Clinical trials - Regulation EU No 536/2014

General information
All clinical trials performed in the European Union are required to be conducted in accordance with the Clinical Trials
Directive until the new Clinical Trials Regulation (CTR) EU No 536/2014 will become applicable, which will be no
earlier than 28 May 2016. For further information please see the information on the Clinical trials Directive and
the transition period.

The new Clinical Trials legislation, which was adopted on 16 April 2014 and entered into force on 16 June 2014, has
taken the legal form of a Regulation. This will ensure that the rules for conducting clinical trials are identical
throughout the EU. This is vital to ensure that Member States, in authorising and supervising the conduct of a clinical
trial, base themselves on identical rules.

The Clinical Trials Regulation aims to create an environment that is favourable for conducting clinical trials, with the
highest standards of patient safety, for all EU Member States.
The main characteristics of the new Regulation are:

A streamlined application procedure via a single entry point, the EU portal.

A single set of documents to be prepared and submitted for the application defined in Annex I of the Regulation.
A harmonised procedure for the assessment of applications for clinical trials, which is divided in two parts. Part I is
jointly assessed by all Member States concerned. Part II is assessed by each Member State concerned separately.
Strictly defined deadlines for the assessment of clinical trial application.
The involvement of the ethics committees in the assessment procedure in accordance with the national law of the
Member state concerned but within the overall timelines defined by the Regulation.
Extension of the tacit agreement principle to the whole authorisation process which, without compromising safety, will
give sponsors, in particular SMEs and academics, increased legal certainty.
Simplified reporting procedures which will spare sponsors from submitting broadly identical information separately to
various bodies and different Member States.
Increased transparency as regards clinical trials and their outcomes.
Union controls in Member states and third countries to ensure that clinical trials rules are being properly supervised
and enforced.
Clinical trials conducted outside the EU, but referred to in a clinical trial application within the EU, will have to comply
with regulatory requirements that are at least equivalent to those applicable in the EU.
The Clinical Trials Regulation has taken up certain provisions from two relevant Directives:

The "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" (the "GCP Directive) ; and
The "Commission Directive 2003/94/EC of 8 October 2003, laying down the principles and guidelines of good
manufacturing practice in respect of medicinal products for human use and investigational medicinal products for
human use" (the "GMP Directive") .
Both the GCP and GMP Directive, to the extent that they concern investigational medicinal products, will be replaced
by the new acts:

An Implementing Regulation on detailed arrangements for inspections procedures on GCP, including qualifications
and training requirements for inspectors; and
A Delegated Regulation on the GMP rules for Investigational Medicinal Products.
More information on the state of play of the Commission implementing measures required by the Clinical Trials
Regulation is available here.
However, during the transitory period the CGP and GMP Directives referred above will continue to apply for the
clinical trials authorised under Directive 2001/20. More information on the transitory period please is available here.
 Guidelines
The Commission has and will continue to issue guidance documents in order to ensure a uniform application of the
legislation on clinical trials in Europe.
The recommendations and guidelines further specifying various aspects of clinical trials, are currently being revised
and updated to be in line with the requirements of the Clinical Trials Regulation.
The guidelines will be launched for public consultation in sets between Q3 and Q4 of 2016. The aim is to finalise and
publish them between the end of 2016 and mid-2017.
This section will be updated progressively once the new guidelines are prepared.

EU Clinical Trial Portal and Database

Article 80 and 81 give the European Medicines Agency (EMA) the responsibility to establish an EU Portal and
Database. The EU Portal will be a single entry point for submission of data and information relating to clinical trials
required by the Regulation. The EU Database will contain all data and information submitted via the EU Portal.
The Portal and Database will considerably facilitate:

the application for clinical trials authorisation, in particular in case of multinational clinical trials, to the sponsor;
the assessment carried out by the Member states authorities;
access to clinical trials information by the general public.
The EU Portal and Database will be the backbone of the new regime for clinical trials in Europe. Therefore, the entry
into application of the Clinical Trials Regulation is made dependant on their full functionality, which will be confirmed
by an independent audit.

EMA together with the Member states and the Commission are currently working in order to set up the portal and
database.

EMA carried out a public consultation on a draft of the functional specifications for the EU portal and EU database to
be audited that closed on 31st October 2014. On 14 December the EMA Management Board endorsed
the Functional specification of the EU portal and EU database to be audited.

Transparency
The Clinical Trial Regulation provides more transparency on the clinical trials data.
All information in the EU database submitted in the clinical trials application and during the assessment procedure
shall be in principle publically accessible unless the confidentiality of the information can be justified on the basis of
any of the below listed grounds:

Protection of commercially confidential information.

Protection of personal data.
Protection of confidential communication between the MS in relation to the preparation of the assessment report.
Ensuring effective supervision of the conduct of clinical trial by Member States.
Additionally the Regulation obliges the sponsor to submit to the Database a summary of results and a lay person
summary 1 year after the end of the trial in the EU .
A Clinical Summary Report should be submitted to the database 30 days after a Member state grants a Marketing
authorisation for the investigational medicinal product, the procedure for granting the marketing authorisation has
been completed, or the applicant for marketing authorisation has withdrawn the application.

The underlying principles to support the transparency requirements of the CT Regulation will be included as an
addendum to the document entitled "Functional specification of the EU portal and EU database to be audited". To this
effect, a draft proposal for an addendum, on transparency, to the "Functional specifications for the EU portal and EU
database to be audited" was launched for public consultation on the EMA website. The consultation ended on 18th
February 2015. More information on the public consultation can be found on the EMA website.
 Safety reporting
The Clinical Trial Regulation simplifies the rules on safety reporting:

The protocol may provide that not all adverse events (AE) and serious adverse events are recorded and reported.
For a clinical trial involving more than one investigational medicinal product (IMP) there is the possibility to submit in
the Clinical Trial Eudravigilance database a single safety report on all IMPs used in that clinical trial.
Suspected unexpected serious adverse reactions (SUSARs) will be reported via the Clinical Trial Eudravigilance
database.
Furthermore, the Regulation obliges Member States to collaborate in assessing the annual Safety Reports and
SUSARs.

Clinical trials conducted outside the EU

If 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" ).

In addition, if an application dossier submitted in accordance with the requirements of Regulation 536/2014 makes
reference to data generated from a clinical trial conducted outside the Union, the clinical trial should be conducted in
accordance with principles equivalent to those of Regulation 536/2014 as regards the rights and safety of the subject
and the reliability and robustness of the data generated in the clinical trial.

Moreover, such data should only be submitted in an application dossier if that clinical trial has been registered prior to
its start in a public register which is a primary or partner registry of, or a data provider to, the WHO ICTRP. Data from
a clinical trial started before the date of application of Regulation 536/2014 shall only be submitted in an application
dossier if that clinical trial is registered in a public register which is a primary or partner registry of, or a data provider
to, the WHO ICTRP or if the results of that clinical trial have been published in an independent peer- reviewed
scientific publication.