTIS.

    Indeed, “there is no specific training for GMO applications in relation to CTIS, as there are no specific requirements concerning GMO applications in the CTR. In practice, a sponsor needs to do one submission through CTIS, and one to each member state for the GMO aspects as applicable“. (Questions and answers – Clinical Trials Information System (CTIS) and Clinical Trials Regulation (CTR))

    In practice:

  • CTIS does not support submission of national GMO specific documents such as the ERA, the EU Common Application Form(s), or other national forms required by GMO competent authorities. These documents must still be submitted separately to each relevant NCA, outside the CTIS platform;
  • There is no coordinated or harmonised assessment of GMO documentation within CTIS. Each Member State continues to apply its own procedures and timelines for GMO authorisation, separate from the clinical trial application process in CTIS;
  • For clinical trials classified as deliberate release under Directive 2001/18/EC, the SNIF must be submitted via the ESFC platform, not via the CTIS.

In conclusion, the CTIS neither streamline nor centralise the GMO authorisation process as sponsors must still navigate separate national GMO procedures and use additional platforms limiting the practical utility of CTIS for GMO-based medicines clinical trials.

This situation could evolve as there is a proposal to integrate GMO authorisation into the CTIS as part of the ongoing EU pharmaceutical legislative review. The Mandate for negotiations with the European Parliament published by the Council of the EU on 2 June 2025 reflects this position: a single, centralised application for clinical trials involving GMO medicines would be possible, with the sponsor submitting a detailed ERA as part of the CTIS application.

Interactions with regulators

While ATMP regulation is centralised with the Centralised procedure for ATMPs via the EMA which offers especially scientific advice and protocol assistance, GMO regulation remains fragmented, requiring developers of GMO-based ATMPs to engage in multiple, parallel interactions with Member State authorities. See also Support for innovative medicines’ development at the EMA level.

Given that, interactions with regulators for sponsors or marketing authorisation applicants should be looking for at national level though each NCA. Early contact with NCAs is the best option to be aware and comply with national requirements on developing and placing on the market GMO-based ATMPs. (See here for additional information on Member State’s policy and national requirements)

Regarding the EMA, applicants intending to submit a marketing authorisation application for medicinal products that contain or consist of GMOs, and for which a specific ERA has not yet been developed, are strongly encouraged to engage with the EMA well in advance of submission (ideally 6 to 12 months prior). Where appropriate, applicants may also seek scientific advice on the ERA during the medicine development phase.

European Union Legislation

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67-128, CELEX number: 32001L0083.

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance), OJ L 136, 30.4.2004, p. 1-33, CELEX number: 32004R0726

Commission Regulation (EC) No 668/2009 of 24 July 2009 implementing Regulation (EC) No 1394/2007 of the European Parliament and of the Council with regard to the evaluation and certification of quality and non-clinical data relating to advanced therapy medicinal products developed by micro, small and medium-sized enterprises (Text with EEA relevance), OJ L 194, 25.7.2009, p. 7–10

Regulation (EU) 2020/1043 of the European Parliament and of the Council of 15 July 2020 on the conduct of clinical trials with and supply of medicinal products for human use containing or consisting of genetically modified organisms intended to treat or prevent coronavirus disease (COVID-19), OJ L 231, 17.7.2020, p. 12–16, CELEX number: 32020R1043

Notice from the Commission on the fulfilment of the conditions for the application of Regulation (EU) 2020/1043 of the European Parliament and of the Council on the conduct of clinical trials with and supply of medicinal products for human use containing or consisting of genetically modified organisms intended to treat or prevent coronavirus disease (COVID-19), C/2024/1379, OJ C, C/2024/1960, 6.3.2024

Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance), OJ L 242, 15.9.2009, p. 3–12, CELEX number: 32009L0120

Regulation (EC) No 1946/2003 of the European Parliament and of the Council of 15 July 2003 on transboundary movements of genetically modified organisms (Text with EEA relevance), OJ L 287, 5.11.2003, p. 1–10, CELEX number: 32003R1946

Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms (Recast) (Text with EEA relevance), OJ L 125, 21.5.2009, p. 75–97, CELEX number: 32009L0041

Commission Decision 2000/608/EC of 27 September 2000 concerning the guidance notes for risk assessment outlined in Annex III of Directive 90/219/EEC on the contained use of genetically modified micro-organisms (notified under document number C(2000) 2736) (Text with EEA relevance), OJ L 258, 12.10.2000, p. 43–48, CELEX number: 32000D0608

Commission Implementing Decision (EU) 2021/1161 of 13 July 2021 amending Decision 2011/891/EU and Implementing Decisions (EU) 2017/1211, (EU) 2017/1212, (EU) 2017/2449, (EU) 2019/2085 and (EU) 2019/2086 as regards the authorisation holder and its representative in the Union for the placing on the market of products containing, consisting of, or produced from certain genetically modified organisms (notified under document C(2021) 5148) (Text with EEA relevance) (Only the Dutch text is authentic), C/2021/5148, OJ L 252, 15.7.2021, p. 1–6, CELEX number: 32021D1161

 Commission Implementing Decision (EU) 2021/184 of 12 February 2021 amending Decisions 2009/813/EC, 2009/814/EC and 2010/429/EU and Implementing Decisions 2012/82/EU, 2012/83/EU, 2012/347/EU, 2013/649/EU, (EU) 2015/683, (EU) 2015/684, (EU) 2015/685, (EU) 2015/686, (EU) 2015/687, (EU) 2015/688, (EU) 2015/689, (EU) 2015/693, (EU) 2015/695, (EU) 2015/696, (EU) 2015/700, (EU) 2015/701, (EU) 2015/2279, (EU) 2015/2281, (EU) 2016/1216, (EU) 2016/1217, (EU) 2017/1207, (EU) 2018/1111, (EU) 2018/2045, (EU) 2018/2046, (EU) 2019/1307, (EU) 2019/1308, (EU) 2019/1309, (EU) 2019/2083 and (EU) 2020/1360 as regards the authorisation holder and its representative in the Union for the placing on the market of products containing, consisting of or produced from certain genetically modified organisms (notified under document C(2021) 826) (Only the Dutch text is authentic) (Text with EEA relevance), C/2021/826, OJ L 55, 16.2.2021, p. 4–23, CELEX number: 32021D0184

Commission Directive (EU) 2018/350 of 8 March 2018 amending Directive 2001/18/EC of the European Parliament and of the Council as regards the environmental risk assessment of genetically modified organisms, OJ L 67, 9.3.2018, p. 30–45, CELEX number: 32018L0350

Commission Implementing Regulation (EU) No 120/2014 of 7 February 2014 amending Regulation (EC) No 1981/2006 on detailed rules for the implementation of Article 32 of Regulation (EC) No 1829/2003 of the European Parliament and the Council as regards the Community reference laboratory for genetically modified organisms, Text with EEA relevance, OJ L 39, 8.2.2014, p. 46–52, CELEX number: 32014R0120

2009/770/EC: Commission Decision of 13 October 2009 establishing standard reporting formats for presenting the monitoring results of the deliberate release into the environment of genetically modified organisms, as or in products, for the purpose of placing on the market, pursuant to Directive 2001/18/EC of the European Parliament and of the Council (notified under document C(2009) 7680) (Text with EEA relevance), OJ L 275, 21.10.2009, p. 9–27, CELEX number: 32009D0770

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (Text with EEA relevance), OJ L 324, 10.12.2007, p. 121-137, CELEX number: 32007R1394

Directive 2008/27/EC of the European Parliament and of the Council of 11 March 2008 amending Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms, as regards the implementing powers conferred on the Commission, OJ L 81, 20.3.2008, p. 45–47, CELEX number: 32008L0027

Commission Regulation (EC) No 1981/2006 of 22 December 2006 on detailed rules for the implementation of Article 32 of Regulation (EC) No 1829/2003 of the European Parliament and of the Council as regards the Community reference laboratory for genetically modified organisms (Text with EEA relevance), OJ L 368, 23.12.2006, p. 99–109, CELEX number: 32006R1981

 Commission Regulation (EC) No 65/2004 of 14 January 2004 establishing a system for the development and assignment of unique identifiers for genetically modified organisms, OJ L 10, 16.1.2004, p. 5–10, CELEX number: 32004R0065

2002/813/EC: Council Decision of 3 October 2002 establishing, pursuant to Directive 2001/18/EC of the European Parliament and of the Council, the summary notification information format for notifications concerning the deliberate release into the environment of genetically modified organisms for purposes other than for placing on the market, OJ L 280, 18.10.2002, p. 62–83, CELEX number: 32002D0813

 2002/812/EC: Council Decision of 3 October 2002 establishing pursuant to Directive 2001/18/EC of the European Parliament and of the Council the summary information format relating to the placing on the market of genetically modified organisms as or in products, OJ L 280, 18.10.2002, p. 37–61, CELEX number: 32002D0812

2002/811/EC: Council Decision of 3 October 2002 establishing guidance notes supplementing Annex VII to Directive 2001/18/EC of the European Parliament and of the Council on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC, OJ L 280, 18.10.2002, p. 27–36, CELEX number: 32002D0811

  • Proposal (available in several official languages of the EU) Proposal for a Council Decision establishing guidance notes supplementing Annex VII to Directive 2001/18/EC of the European Parliament and of the Council on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC /* COM/2002/0359 final */ OJ C 262E , 29.10.2002, p. 325–335
  • Original text (available in the 24 official languages of the EU)

Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive90/220/EEC - Commission Declaration, OJ L 106, 17.4.2001, p. 1–39, CELEX number: 32001L0018

96/134/EC: Commission Decision of 16 January 1996 amending Decision 91/448/EEC concerning guidelines for classification referred to in Article 4 of Council Directive 90/219/EEC on the contained use of genetically modified micro-organisms (Text with EEA relevance), OJ L 31, 9.2.1996, p. 25–27, CELEX number: 31996D0134

93/572/EEC: Commission Decision of 19 October 1993 concerning the placing on the market of a product containing genetically modified organisms pursuant to Article 13 of Council Directive 90/220/EEC, OJ L 276, 9.11.1993, p. 16–17, CELEX number: 31993D0572

 91/596/EEC: Council Decision of 4 November 1991 concerning the Summary Notification Information Format referred to in Article 9 of Directive 90/220/EEC on the deliberate release into the environment of genetically modified organisms, OJ L 322, 23.11.1991, p. 1–16, CELEX number: 31991D0596

Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance, OJ L 158, 27.5.2014, p. 1–76, CELEX number: 32014R0536

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, OJ L 121, 1.5.2001, p. 34–44, CELEX number: 32001L0020

Reform of the EU Pharmaceutical legislation

European Commission, Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006, COM/2023/193 final, CELEX number: 52023PC0193, 26 April 2023

  • Original text (available in the 24 official languages of the EU)

European Commission, Proposal for a Directive of the European Parliament and of the Council on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC, COM/2023/192 final, CELEX number: 52023PC0192, 26 April 2023

  • Original text (available in the 24 official languages of the EU)

European Parliament, Report on the proposal for a regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006 – 21/03/2024, 21 March 2024

Council of the European Union, Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006 - Mandate for negotiations with the European Parliament, 2 June 2025

Proposal for a European Biotech Act

Proposal for a Regulation of the European Parliament and of the Council on establishing a framework of measures for strengthening Union’s biotechnology and biomanufacturing sectors particularly in the area of health and amending Regulations (EC) No 178/2002, (EC) No 1394/2007, (EU) No 536/2014, (EU) 2019/6, (EU) 2024/795 and (EU) 2024/1938 (European Biotech Act), COM/2025/1022 final

European Union Guidance

The answers provided to the questions reflect the interpretation by the national competent authorities responsible for the application of the medicinal products and the GMO regulatory frameworks.

GMO requirements for investigational products

In-vivo gene therapy:

Human cells genetically modified

Oncolytic viruses

  • Oncolytic viruses: Considerations for the evaluation of Shedding – V2 01/2022
    This document has been endorsed by the NCAs of the following Member States: Austria, Belgium, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Portugal, Romania, Slovenia, Spain, Sweden and Norway.

Repository of national regulatory requirements

E-Submission Food Chain Platform

EMA guidance documents

NCAs:

Relevant literature

  1. Les « petites » histoires du droit de l’Union de la bioéthique : le cas de l’édition génomique - Brosset, Estelle. Revue de l’Union européenne | Dalloz, no. 656 (3/2022): 158-166.
     
  2. Chimeric Antigen Receptor-T Cell Therapy - Buechner, Jochen, Marie José Kersten, Miriam Fuchs, Florence Salmon, and Ulrich Jäger. HemaSphere 2, no. 1 (2/2018): e18.
  3. EMA commentary on the guideline on quality, nonclinical and clinical aspects of medicinal products containing genetically modified cells - Celis, Patrick, Giada Farinelli, Ana Hidalgo-Simon, Pauline Meij, Mara Tihaya, Martina Schüssler-Lenz, and Marcos Timón. British Journal of Clinical Pharmacology 90, no. 5 (2024): 1203–1212.
  4. Protection de l’environnement et protection de la santé humaine, deux objectifs conflictuels aux temps de la pandémie de la Covid-19: focus sur les essais de médicaments à usage humain contenant des organismes génétiquement modifiés ou consistant en de tels organismes - Chevreau, Laura. Journal de Droit de la Santé et de l’Assurance Maladie (JDSAM), no. 27 (12/ 2020): 104-109.
     
  5. ATMP Environmental Exposure Assessment in European Healthcare Settings: A Systematic Review of the Literature - Damerval, Margaux, Christine Fagnoni-Legat, Aurélien Louvrier, Sarah Fischer, Samuel Limat, Anne-Laure Clairet, Virginie Nerich, Isabelle Madelaine, and Marie Kroemer. Frontiers in Medicine 8 (12/2021).
  6. Are genome-edited micro-organisms covered by Directive 2009/41/EC?—implications of the CJEU’s judgment in the case C-528/16 for the contained use of genome-edited micro-organisms - Dederer, Hans-Georg, and David Hamburger. Journal of Law and the Biosciences 9, no. 1 (2022): 1-27.
  7. Comparative Analysis - Dederer, Hans-Georg. In Regulation of Genome Editing in Human IPS Cells, 289–329. Springer, Cham, 2022.
  8. Introductory Remarks - Dederer, Hans-Georg. In Regulation of Genome Editing in Human IPS Cells, 1–14. Springer, Cham, 2022.
  9. Circuit pharmaceutique du médicament de thérapie innovante (MTI) en France : état des lieux et perspectives - Fabri, Benjamin, Guillaume Sicard, Laurence Gauthier-Villano, and Bertrand Pourroy. Annales Pharmaceutiques Françaises, (4/2023).
  10. The EU legal framework on clinical trials directed to therapeutic germline gene alteration: A critical and systematic analysis - Faltus, Timo, and Iñigo de Miguel Beriain. Medical Law International 23, no. 1 (3/2023): 44-70.
  11. Advanced Therapy Medicinal Products - Inesa Fausch, Aurélie Mahalatchimy, Oxford Public International Law, 02/2025
  12. Unlocking the value of innovative medicines: Insights from the advanced therapy medicinal products (ATMP) innovation systems in Germany and Sweden - Fischer, Piret, Thomas Reiss, Jörg Mahlich, Erwan Gicquel, Heike Aichinger, Liliya Pullmann, and Tanja Bratan. Health Policy and Technology 12, no. 2 (6/2023): 100744.
  13. The national legislation accompanying the approval procedure for clinical trials of medicinal products for human use under Regulation (EU) No. 536/2014 - Frech, Marion, Florian Dexel, Margareta Burgard, and Yvonne Seibel. Die nationale Begleitgesetzgebung zum Genehmigungsverfahren klinischer Prüfungen mit Humanarzneimitteln im Rahmen der Verordnung (EU) Nr. 536/2014’. Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 66, no. 1 (01/2023): 12-20.
  14. Regulation of Genome Editing in Human IPS Cells: Germany - Frenken, Gregor, and Hannah Lüttge. In Regulation of Genome Editing in Human IPS Cells, 29–81. Springer, Cham, 2022.
  15. Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side - Garcia-Perez, Laura, Anita Ordas, Kirsten Canté-Barrett, Pauline Meij, Karin Pike-Overzet, Arjan Lankester, and Frank J. T. Staal. Pharmaceutics 12, no. 6 (6/2020): 549.
  16. Clinical trials with GMOs in the EU - from regulatory to sites - Elena Gueudar Delahaye, Julie Liberman, and Marie Michel, Regulatory Rapporteur (Vol. 17, N0 6, (06/2020):4-8
  17. Temporary derogation from European environmental legislation for clinical trials of genetically modified organisms for coronavirus disease 2019 - Carolina Iglesias-Lopez. Cythotherapy, Volume 23, Issue 1, (01/2021):10-11
  18. Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe - Ham, Renske M. T. ten, Jarno Hoekman, Anke M. Hövels, Andre W. Broekmans, Hubert G. M. Leufkens, and Olaf H. Klungel. Molecular Therapy - Methods & Clinical Development 11 (12/2018): 121–130.
  19. Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts - Hartmann, Jessica, Martina Schüßler‐Lenz, Attilio Bondanza, and Christian J Buchholz. EMBO Molecular Medicine 9, no. 9 (09/2017): 1183–1197.
  20. Comparison of regulatory framework of clinical trial with genetically modified organism-containing vaccines in the Europe, Australia, and Switzerland - Jose, Jobin, and Swathi Pai. Clinical and Experimental Vaccine Research 10, no. 2 (5/2021): 93-105.
  21. Clinical trials with GMO-containing vaccines in Europe: Status and regulatory framework - Kauffmann, Florence, Pierre Van Damme, Geert Leroux-Roels, Corinne Vandermeulen, Nele Berthels, Claire Beuneu, and Stéphanie Mali. Vaccine 37, no. 42 (09/2019): 6144-6153.
  22. Is it time to reform oversight of clinical gene therapy in the EU? - Kenter, Marcel J.H.. British Journal of Clinical Pharmacology 85, no. 1 (2019): 8–10.
  23. Regulatory Flexibilities and Guidances for Addressing the Challenges of COVID-19 in the EU: What Can We Learn from Company Experiences? - Klein, Kevin, Pieter Stolk, Pär Tellner, Virginia Acha, Sarah Montagne, and Isabelle Stöckert. Therapeutic Innovation & Regulatory Science 56, no. 2 (03/2022): 366–377.
  24. Le cas particulier des médicaments de thérapie innovante préparés ponctuellement composés en tout ou partie d’OGM. Lamy droit de la responsabilité, Wolters Kluwer France, 1/10/2020.
     
  25. Vers une utilisation des vaccins-OGM dans le traitement du cancer ?: De la théorie à la pratique hospitalière - Guillaume Leseigneur, Fabienne Divanon. Le Pharmacien Hospitalier, Volume 42, Issue 169, (06/2007): 97-106
  26. Framing and Legitimating EU Legal Regulation of Human Gene-Editing Technologies: Key Facets and Functions of an Imaginary  - Mahalatchimy, Aurelie, Pin Lean Lau, Phoebe Li, and Mark L. Flear. Journal of Law and the Biosciences 8, no. 2 (2021): 1-30.
  27. Regulation of Genome Editing in Human iPS Cells: France - Mahalatchimy, Aurélie. In Regulation of Genome Editing in Human IPS Cells, 83–106. Springer, Cham, 2022.
  28. Deciphering the Fragmentation of the Human Genome Editing Regulatory Landscape - Mahalatchimy, Aurélie, and Emmanuelle Rial-Sebbag. Frontiers in Political Science 3 (01/2022).
  29. Comparative analysis of GMO regulatory requirements for AAV vectors in the EU and Japan focusing on the shedding data and containment measures - Mizoguchi, Hirokuni, Tobias Fleischmann, Masato Komuro, Takahiro Hirai, Akiko Ikeda, Kojiro Saito, Tomohiro Watahiki, and Gentaro Tajima. Expert Opinion on Biological Therapy 24, no. 6 (06/2024): 529–542.
  30. Biomodifying the ‘natural’: from Adaptive Regulation to Adaptive Societal Governance - Mourby, Miranda, Jessica Bell, Michael Morrison, Alex Faulkner, Phoebe Li, Edison Bicudo, Andrew Webster, and Jane Kaye. Journal of Law and the Biosciences 9, no. 1 (2022): 1-28.
  31. Gene therapy regulation: could in-body editing fall through the net? - Mourby, Miranda, and Michael Morrison. European Journal of Human Genetics 28, no. 7 (07/2020): 979-981.
  32. Gestion pharmaceutique des études cliniques de thérapie génique en France - J., L. Bernard, P. Chennell, and V. Sautou. Le Pharmacien Hospitalier et Clinicien 50, no. 4 (12/2015): 434-443.
  33. Policy statement on the social, ethical and public awareness issues in gene therapy - The Journal of Gene Medicine 4, no. 6 (2002): 687–691.
  34. GMO Regulation in Crisis – The Experimental Potential of Regulation (EU) 2020/1043 on Covid-19 in Addressing Both a Crisis and a Pandemic: Special Issue Experimental Legislation in Times of Crisis - Lonneke Poort, Willem J. Kortleven. Law and Method, (10/2021)
  35. Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany - Renner, Matthias, Brigitte Anliker, Ralf Sanzenbacher, and Silke Schuele. In Regulatory Aspects of Gene Therapy and Cell Therapy Products: A Global Perspective, edited by Maria Cristina Galli and Mercedes Serabian, 87–101. Cham: Springer International Publishing, 2015.
  36. Regulatory landscape and challenges in CAR-T cell therapy development in the US, EU, Japan, and India - S s, Kirthiga Devi, Ramesh Joga, Saurabh Srivastava, Kalpana Nagpal, Isha Dhamija, Parul Grover, and Sandeep Kumar. European Journal of Pharmaceutics and Biopharmaceutics 201 (08/2024): 114361.
  37. Japanese Pharmaceutical Regulations of Engineered Viral Vectors for Medical Use Compared With Those in the United States and the European Union - Sakurai, Akira, Seiichi Kanzaki, and Futaba Honda. Clinical Pharmacology & Therapeutics 113, no. 5 (2023): 960–962.
  38. Off-Label Prescription of Genetically Modified Organism Medicines in Europe: Emerging Conflicts of Interest? - Schagen, Frederik H. E., Rob C. Hoeben, and Geke A. P. Hospers. Human Gene Therapy 25, no. 10 (10/2014): 893-896.
  39. Regulation of Genome Editing in Human IPS Cells: Switzerland - Schweizer, Rainer J., Hans Peter Bernhard, and Antonia S. Straden. In Regulation of Genome Editing in Human IPS Cells, 107–198. Springer, Cham, 2022.
  40. Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects - Schuurman, Henk-Jan, and Karin Hoogendoorn. Xenotransplantation 27, no. 3 (2020): e12608.
  41. Impact of genetically modified organism requirements on gene therapy development in the EU, Japan, and the US - Tajima, Gentaro, Seoan Huh, Natalie Anne Schmidt, Judith C. Macdonald, Tobias Fleischmann, and Keith Merrell Wonnacott. Molecular Therapy - Methods & Clinical Development 26 (09/2022): 74-83.
  42. Is the Covid‐19 Pandemic a Game Changer in GMO Regulation? - Justus Wesseler, Kai Purnhagen. EuroChoices, (02/2021), 19(3):49–52
  43. Environmental risk assessment of advanced therapies containing genetically modified organisms in the EU - Whomsley, Rhys, Victoria Palmi Reig, and Ana Hidalgo-Simon. ‘Environmental Risk Assessment of Advanced Therapies Containing Genetically Modified Organisms in the EU’. British Journal of Clinical Pharmacology 87, no. 6 (2021): 2450-2458.

More

EU Pharmaceutical legislation reform

COVID-19 temporary derogation:

Member States and European countries:

Gene Therapy Net provides an overview for sponsors and researchers of the different international regulations and guidelines associated with clinical gene therapy trials; ie:

Regulatory Landscapes of GMO Research Programs – CROMOS Pharma – 25/08/2023

France:

Spain:

Belgium:

Netherlands:

UK:

Other:

Acknowledgements

Published: 09/03/2026 by Valentin Roby

Authors:

Aurélie Mahalatchimy, EuroGCT WP4 Convenor, UMR 7318 DICE CERIC, Aix-Marseille University, CNRS, Aix-en-Provence, France

Luc-Sylvain Gilbert, EuroGCT information officer on Ethical, Legal and Societal Issues

Research Pathways Overview

Table of contents

War der Inhalt dieser Seite nützlich? Teilen Sie Ihre Gedanken und Eindrücke mit uns.
-
Your feedback helps us keep EuroGCT online. Please can you take 30 seconds to answer these quick questions?
How would you rate your experience using EuroGCT.org today?
Poor
Great
Is the information on this website understandable?
Not at all understandable
Very understandable
Is the information on this website useful?
Not at all useful
Very useful
Is the website easy to use and navigate?
Not at all easy
Very easy
Why are you interested in gene and cell therapies and research?
CAPTCHA
Diese Sicherheitsfrage überprüft, ob Sie ein menschlicher Besucher sind und verhindert automatisches Spamming.