Gene therapy trials: a harmonized procedure across EU?

#Gene therapy trials: a harmonized procedure across EU?

After the first clinical trial with a gene therapy medicinal product (GTMP) in 1989 and years of development and improvements, more and more GTMPs are now entering late-stage clinical trials and the first therapies have received market approval. In view of these developments, it seems that the field of Gene Therapy is about to pay-off and regarding the tremendous potential of emerging technologies (e.g. CRISPR-Cas), even more promising developments in the field of GTMPs seem to be ahead of us.

With the installation of a new Clinical Trials Regulation, the European Commission (EC) aimed to harmonize and thereby ease the application of clinical trials within the EU. However, the environmental legislative divergence between the Member States seems to neutralize the benefits of this Regulation for the clinical development of GTMPs.


In contrast to an application for market authorization, an application for a clinical trial is currently not harmonized in the EU and requires a separate submission in each Member State in which the trial will be conducted. In addition to all regular requirements of Directive 2001/20/EC, a GTMP trial is also subject to specific environmental legislation because it contains or consists of genetically modified organisms. This legislation requires an assessment of the potential risks for man and the environment. In the EU, two different Directives can apply to a clinical trial with GTMPs:

  • Directive 2001/18/EC, in which the trial is considered as deliberate release of a GMO into the environment (the GMOs are expected to be introduced in the environment),
  • Directive 2009/41/EC, in which the trial is considered as contained use of a GMO (the GMOs are expected to remain in dedicated rooms in the hospital).

All Member States have implemented these two Directives in their national GMO legislation and whether a clinical gene therapy trial is seen as deliberate release or contained use, differs among the Member States. Several Member States have chosen one of the Directives to apply to all gene therapy trials, which are performed in their country. However, in other Member States a clinical gene therapy trial is in one situation considered as deliberate release, while in another situation as contained use. In these Member States, it depends on the characteristics of the trial and the classification of the GMO used, which of the Directives applies.

Apart from the fact that each Member State has its own national legislation, they also have their own procedures and timelines for filing and assessing a clinical GTMP trial application. It goes without saying that the requirement for an environmental risk assessment combined with differences in legislation, procedures and timelines doesn’t exactly ease the path for a multicenter GTMP trial across several EU Member States and requires regulatory expertise and know how to coordinate and apply for such a clinical trial.


In 2014, the European Parliament launched a new Regulation (No. 536/2014) on clinical trials with medicinal products for human use, replacing the Clinical Trials Directive 2001/20/EC. Its objective is to harmonize the electronic submission of and the assessment process for clinical trials conducted in multiple Member States. In short, medical-scientific and product quality assessments will be centralized, but national issues like informed consent and compensation arrangements will still be evaluated separately by each Member State. Although this Regulation came into force directly after its publication in the Official Journal of the European Union, it won’t be applicable until the necessary EU portal and database are fully functional, which isn’t to be expected before the end of 2018.


The new Regulation applies to all clinical trials with medicinal products for human use, and therefore includes GTMPs. Unfortunately, it doesn’t cover the requirements for the extensive assessment of the potential environmental risks. This means that the approval of a GTMP trial, in terms of its environmental safety, still resides at the level of the Competent Authority of each Member State with all its differences in national legislation, procedures and timelines. Consequently, gene therapy trials still face complex and non-harmonized regulatory requirements and procedures in EU.


Obviously, it would be most desirable if EU Member States could agree on the harmonization of the environmental legislation for clinical trials with GTMPs. Unfortunately, the EU Member States are widely divided in their GMO policy. This makes it unlikely that a centralized procedure for clinical trials with GTMPs, which also covers the environmental risk assessment, will come into effect in the near future, if at all. Until that time, one should consider carefully if a multicenter gene therapy trial in different EU Member States is really worth the effort to apply for the required environmental approval in each one of them.


  1. Limit the multicenter trial to a minimum of Member States (preferably one).
  2. If more than one Member State is required, choose your primary Member State based on your contact and previous experience with potentially qualified clinical centres.
  3. List the Member States with similar legislation for gene therapy trials as your primary Member State of choice, i.e. Member States with national environmental legislation that is based on the same Directive,
  4. Identify and contact the different involved parties in each Member State of choice to get insight in:
    1. the requirements for environmental approval
    2. the procedure of assessment
    3. the timelines that apply
  5. Select the Member States that most closely resemble the requirements, procedure, and timelines of your primary Member State of choice and that contain the most qualified clinical centres to perform your trial in.

If you're looking for additional experience and/or know how on GMO legislation and environmental risk assessments for clinical trials with gene therapies feel free to contact us and one of our experts will get back to you! We are familiar with the differences in national requirements and could support your company to navigate in this complex and non-harmonized playing field in order to design your regulatory strategy and work on a successful submission process

Blog by: Erik Schagen - Sr. Consultant at Xendo

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