Medicinal products for human use
Clinical trials are investigations in humans intended to discover or verify the effects of one or more investigational medicinal products ("IMPs").
Requirements for the conduct of clinical trials in the EU are provided for in " 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" (" the Clinical Trials Directive ").
The Clinical Trials Directive is concretised further by " 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" (Good Clinical Practice - " the GCP Directive ").
Clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials Directive. If the clinical trials are conducted outside the EU, but submitted in an application for marketing authorisation in the EU, they have to follow the principles which are equivalent to the provisions of the Clinical Trials Directive (cf. Annex I, point 8 of the " 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" - " the Community Code for medicinal products ").
There are a number of guidelines further specifying various aspects of clinical trials, and in particular:
- The inforation to be submitted to the competent authorities and to the ethics committees
- The requirements on safety monitoring and the reporting of adverse reactions
- The requirements regarding Good Clinical Practice, including the documentation, of the clinical trials
- The specific requirements regarding the products and the clinical trials
- The inspections of competent authorities and the applicable procedures
These guidelines have been published by various bodies:
- By the European Commission: In this case, they are published in Volume 10 of "EudraLex - The rules governing medicinal products in the European Union"
- By the European Medicines Agency ("EMA") These guidelines concern in particular:
- Inspection procedures and guidance for GCP inspections conducted in the context of the Centralised Procedure
- Requirements relating to the quality, safety and efficacyof products, as well as specific types of products. Volume 3 of EudraLex
- Moreover, the Heads of Medicines Agencies have established a Clinical Trials Facilitation Group ("CTFG") (in which the Commission and EMA are observers), in order to discuss ongoing technical issues.
Clinical trial application
The Clinical Trials Directive harmonises the rules in the EU for the approval of a clinical trial conducted in a Member State. As regards national competent authorities, the details are set out in the 'Commission Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)' published in EudraLex Volume 10.
A European database - EudraCT - contains all ongoing or completed clinical trials falling within the scope of Directive 2001/20/EC, i.e. with at least one investigator site in the EU (incl. the European Economic Area) and commencing after implementation of Directive 2001/20/EC by the Member States. This database gives the competent authorities of the Member States, the EMA and the Commission the necessary information to communicate on clinical trials and to maintain oversight of clinical trials and IMP development. This provides for enhanced protection of clinical trial subjects and patients receiving IMPs. More information, including a user manual for EudraCT is available on the EudraCT Supporting Documentation web page.
<>Paediatric clinical trials that form part of a Paediatric Investigation Plan (PIP) but are conducted in third countries will also be included in the near future (paediatric clinical trials with sites in the EU/EEA are already included).
Transparency of information related to clinical trials
Union legislation provides that certain information contained in EudraCT is to be made accessible to the public. This public accessibility concerns clinical trials with paediatric as well as non-paediatric participants. It englobes protocol-related information and result-related information. And it covers both negative and positive results.
To implement the legislation further, the Commission has issued a set of guidelines, which are accessible via chapter V of EudraLex, Volume 10.
These guidelines consist of three "mother guidelines" (Guideline 2008/C168/02; Guideline 2009/C28/01, Guideline 2012/C302/03), setting out the principles, responsibilities, and procedural aspects. The "mother guidelines" are further concretised by way of a number of very detailed "daughter guidelines".
With regard to result-related information, this information is presently not contained in EudraCT at all. Therefore, prior to making anything public, the necessary guidelines had to be adopted and published. These are published in EudraLex, Volume 10. Programming of the relevant databases is currently ongoing. More information is available here.
For all additional information, reference is made to the applicable guidelines in chapter V of EudraLex Volume 10.
The Clinical Trials Directive introduces rules on safety reporting in the context of a clinical trial. Further details are set out in 'the Commission Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’)' published in EudraLex Volume 10. Regarding suspected unexpected serious adverse reactions (SUSARs), this guidance provides inter alia the rules for reporting directly to the national competent authority. In order to obtain the national address for the direct reporting, click on the relevant Member State:
Austria (mail or by fax to: Bundesamt für Sicherheit im Gesundheitswesen (BASG), Österreichische Agentur für Gesundheit und Ernährungssicherheit (AGES) PharmMed, Institut Pharmakovigilanz, Schnirchgasse 9, A-1030 Wien, Österreich, Fax: +43 (0) 50555-36207), Denmark, Germany, Greece, Ireland, Italy (email@example.com), Netherlands, Portugal, Sweden, United Kingdom.
Adoption of the proposal for a "Clinical Trials Regulation"
On 17 July 2012, the Commission has adopted a "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 " (hereinafter "Clinical Trials Regulation") .
In addition, a 'citizen summary' has been published.
The proposal has been submitted to the European Parliament and the Council who engage in ordinary legislative procedure. You find an overview of this procedure here. To follow the proposal in the different steps of the procedure, please consult the "legislative observatory" of the European Parliament or PreLex, the EU-database on interinstitutional procedures.
Preparation of the Commission proposal
In its Communication of 10 December 2008 to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on “Safe, Innovative and Accessible Medicines: a Renewed Vision for the Pharmaceutical Sector”, the Commission announced that an assessment would be made of the application of the Clinical Trials Directive.
This assessment would consider, in particular, various options for improving the functioning of the Clinical Trials Directive with a view to making legislative proposals, if appropriate, while taking the global dimension of clinical trials into account.
In 2009, a public consultation document along this line was published here. The responses have been published here. A summary document of the responses is available here.
A 'roadmap' of the Commission impact assessment, setting out the main structure and the next steps, was made available here.
On 9 February 2011, a public consultation on a concept paper on the revision of the 'Clinical Trials Directive' 2001/20/EC has been launched. The concept paper presented:
- a 'preliminary appraisal' of which option appeared to be the most suitable one to address some of the key concerns of the Clinical Trials Directive, on the basis of the current state of the impact assessment; and
- the main figures used to evaluate the impacts of the different policy options.
Useful contact points
For further information, please find below the relevant contact points:
- Concerning the regulatory framework for clinical trials
- Concerning guidelines on inspections
- Concerning EudraCT
- Member State contacts
Other useful links
- Guidelines on clinical trials of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
- Council for International Organizations of Medical Science (CIOMS)
- World Medical Association (WMA)
- International Clinical Trials Registry Platform (ICTRP) of the World Health Organisation (WHO)