Clinical Trial Regulation
The way clinical trials are conducted in the European Union (EU) will undergo a major change when the Clinical Trial Regulation (Regulation (EU) No 536/2014) comes into application. The Regulation harmonises the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS). CTIS will contain the centralised EU portal and database for clinical trials foreseen by the Regulation. The European Medicines Agency (EMA) will set up and maintain CTIS, in collaboration with the Member States and the European Commission.
Although the Clinical Trials Regulation was adopted and entered into force in 2014, the timing of its application depends on confirmation of full functionality of CTIS through an independent audit. The Regulation becomes applicable six months after the European Commission publishes notice of this confirmation.
When the Regulation becomes applicable, it will repeal the existing EU Clinical Trial Directive (EC) No. 2001/20/EC and national legislation that was put in place to implement the Directive. It will also apply to trials authorised under the previous legislation if they are still ongoing three years after the Regulation has come into operation.
The authorisation and oversight of clinical trials remains the responsibility of Member States, with EMA managing CTIS and supervising content publication on the public website.
The goal of the Clinical Trial Regulation is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information. The Regulation will require:
- consistent rules for conducting clinical trials throughout the EU;
- information on the authorisation, conduct and results of each clinical trial carried out in the EU to be publicly available.
This will increase the efficiency of all trials in Europe with the greatest benefit for those conducted in multiple Member States. It aims to foster innovation and research, while helping avoid unnecessary duplication of clinical trials or repetition of unsuccessful trials.
The key benefits of the Regulation include:
- harmonised electronic submission and assessment process for clinical trials conducted in multiple Member States;
- improved collaboration, information-sharing and decision-making between and within Member States;
- increased transparency of information on clinical trials;
- highest standards of safety for all participants in EU clinical trials.
CTIS will be the single entry point for submitting clinical trial information in the EU, which will be stored in the system. EMA will make information stored in CTIS publicly available subject to transparency rules.
The clinical trial application form and supporting dossier will cover all regulatory and ethics assessments from the Member States concerned. It will also include the public registration of the clinical trial and any subsequent updates.
EMA published the functional specifications for the EU portal and database available through CTIS to be audited in December 2014, following a public consultation:
The system will support the day-to-day business processes of Member States and sponsors throughout the life-cycle of a clinical trial in a user-friendly way.
It will provide regulatory oversight of clinical trials and tools for supervision and monitoring.
It will contain collaboration tools, workflow and document management capabilities, accessible via individual workspaces.
A secure workspace will assist clinical trial sponsors in preparing and compiling data to submit to the system for assessment by Member States. It will allow sponsors to:
- manage users and user roles. within their organisations;
- compile clinical trial application dossiers for new and updated trials;
- cross-reference to product documents in other clinical trials;
- upload documents for clinical trial application submission;
- receive alerts and notifications for ongoing trials;
- respond to requests for information and view deadlines;
- search and access clinical trials;
- record clinical trial results.
A secure workspace will support the activities of Member States and the European Commission in overseeing clinical trials. It will allow Member States to:
- manage users and user roles within their organisations;
- view clinical trial application dossiers;
- manage tasks related to the assessment of clinical trials;
- collaborate within and between Member States;
- receive alerts and notifications for ongoing trials;
- download documents submitted by clinical trial sponsors;
- record inspections of sites and clinical trials.
Through the website, members of the public can access detailed information on all clinical trials conducted in the EU, in all official EU languages. The website will provide the following features:
- overview of clinical trial statistics;
- advanced search;
- download data and reports;
- site updates and announcements.
EMA's Management Board endorsed a delivery timeframe in December 2015. However, the system's go-live date has been postponed due to technical difficulties with the development of the IT systems.
The IT supplier has submitted to EMA a revised project plan with improved project management, development and testing processes, resources and increased contingency. EMA has also subsequently revised the CTIS project methodology and delivery plan.
Member States and stakeholders are directly engaged in the development of CTIS through nominated ‘product owners’ to ensure that their expectations are taken into account. This means that nominated business experts representing user groups from the national competent authorities and ethics committees and from sponsors have an enhanced and continuous opportunity to test, review, select and verify functionalities.
Since June 2019, the development of CTIS has been following an agile and iterative delivery model, with functionalities delivered in short development cycles.
At the end of 2019, EMA, the nominated product owners and the IT supplier carried out a first audit readiness assessment to identify critical business blockers and agreed a plan outlining items that still need to be developed or fixed for audit.
The latest release of the system that was validated by the nominated product owners in December 2019 enhances CTIS functionalities for processing the evaluation of clinical trial applications, data submission and view of data, management of user access, users’ oversight of activities and data transparency. These enhancements relate mainly to the authority and sponsor workspaces in the system.
The audit of the system will commence in December 2020.
Update: In March 2020, EMA's Management Board endorsed the audit methodology for CTIS enabling the process for the selection of the supplier for the audit of the system to commence.
EMA, together with product owners, is carrying out a second readiness assessment in the first months of 2020 to identify critical items that must be addressed prior to the audit. This will be followed by a further operational assessment (including of the public portal) to determine the full scope of the auditable version. Specialised users, in collaboration with the product owners, have already assessed the 'union control' and 'inspection' modules of CTIS.
EMA is closely monitoring performance of the IT supplier to ensure timely delivery of a reliable audit version of CTIS.
For more information on the original delivery timeframe, see:
The Clinical Trial Regulation requires all information stored in the database to be publicly available, unless exempted under the Regulation to protect:
- personal data;
- commercially confidential information, in particular the marketing-authorisation status of the medicine, unless there is an overriding public interest;
- confidential communication between Member States in the preparation of their assessment;
- supervision of clinical trials by Member States.
EMA has added two sets of requirements to the functional specifications for applying the exceptions:
- features to support making information public;
- disclosure rules describing the practical implementation of the transparency rules.
The EMA Management Board endorsed both documents in 2015:
European Commission consultations
In preparation for the implementation of the Regulation, the European Commission published on 1 June 2016 the following guidance documents for public consultation until 31 August 2016:
- Risk proportionate approaches in clinical trials
- Summary of Clinical Trial Results for laypersons
- Definition of investigational medicinal products and use of auxiliary medicinal products
- Ethical considerations for clinical trials on medicinal products conducted with minors
For more information, see European Commission: Clinical trials - Major developments.
The Agency consults on its proposals with EU Member States, the European Commission and stakeholders representing non-commercial and commercial clinical-trial sponsors, healthcare professionals and patient groups.
EMA consulted on the draft functional specifications in October 2014. A total of 47 individuals and organisations submitted more than 500 comments:
- Draft functional specifications for the EU portal and EU database to be audited
- Overview of comments received on 'Draft functional specifications for the EU portal and EU database to be audited'
EMA held a three-month consultation in 2015 on implementing the transparency rules. Over 80 different individuals and organisations submitted more than 1,100 comments:
- Draft proposal for an addendum, on transparency, to the “Functional specifications for the EU portal and EU database to be audited
- Draft Appendices to Draft proposal for an addendum, on transparency, to the Functional specifications for the EU portal and EU database to be audited
- Overview of comments on EMA/641479/2014 Draft proposal for an addendum, on transparency, to the “Functional specifications for the EU portal and EU database to be audited - EMA/42176/2014”
- Specific comments on sections 1 to 4.3
- Specific comments on section 4.4
- Specific comments on sections 4.5 to 5
- Questions and answers - Public consultation on implementation of transparency requirements of the European Clinical Trial Regulation