Clinical Trial Regulations in European Union (EU) Countries

For clinical trials in European Union countries, the regulations are mainly based on:

•  European Union (EU) clinical-trial legislation (Directive 2001/20/EC) and EU Legislation – Eudralex Volume 1 “Pharmaceutical Legislation Medicinal Products for Human Use”; Volume 10 “Clinical trials guidelins”
• Regulatory guidelines from The European Medicines Agency (EMA)
• Some guideline documents from The Heads of Medicines Agencies

According to EU Directive 2001/83/EC, “All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC of the European Parliament and of the Council 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. To be taken into account during the assessment of an application, clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of principles, which are equivalent to the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.”

There are two updates to the Directive 2001/20/EC:

• COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products
• 2012/0192 (COD)  Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

The European Medicines Agency (EMA) is the closest counterpart of US FDA and is the main body in EU to provide the regulatory guidelines for conducting clinical trials.

“The European Medicines Agency relies on the results of clinical trials carried out by pharmaceutical companies to reach its opinions on the authorisation of medicines. Although the authorisation of clinical trials occurs at Member State level, the Agency plays a key role in ensuring that the standards of good clinical practice (GCP) are applied across the European Economic Area in cooperation with the Member States. It also manages a database of clinical trials carried out in the European Union.”

The Heads of Medicines Agencies (HMA) is a network of the Heads of the National Competent Authorities whose organisations are responsible for the regulation of Medicinal Products for human and veterinary use in the European Economic Area. The Heads of Medicines Agencies is supported by working groups covering specific areas of responsibility and by the Heads of Medicines Agencies Management Group and Permanent Secretariat.
The Heads of Medicines Agencies co-operates with the European Medicines Agency and the European Commission in the operation of the European Medicines Regulatory Network (“the Network”).

The guidelines related to statistics are mainly under Clinical efficacy and safety: General and Clinical efficacy and safety: Clinical pharmacology and pharmacokinetics

Some of the guidelines are listed below with comparison to the corresponding FDA guidance.

EMA	FDA
Guideline on adjustment for baseline covariates
Guideline on Missing Data in Confirmatory Clinical Trials
Concept paper on the need for a Guideline on the use of Subgroup Analyses in Randomised Controlled Trials
Guideline on Clinical Trials in Small Populations
Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design	Adaptive Design Clinical Trials for Drugs and Biologics
Guideline on Data Monitoring Committees	Establishment and Operation of Clinical Trial Data Monitoring Committees
Guideline on the Choice of the Non-Inferiority Margin	Non-Inferiority Clinical Trials
Points to consider on switching between superiority and non-infeirority	Non-Inferiority Clinical Trials
	Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials
Points to Consider on Multiplicity Issues in Clinical Trials Concept paper on the need for a guideline on multiplicity issues in clinical trials
Reflection Paper on the Regulatory Guidance for the Use of Health Related Quality of Life (HRQL) Measures in the Evaluation of Medical Products	Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims
Points to consider on application with 1. Meta-Analyses; 2. One pivotal study	-          Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products -          Integrated Summary of Effectiveness
Guideline on the Investigation of Bioequivalence	Statistical Approaches to Establishing Bioequivalence

Other EU regulatory guidelines that I have been exposed to are:

•  Clinical efficacy and safety: Blood products (including biotech alternatives)
• Guidance for the format and content of the final study report of non-interventional post-authorisation safety studies
• ENCEPP Considerations on the Definition of Non-Interventional Trials Under the Current legislative Framework (“Clinical Trials Directive” 2001/20/EC)
• Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies
• Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submissions (NeeS) for human medicinal products
• TIGes Harmonised Guidance for Non-eCTD electronic Submissions (NeeS) for human medicinal products in the EU
• Dossier Format: Regulatory and procedural guidance
• Multinational Clinical Trials in Europe and the Voluntary Harmonisation Procedure (VHP)
• Guidance document for sponsors for a Voluntary Har-monisation Procedure (VHP) for the assessment of mul-tinational Clinical Trial Applications