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4. Current European Legislation Situation

Prior to 2001, each EU member state had its own national clinical trials regulations and approval systems, (e.g. Clinical Trials Act 1987 and 1990 in Ireland). This increased the complexity of multi-national European clinical research, primarily due to differing requirements and approval mechanisms between countries. In an attempt to standardise and harmonise clinical trial approvals amongst member states the European Commission introduced the first European Clinical Trials Directive. In Europe all clinical trials are subject to approval by a regulatory authority and favourable opinion by a Research Ethics Committee (REC). The CT Directive set out the minimum requirements for clinical trials with a specific sub-category of medicines called ‘investigational medicinal products’ (IMPs). This had to be implemented into national law in each European country by May 2004.
These requirements included:
  • Protection of trial participants as stated in the Declaration of Helsinki.
  • Regulatory authority approval per member state, within specific timelines.
  • A single REC opinion (per member state), within specific timelines.
  • Common quality standard of GCP (ICH-GCP).
To find out about the requirements of individual countries please visit the EMA website, where in the EU Member states section there is a list of National Competent Authorities (NCAs).
One of the major changes introduced is an application procedure that will require sponsors to apply for authorisation to conduct an interventional/low-intervention clinical trial (CT) via a new EU portal.1 The regulation’s effective date is dependent on the availability of the portal and its associated database, which are in development and subject to user acceptance testing by EMA stakeholders. The regulation introduces a single approach for the application and maintenance of a CT authorisation, and applies to both single or multiple member state trials. This procedure not only combines the content of what can be currently referred to as the “regulatory” and “ethics” applications, but also combines the scientific, technical, and ethical review necessary to receive approval to conduct a CT in the EU. In addition, the regulation defines procedural timelines, harmonizes document requirements, and aims to reduce the administrative burden of applications.
The application content and assessment are divided into two parts: Part I contains scientific and medicinal product documentation; Part II contains the national and patient-level documentation (see Table 1, adapted from Juliette L. Kirk, 2017).
Table 1: New CT application summary

Part I

Part II

Application form

Informed consent form and subject
information leaflet

Cover letter (including sponsor’s justification for the classification as a low intervention CT, if necessary

Compensation arrangements

Investigator’s brochure

Suitability of investigators and facilities

Good manufacturing practice
documentation

Proof of insurance or indemnification

Investigational medicinal product dossier/
Auxiliary medicinal product dossier

Data protection rules

Scientific advice

Proof of fee payment

EU Paediatric Investigation Plan decision

Note: Precise content will be determined
by each member state

Example of investigational and auxiliary
medicinal product labelling
In Summary
The EU CT regulation introduces a new procedure, new timelines, and revised application content. Although it may increase or decrease the overall timelines in some MSs, it will bring increased predictability for CT start in the EU.
Significant changes for the MS competent authorities, ethics committees, and sponsors.

  • At the MS level, ethics committees and competent authorities will need to agree how to work together to achieve the review outcome within the required timelines.
  • At the EU level, MSs will need to agree how to work together to achieve what is required to complete the application review.
  • Industry CT sponsors will need to prepare themselves to confirm country selections without negatively affecting planned study start (i.e., avoiding multiple applications to add MSs), respond to application review queries within short timelines, and manage changes so they can be submitted when needed rather than waiting for an ongoing application to complete.
1. European Commission. Clinical Trials. Directive No. 2001/20/EC. 4 April 2001. Available at: http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf
2. Official Journal of the European Union. Regulations. “Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC.” 27 May 2014. Available at: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf
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