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Gene Therapy Legislation in Europe

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.

The EU also provides an overview of national regulatory requirements (EU countries and Norway) for medicinal products containing GMOs. This overview has been developed in 2018 as a result of joint efforts to harmonize between the GMO legislation and the legislation on medicinal products.

EU Clinical Gene Therapy Trials Legislation

The collection of rules and regulations governing medicinal products in the European Union is EudraLex and it consists of 10 volumes. The body of European Union legislation in the pharmaceutical sector for human use is compiled in Volume 1 - EU pharmaceutical legislation for medicinal products for human use. The basic legislation is supported by a series of guidelines that are also published in the following volumes of "The rules governing medicinal products in the European Union". Volume 10 - Clinical trials guidelines contains guidance documents concerning medicinal products for human use in clinical trials (investigational medicinal products).

Clinical Trial Directive
This EudraLex guidance document on clinical trials is based on Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. The EU Clinical Trials Directive 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. As regards the term ‘medicinal products’, this refers to medicinal products for human use as defined in 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. This includes medicinal products where the pharmacological, immunological, or metabolic action of the product is still uncertain and being explored.

Advanced Therapy Medicinal Products (ATMPs)
Medicinal products for paediatric use, orphan, herbal medicinal products and advanced therapies are governed by specific rules. Advanced therapy medicinal products (ATMPs) are new medical products based on genes (gene therapy), cells (cell therapy) and tissues (tissue engineering). These advanced therapies herald revolutionary treatments of a number of diseases or injuries, such as skin in burns victims, Alzheimer's, cancer or muscular dystrophy. They have huge potential for patients and industry. The lack of an EU-wide regulatory framework in the past led to divergent national approaches which hindered patients' access to products, hampered the growth of this emerging industry and ultimately affected EU competitiveness in a key biotechnology area. The EU institutions agreed on a Regulation on advanced therapies (Regulation (EC) 1394/2007), designed to ensure the free movement of advanced therapy products within Europe, to facilitate access to the EU market and to foster the competitiveness of European companies in the field, while guaranteeing the highest level of health protection for patients. The main elements of the Regulation are:

  • A centralised marketing authorisation procedure, to benefit from the pooling of expertise at European level and direct access to the EU market.
  • A new and multidisciplinary expert Committee (Committee for Advanced Therapies), within the European Medicines Agency (EMA), to assess advanced therapy products and follow scientific developments in the field (see below)
  • Technical requirements adapted to the particular characteristics of these products.
  • Special incentives for small and medium-sized enterprises.

For more information, see Advanced therapies - Major developments

Genetically Modified Organisms (GMOs)
Clinical gene therapy trials often involve genetically modified organisms (GMOs) like recombinant viral vectors. 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 2009/41/EC. Although the approach of Directive 2009/41/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.

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 2009/41/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.

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 is initially based on Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. 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.

Regulation (EC) No 726/2004 and Directive 2001/83/EC were amended by Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products (ATMPs). As briefly mentioned above, ATMPs are any of the following medicinal products for human use:

  • a gene therapy medicinal product as defined in Part IV of Annex I to Directive 2001/83/EC;
  • a somatic cell therapy medicinal product as defined in Part IV of Annex I to Directive 2001/83/EC, or
  • a tissue engineered product that contains or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue.

Committee for Advanced Therapies (CAT)
In accordance of this ATMP regulation the Committee for Advanced Therapies (CAT) has been established. The CAT is a multidisciplinary committee, gathering together experts in Europe to assess the quality, safety and efficacy of ATMPs and follow scientific developments in the field. The main responsibility of the CAT is to prepare a draft opinion on each ATMP application submitted to the European Medicines Agency, before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on the granting, variation, suspension or revocation of a marketing authorisation for the medicine concerned. At the request of the EMA Executive Director or of the European Commission, an opinion is also drawn up on any scientific matter relating to ATMPs. The CAT is composed of different members, including five members or co-opted members of the CHMP. These members are appointed by the CHMP itself.

Committee for Medicinal Products for Human Use (CHMP)
The CHMP is the committee at the European Medicines Agency that is responsible for preparing opinions on questions concerning medicines for human use. Assessments conducted by the CHMP are based on purely scientific criteria and determine whether or not the medicines concerned meet the necessary quality, safety and efficacy requirements (in accordance with EU legislation, particularly Directive 2001/83/EC). These processes ensure that medicines have a positive risk-benefit balance in favour of patients/users of these products once they reach the marketplace.

Gene Therapy Working Party (GTWP)
The CAT Gene Therapy Working Party (GTWP) was a multidisciplinary group of European experts that provided recommendations to the CAT on all matters relating directly or indirectly to gene therapy. It was established following the discontinuation of the Gene Therapy Working Party of the CHMP. The GTWP was replaced by ad-hoc drafting groups in September 2012.

EU Directives and Regulations

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 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 2009/41/EC of 6 May 2009 on the contained use of genetically modified micro-organisms (Official Journal L 125/75).

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).

Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products (ATMPs).(Official Journal L 324, 10/12/2007).

EUR-Lex - The portal to European Union law

EMA Documents and Guidelines

Overview of scientific gene therapy guidelines by the EMA. Adopted as well as draft document can be found here. Below is a selection of guidelines.

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.

Literature and Guidance Documents

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).