The implementation of the European Union (EU) directives and guidelines for clinical gene therapy trials in the different EU member states and other European countries is gathered for the following countries: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, United Kingdom.

EU Clinical Gene Therapy Trials Legislation
The EU has several directives and guidelines for conducting clinical gene therapy trials. EU Directive 2001/83/EC provides a consolidated Community code relating to medicinal products for human use. The directive describes in great detail the considerations for conducting clinical trials without reference to specific requirements for trials involving genetically modified organisms (GMOs) as is often the case in gene therapy trials.

The EU Clinical Trials Directive 2001/20/EC establishes specific provisions regarding the conduct of clinical trials, including multi-centre trials, on human subjects involving medicinal products in particular relating to the implementation of good clinical practice. Its main purpose is to protect clinical trial subjects by establishing quality, safety and ethical criteria to be observed. In this evaluation the Ethics Committees at national level have a key role in evaluating the different aspects and providing an opinion before the trial can start. Although the Directive 2001/20/EC has led to harmonized procedures for authorizations of clinical trials in the EU member states, the detailed procedures at national level are still somewhat different.

The legislative framework for the application of genetically modified organisms (GMOs) in clinical gene therapy research is provided by several European directives and regulations. Some EU member states consider clinical trials with gene medicines as deliberate release according to Directive 2001/18/EC, while others consider them as contained use according to Directive 98/81/EC.

Contained use is defined as any activity with GMOs for which specific containment measures are used to limit their contact with the environment. The focus of Directive 98/81/EC is on the assessment of the biosafety level classification of the GMO and the implementation of physical, chemical and biological barriers. The risk classification has consequences for the procedure and review period of the application.

Deliberate release is defined as any activity with GMOs that is not contained use. Directive 2001/18/EC is based on a case-by-case environmental risk assessment (ERA) covering effects on human health or the environment. The ERA should be carried out in accordance with the principles set out in Annex II of this Directive. In short, the five steps involved in the ERA are i) identification of potential adverse effects, ii) estimation of the likelihood, iii) risk estimation, iv) risk management and v) assessment of the overall environmental impact. Although the approach of Directive 98/81/EC is different from Directive 2001/18/EC, both directives aim at protecting the environment and human health and therefore require a risk assessment preceding the activity.

EU Market Authorization Procedure
The final stage in the development of a gene therapy product after conducting clinical trials is the market application. The European Medicines Agency (EMA) (formerly known as EMEA) is a European agency for the evaluation of medicinal products, including gene therapy medicinal products. The legislative framework for market authorization of human gene therapy products and other medicinal products containing or consisting of GMOs is based on Directive 2001/83/EC, Regulation (EC) No 726/2004 and Directive 2001/18/EC. If the application concerns a product that contains a GMO, the market authorisation dossier submitted directly to the EMA should also contain the environmental risk assessment in accordance with the principles set out in Annex II to Directive 2001/18/EC. Regulation (EC) 726/2004 also describes that the competent authorities of 2001/18/EC must be consulted. In addition, the regulation indicates that an application must be accompanied by a written consent to the deliberate release into the environment of GMOs for research and development purposes provided for in part B of Directive 2001/18/EC.
Thus, there is a clear connection between market authorisation of a gene therapy product and the environmental risk assessment based on Directive 2001/18/EC for clinical trials. More information regarding the placing on the market of human medicinal products can be found on the EMA website or check directly the Gene Therapy Working Party (GTWP) or the Advanced Therapies section.

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 (Official Journal L 311, 28/11/2001 p.67–128).

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 (Official Journal L 121, 1/5/2001 p.34–44).

Directive 98/81/EC of 26 October 1998 amending Directive 90/219/EEC on the contained use of genetically modified micro-organisms (Official Journal L 330, 5/12/1998 p. 13 - 31).

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 Directive 90/220/EEC (Official Journal L 106, 17/4/2001 p. 1 - 39).

Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Official Journal L 136, 30/4/2004 p. 1–33).

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ICH Considerations - General Principles to Address Virus and Vector Shedding (EMEA/CHMP/ICH/449035/2009). Assessment of shedding can be utilized to understand the potential risk associated with transmission to third parties and the potential risk to the environment. The scope of this document excludes shedding as it relates to environmental concerns because it is regulated differently in various regions. The focus of this document is to provide recommendations for designing non-clinical and clinical shedding studies when appropriate. In particular, emphasis will be on the analytical assays used for detection, and considerations for the sampling profiles and schedules in both non-clinical and clinical studies. The interpretation of non-clinical data and its use in designing clinical studies is also within the scope of this paper, as well as the interpretation of clinical data in assessing the need for virus / vector transmission studies. Date for transmission to CHMP: July 2009.

Guideline on Scientific Requirements for the Environmental Risk Assessment of Gene Therapy Medicinal Products (EMEA/CHMP/GTWP/125491/2006). This guideline deals with the scientific principles and methodology to be used for the environmental risk assessment (ERA) of gene therapy GMO-containing medicinal products for human use, as required for marketing authorisation (MA) under the centralised procedure. Guidance is given on application of the methodology laid down in the Directive 2001/18/EC on the deliberate release of genetically modified organisms into the environment. Date for coming into effect: November 2008.

Guideline on Follow-up of patients administered with gene therapy medicinal products (CHMP/GTWP/60436/07). The guideline is describing recommendations for clinical monitoring and follow-up after treatment with Gene Therapy (GT) medicinal products in order to detect early signals of delayed adverse reactions, to prevent clinical consequences of such reactions and to ensure timely treatment and to gain information on the long-term safety and efficacy of the intervention. The principles laid down in this guideline are applicable for patients enrolled in clinical trials using GT medicinal products and for patients administered with authorised GT medicinal products. The follow-up recommendations take into consideration the risk profile of the gene therapy, the disease, co-morbidity and the patient target population and characteristics. Released for Consultation: May 2008.

Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/125459/06). This guideline defines scientific principles and provides guidance to applicants developing gene therapy medicinal products (GTMPs). Its focus is on the non-clinical studies required before the first use of a GTMP in human subjects. Date for coming into effect: November 2008.

General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors (CHMP/ICH/469991/2006). This document identifies general principles for investigating and addressing risks for inadvertent germline integration and provides considerations to minimise this potential risk in humans enrolled in clinical trials. This document applies to gene therapy vectors and could also apply to oncolytic viruses. Released for information: November 2006.

Environmental Risk Assessments for Medicinal Products Containing, or Consisting of, Genetically Modified Organisms (GMOs) (Module 1.6.2) (EMEA/CHMP/BWP/135148/2004). The application of the Centralised procedure to Marketing Authorisation (MA) applications for medicinal products consisting of or containing GMO(s) (GMO(s) as or in medicinal products) constitutes the scope of this document. Proposals for using GMOs in clinical trials fall outside the scope. Specifically, the guidance presented outlines both the procedural issues affecting applications for MA for these products and the information related to the Environmental Risk Assessment (ERA) which should be included in the applications. Date for coming into operation: End of 2005.

Guideline on Development and Manufacture of Lentiviral Vectors (CHMP/BWP/2458/03). This guideline describes quality aspects and non-clinical testing that are in general relevant for lentiviral vectors that are intended for ex vivo or in vivo application. Date for coming into operation: November 2005.

Gene therapy bio-safety: scientific and regulatory issues. Gene Ther 2005; 12: S146–152. This paper discusses the topics during the round table of the 2nd European Conference & Practical Course: Towards Clinical Gene Therapy: Preclinical Gene Transfer Assessment, held in Bellaterra (Spain), 1–14 February, 2004.

Opinion paper on the current status of the regulation of gene therapy in Europe. Hum. Gene Ther. 2002; 13:2085-110. A summary description of the current regulatory status of gene therapy in each European country is provided in order to emphasize the requirement for standardization and therefore foster the development of gene therapy. This description is followed by consensus comments and recommendations of the Euregenethy Network.

Analysis of the applicability of the contained use legislation for clinical trials (2006). Perseus BVBA. This report is the result of an initiative of the European Commission to perform an analysis of the applicability of the contained use legislation for clinical trials. The objectives of the project were to collect and prepare background information and data concerning clinical trials and the suitability of the legislation under which they are governed, and to undertake a detailed appraisal of the current legislation in terms of the suitability and adequacy of their provisions to address the potential risks from clinical trials.

European Association of Hospital Pharmacists (EAHP) Guidance on the Pharmacy Handling of Gene Medicines. EJHP 2007; 5: 29 -39. This guidance for the handling of gene medicines specifies the requirements for each step in the process from storage, dispensing and administration to the disposal of all materials involved in handling such therapeutic agents.

Environmental risk assessment of replication competent viral vectors in gene therapy trials (RIVM rapport 601850001; 2008). The Netherlands National Institute for Public Health and the Environment (RIVM) has developed a method to estimate the risks for man and the environment of the application of replication competent viral vectors in cancer therapy. Since such a method did not exist, this report will be a significant aid in the risk assessment of replication competent viruses and in guiding applications for a gene therapy license involving the use of these viruses through the regulatory process in the Netherlands. Supplementary document: Overview of replication competent viral vectors (RIVM rapport 601850002; 2008).

	European Agency for Safety and Health at Work
	European Commission - Biotechnology
	European Department for the Quality of Medicines
	European Federation of Pharmaceutical Industries and Associations (EFPIA)
	European Medicines Agency (EMA)
	European Society of Regulatory Affairs
	International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use