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. 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.
Human cells genetically modified
In December 2018, the EU published A Good Practice document on the assessment of GMO-related aspects in the context of clinical trials with human cells genetically modified, which has been developed by the national competent authorities and the Commission services. This document, which builds on possibilities under the existing legislation to facilitate the conduct of clinical trials with this type of medicinal products, has been endorsed by Austria, Belgium, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Malta, Portugal, Romania, Spain, Sweden and Norway. Developers that intend to conduct a clinical trial in these countries can follow the approach laid down in this document.
Moreover, a common application form has been endorsed by the competent authorities in Austria, Belgium, Cyprus, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Malta, Portugal, Romania, Spain, Sweden and Norway.