Finally! EU Regulation 536/2014 progresses from a directive to a regulation, achieving regulatory harmonisation for clinical trials. There's a lot to cover and unpack on the topic, so we asked one of our resident experts to break it down as simply as possible. Let's take a look at what this new regulation means for you, the benefits it presents, and how to transition to it.
Understanding EU regulation 536 / 2014
Regulation (EU) No 536/2014 on clinical trials (CT) on medicinal products for human use came into application on January 31, 2022. This regulation (named the CT Regulation) establishes a new set of harmonised rules applicable to clinical trials performed in the European Union (EU) and the European Economic Area (EEA).
Prior to application of EU Regulation 536/2014, clinical trials in the European Union were governed by Directive 2001/20/EC (known as the CT Directive). Under the directive, individual Member States enacted their own national legislation for clinical trials. By virtue of being a directive, a shortcoming was suffered – the inherent differences in implementation at the national level meant that multinational clinical trials were highly complex and fragmented. The goal of providing a common set of rules for the conduct of clinical trials in the EU was not fully achieved by the CT Directive.
The CT Regulation (EU) No 536/2014 repeals the CT Directive 2001/20/EC. As a regulation, the CT Regulation is binding in its entirety on all EU countries without needing to be transposed into national law. The transformation of the type of legislation (from directive to regulation) is in itself a significant gesture that demonstrates the EU’s desire to simplify and standardise the rules for conducting clinical trials, and thereby increases the attractiveness of the European Union as a region for clinical research.
Clinical Trials Information System (CTIS)
The CT Regulation (EU) No 536/2014 was adopted and entered into force in 2014, however the timing of its application was contingent on the readiness of the Clinical Trials Information System (CTIS). This portal is the backbone for harmonising the submission, assessment, and supervision processes for clinical trials. On January 31, 2022, the European Medicines Agency’s (EMA) launched the CTIS, accessible through a website. It will serve as the single point of entry for submitting clinical trial information in the EU/EEA.
The CTIS targets three main categories of users:
- Sponsors: Clinical trial sponsors (researchers from industry and academia) will use the CTIS to apply for authorisation to run a clinical trial in up to 30 EU/EEA countries via a single application. Sponsors can use the CTIS to provide updates to national regulators about a trial and to submit trial results.
- Authorities: EU/EEA national regulators (National competent authority, Ethics committee) will use the CTIS collaboratively to assess clinical trial applications, to authorise or refuse a trial, and to oversee an authorised trial.
- General Public: Anyone can use the CTIS to search for information on clinical trials. In line with the transparency objectives of the CT Regulation, clinical trial data will become publicly available through the CTIS once a decision on a clinical trial has been made.
Benefits gained from EU Regulation 536/2014
A simpler authorisation process
Prior to the enactment of the CT Regulation (EU) No 536/2014, sponsors had to submit clinical trial applications separately to national competent authorities and ethics committees in each country. Sponsors waiting for regulatory approval to run a clinical trial inevitably experienced administrative delays.
Under the CT Regulation (Chapter II), it remains that a clinical trial shall undergo scientific and ethical review and requires prior authorisation. With the CTIS, the authorisation process is greatly simplified. Duplication of efforts is removed as the sponsors can now submit a single application for authorisation to run a multinational clinical trial, resulting in a single decision for all Member States concerned. The decision on the clinical trial is communicated to the sponsor via the CTIS.
Highest standards for the protection of subjects and patient safety
Under the CT Regulation (Chapter V), it remains that anticipated benefits justify the foreseeable risks and inconveniences that a clinical trial presents to subjects. Informed consent must be given by the subject, and the CT Regulation presents harmonised rules for informed consent.
The CTIS facilitates regulatory oversight of trials by enabling the exchange of information between sponsors and authorities throughout the lifecycle of a clinical trial. Safety reporting obligations are outlined in the CT Regulation (Chapter VII). The reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) remains a responsibility of the sponsor. The most relevant change for sponsors is the legal obligation for the electronic reporting of SUSARs to the EudraVigilance database for a clinical trial performed in at least one Member State. The sponsor must also submit annually a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor. This Annual Safety Report (ASR) is to be submitted via the CTIS.
Reliability and robustness of clinical trial data
Chapter VIII of the CT Regulation addresses the conduct of a clinical trial. It draws on the principles of Good Clinical Practice and explicitly calls on the ICH guidelines for this matter. The conduct of a clinical trial must be monitored to ensure that the reported data are reliable and robust. A clinical trial master file (TMF) containing all the essential documents relating to a clinical trial must be maintained by the sponsor and the investigator, allowing for the verification of the conduct of a clinical trial and the quality of the data generated. According to the CT Regulation, the content of the TMF must be archived for at least 25 years after the end of the clinical trial. By leveraging an eTMF system like Montrium’s eTMF Connect, organizations are able to retain essential documents in an easily accessible digital repository, eliminating the archiving costs and storage burdens associated with maintaining a paper TMF.
Enhanced public transparency of clinical trial data
Data and information submitted through the CTIS are stored in the EU database. In Chapter XIV, the CT Regulation clearly defines the publication aspect of the clinical trial information contained in the EU database. As a general rule, all data will be made public at the first opportunity. The CTIS will make clinical trial data publicly accessible, via a searchable website, once a decision on a clinical trial data. Exceptions will be made for personal data and commercially confidential information.
Transitioning to EU Regulation 536/2014
The CT Regulation (EU) No 536/2014 foresees a 3-year transition period to CTIS. During the first year, sponsors can choose for themselves whether to apply to start a clinical trial via the new CTIS or under legacy methods (e.g. EudraCT) under the CT Directive 2001/20/EC. After the first transition year (from January 31, 2023), all new clinical trial applications must be submitted through CTIS. After the third transition year (by January, 2025), all ongoing trials must be migrated to CTIS.
Getting set up in the CTIS
While the CTIS website provides an open search function for public users, sponsors and authorities can each access their own secure workspace in the CTIS designed to support their respective business processes.
To access a secure workspace, user login (with EMA Account credentials) is required. Individuals can register and create an EMA Account via the EMA Account Management portal. The same EMA Account will provide access to other systems, such as SPOR (substances, products, organisations and referentials database), EudraCT, and EVDAS (EudraVigilance data analysis system).
The CTIS also requires an organisation to be registered in the Organisation Management Service (OMS) . The OMS stores master data (such as organisation name, location address, contact information) that can be retrieved and used to populate the clinical trial application.
Harmonising Study Documents
Transitioning a trial to the CTIS requires some planning. Sponsors will need to ensure that all documentation is available in electronic format for submission via CTIS. Some study documents may need to be reviewed and duly amended. Multinational clinical trials approved under the repealed Clinical TrialsCT Directive should be transitioned as a single multi-country clinical trial application. For this, a harmonised or consolidated protocol is required.
Preparing documents for public access
Another point of concern is the eventual exposure of the clinical trial information through the CTIS. This implies the preparation of a ‘for publication’ and a ‘not for publication’ version of trial documents. Extended redaction of documents to conceal personal data and commercially confidential information is expected. Sponsors should implement procedures for the redaction of documents.
The CT Regulation offers a legal framework that provides regulatory harmonisation for clinical trials in the EU/EEA. The regulation has as an objective to ensure that clinical trial data are reliable and robust while ensuring respect for the rights, safety, dignity, and well-being of subjects.
The regulation fosters innovation by simplifying the clinical trial application process and facilitating the conduct of multinational trials in the EU/EAA. The regulation increases the transparency of clinical trials information and overcomes current limitations of data availability to the public. The net effect will be (hopefully) to increase the attractiveness of the European Union as a location for clinical research. In order to ensure increased transparency, it is important to create critical documents—such as the Protocol and IB—in a validated system, such as Montrium’s eTMF Connect. This facilitates the creation of an audit trail for the entire lifecycle of these documents and allows for more efficient collaboration between stakeholders.