The Moving Regulatory Landscape for Gene Therapy Trials in EU

August 12, 2025

Submitting a GMO Application for a Clinical Trial with AAV Viral Vectors

Navigating the regulatory landscape for clinical trials in the European Union (EU) has become more streamlined with the mandatory use of the centralized Clinical Trial Information System (CTIS) under the Clinical Trial Regulation No 536/2014 (CTR). This system is now the go-to platform for submitting all clinical trial applications (CTAs), including those for gene therapy trials. However, gene therapy trials often face additional hurdles due to the need to comply with either the Contained Use Directive (2009/41/EC) or the Deliberate Release Directive (2001/18/EC), which address the potential risks posed by genetically modified organisms (GMOs) to humans and the environment. As a result, most gene therapy trials require a separate GMO application, which unfortunately cannot be submitted via CTIS and must adhere to specific procedures and requirements set by individual Member States (MS).

A few years ago, the introduction of three product-specific Common Application Forms (CAF) aimed at simplifying the GMO application process across the EU. These forms were discussed in a previous blog, which provides detailed information on their usage and requirements. While many Member States have endorsed the CAFs, not all have done so, and some have only partially adopted them. This partial endorsement has led to a slight improvement in the application process for the clinical use of GMOs, but it remains complex. The lack of EU-wide acceptance of the CAFs, coupled with varying Member State procedures and unclear directives (2001/18/EC vs 2009/41/EC), adds to the complexity.

To shed light on this intricate process, we explore the specific procedures and requirements of several Member States for submitting a GMO application for clinical trials involving AAV vectors.

Utilizing the Common Application Form (CAF) for AAV Vector Trials: Opportunities and Limitations Across Member States

One of the product-specific CAFs is dedicated to investigational medicinal products (IMP) consisting of or containing AAV vectors. This CAF for AAV vectors can be considered as the central document of the GMO application for a clinical trial with AAV vectors, in case the CAF is endorsed by the MS(s) of interest. Whether the benefit of the CAF is fully applicable, depends on the characteristics of the IMP and relates to the pre-defined Environmental Risk Assessment (ERA) or classification in Biosafety Level-1 that has been provided by the agencies in the CAF-related Good Practice document. If the IMP does not contain replication competent AAV and if its transgene is not harmful, the pre-defined ERA or classification will be applicable and releases the applicant of the requirement to provide an ERA or justification of the classification in the GMO application. In this case a simple cross-reference to the pre-defined ERA of classification in the CAF will be due. However, if the requirements are not met, the applicant does have to generate and provide an ERA of the clinical trial in accordance with Annex II of Directive 2001/18/EC or classification of the clinical trial in accordance with Article 4 of Directive 2009/41/EC.

The use of the CAF for AAV vectors is only applicable if this CAF form is endorsed by the MS of choice. Most EU Member States did, but unfortunately the CAF form can't be used in the following Member States:

  • Bulgaria
  • Malta
  • Poland
  • Slovakia
  • Cyprus
  • Greece
  • Sweden

These MSs still rely on their national GMO documents, which demands particular knowledge of the national requirements and, apart from Cyprus and Sweden, most of the required documents have to be written in the national language of the specific MS.

Requirement of Summary Notification Information Format Form

The GMO package should include a Summary Notification Information Format (SNIF) in case the clinical trial is seen as deliberate release in the MS of choice. This is the case, that includes the following MSs:

  • Germany
  • Greece
  • Spain
  • Hungary
  • Ireland
  • Latvia
  • Netherlands
  • Sweden
  • Slovenia
  • Slovakia
  • Romania

In three MSs, (Austria, Denmark, and Poland) a clinical trial must comply with the Contained Use Directive (Dir 2009/41/EC). In these MSs, the GMO application does not need to contain a SNIF.

Unfortunately, in some MSs it is less straightforward. In these MSs, a clinical trial with a GMO can be seen either as Deliberate Release or as Contained Use. Each MS does have its own arguments and assessment regarding whether a particular clinical trial is considered either contained use or deliberate release. This can be dependent upon the characteristics of the GMO, the trial design and proposed management measures, etc., and is a case-by-case assessment.

Nevertheless, a clinical trial with an AAV vector is most likely seen as contained use in Belgium, Czechia, Finland, France and Italy, while it is seen as Deliberate Release in Portugal. For the remaining MSs, it is unclear which Directive is considered leading in case of a clinical trial with AAVs, simply because these countries haven't (or barely) any experience with clinical trials consisting of or containing GMOs. For a more detailed insight in the use and applicability of the SNIF, one is referred to a previous blog .

Submission of a GMO Application in Europe

Despite the intention of the CTR to harmonize and centralize the CTAs throughout the EU, and despite the availability of the CAF as core document for the GMO package, the submission of the GMO application is still a unique procedure for each MS. To provide some insight in the different submission requirements and procedures for a clinical trial with an AAV vector an overview is provided in table 1, which indicates specifics of the GMO application in seven different European countries.

These countries (United Kingdom, Germany, France, Switzerland, Spain, the Netherlands, and Italy), along with the US, China, and Japan, form the top ten countries that host most gene therapy clinical trials world-wide. Obviously, both UK and Switzerland are not Member States within the EU, making the CAF not applicable in these countries. In contrast, the CAF is applicable in the listed EU MSs. While Germany, France, and the Netherlands allow the CAF to be completed in English, Spain and Italy require the use of their national language to do this. Similarly, the inclusion of a SNIF document is not applicable in UK and Switzerland and is not required in France and Italy, since these MSs do consider a clinical trial with an AAV as contained use. The way to submit the GMO application to the different authorities is quite diverse and unique for each MS. It might require a portal, (certified) email account, regular post-delivery or a combination of these options.

It is also important to note that the official route for a GMO application in the Netherlands is indicated in the table. However, dependent upon the selected Dutch site, a GMO application might not be needed. In the Netherlands, several academic medical centers applied for and received a general GMO license for AAV-based clinical trials. This license might cover your clinical trial as well, making a GMO application superfluous.

a: No separate GMO application in Switzerland, b:Applicable to all documents, unless indicated otherwise, c:Based on experience with PEI the addition of a product administration manual is recommended, although not specifically indicated to be required, d: As one of the documents to be included in CTA package, ANSM: Agence Nationale de Sécurité du Médicament et des produits de santé, CAF: Common Application Form, CESP: Common European Submission Portal, CU: Contained Use, ESFC: E-Submission Food Chain, DR deliberate Release, HSE: Health and Safety Executive, MAPA: Ministry of Agriculture, Fisheries and Fooda: No separate GMO application in Switzerland, b:Applicable to all documents, unless indicated otherwise, c:Based on experience with PEI the addition of a product administration manual is recommended, although not specifically indicated to be required, d: As one of the documents to be included in CTA package, ANSM: Agence Nationale de Sécurité du Médicament et des produits de santé, CAF: Common Application Form, CESP: Common European Submission Portal, CU: Contained Use, ESFC: E-Submission Food Chain, DR deliberate Release, HSE: Health and Safety Executive, MAPA: Ministry of Agriculture, Fisheries and Fooda: No separate GMO application in Switzerland, b:Applicable to all documents, unless indicated otherwise, c:Based on experience with PEI the addition of a product administration manual is recommended, although not specifically indicated to be required, d: As one of the documents to be included in CTA package, ANSM: Agence Nationale de Sécurité du Médicament et des produits de santé, CAF: Common Application Form, CESP: Common European Submission Portal, CU: Contained Use, ESFC: E-Submission Food Chain, DR deliberate Release, HSE: Health and Safety Executive, MAPA: Ministry of Agriculture, Fisheries and Food
Table 1: Procedure of GMO application and SNIF submission for an AAV based clinical trial in the European countries hosting most gene therapy trials
European Country (# of Trials) CU/DR Content GMO Package Submission of GMO Application SNIF Submission Language
United Kingdom (245) CU
  • Cover letter
  • CU1 form
Via email to HSE Not applicable English
Germany (115) DR
  • Cover letter
  • CAF for AAV including indicated German-specific information
  • Proof of submission SNIF
  • Product administration manual
Via CESP to Paul Ehrlich Institute SNIF (English) submission via EFSC platform German or English
France (66) CU
  • CAF for AAV including site plans
  • List of facilities
Via "Simplified procedures" platform to ANSM Not required French or English
Switzerland (50) CU or DC
  • Environmental data documentation (case A, B1, or B2)
Via regulator post; paper version and electronic copy to Swissmedic Not applicable German, French, or Italian
Spain (45) DR
  • Cover letter
  • Clinical trial request form (Spanish)
  • CAF for AAV (Spanish)
  • SNIF (English and Spanish)
  • Proof of Payment
Via email and regular post to MAPA or electronically via "sede electronica del MAPA" After approval by MAPA, submit SNIF (English) via ESFC platform Spanish (except for cover letter and SNIF for ESFC platform)
the Netherlands (41) DR
  • Cover letter
  • CAF for AAV
  • Personal data (confidential)
Via regular post to Loketgentherapie or electronically via “berichtenbox”  SNIF(English) submission via ESFC platform Dutch or English
Italy (39) CU
  • Cover letter
  • CAF for AAV
  • Proof of Payment
Via certified email account (PEC) Not required Italian

a: No separate GMO application in Switzerland,
b:Applicable to all documents, unless indicated otherwise,
c:Based on experience with PEI the addition of a product administration manual is recommended, although not specifically indicated to be required,
d: As one of the documents to be included in CTA package, ANSM: Agence Nationale de Sécurité du Médicament et des produits de santé, CAF: Common Application Form, CESP: Common European Submission Portal, CU: Contained Use, ESFC: E-Submission Food Chain, DR deliberate Release, HSE: Health and Safety Executive, MAPA: Ministry of Agriculture, Fisheries and Food

Preparing for Regulatory Change: Expert Support for AAV GMO Application Across Europe

The CTR is, in part, beneficial to gene therapy clinical trials, but it does not ease the burden of complex GMO applications that are required for this category of trials in addition to a CTA. In case of clinical trials with AAV-based vectors, the development of a CAF form did simplify the preparation of the GMO application package. Although the CAF is not endorsed by all EU MSs, it can be considered as central document of the GMO application package in the MSs that did. Unfortunately, many differences in requirements and procedures between the MSs remain, as is illustrated in Table 1, that provides the situation in seven European countries which belong to the top-ten countries hosting the most gene therapy clinical trials world-wide. Hopefully, the proposal for a new pharmaceutical legislation that was adopted on April 26, 2023, by the European Commission, will be implemented in the near future. In this proposal, amendments of the CTR are suggested and include the possibility to submit the ERA or CAF via the EU portal CTIS. Additionally, it has been proposed to have the ERA or CAF assessed by the Committee for Medicinal Products for Human Use. Whether this proposed centralized and uniform submission and assessment of the GMO application will become available in full is to be seen, but any of these advancements that will be implemented, will ease the current complexity and make the EU more attractive for the conduct of gene therapy clinical studies.

ProPharma holds significant expertise within the regulatory requirements for cell and gene therapies and is uniquely positioned to help you navigate this field, including the legal requirements for GMO applications in the different Member States of the EU/ EEA. Furthermore, ProPharma is equipped to handle every aspect of the submission process for clinical trials with AAV vectors in Europe. This includes comprehensive regulatory support for GMO submissions, Clinical Trial Applications (CTAs), and the necessary submissions for performance testing of devices under the In Vitro Diagnostic Regulation (IVDR). With ProPharma's expertise, you can be confident that all regulatory requirements will be met, allowing you to focus on advancing your clinical research.

At ProPharma, we are continually reviewing the regulatory landscape to maintain current knowledge of the latest legislative developments within the cell and gene therapy realm to best support our clients. In the case of abovementioned GMO applications we can provide all regulatory affairs support you might need; from support with a CTA or Market Authorization Application (MAA), to advice about the contained use or deliberate release procedure, the required documents for each of these procedures, and in which Member States these apply, or even just for supporting your submission to the right competent authority via the appropriate portal. Our team of expert regulatory consultants can help you achieve successful regulatory outcomes for your product.

ProPharma: The World’s Leading Regulatory Consultancy

Interested in learning more? Contact us today to find out how to successfully apply for a GMO license for your clinical trial or to learn more about ProPharma’s Regulatory Science expertise and experience in the field of cell and gene therapies.

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