Regulation (EU) No 536/2014

From Codex of clinical research

The European Union Clinical Trials Regulation (CTR) (EU No 536/2014) is a legislation that aims to simplify and harmonize the administrative provisions governing clinical trials in the European Union. The Regulation came into force on 31 January 2022 and repealed the previous legislation, namely the Clinical trials Directive 2001/20/EC. Main objectives of the Regulation are to:

  • harmonise the rules on clinical trials across the EU;
  • facilitate the conduct of multinational clinical trials;
  • improve efficiency, transparency, and data robustness;
  • strengthen subject safety and regulatory supervision.

Legal status and applicability

  • Adopted: 16 April 2014
  • Became applicable: 31 January 2022. This delay was due to the required development and validation of the EU Clinical Trials Information System (CTIS).
  • Repealed: Directive 2001/20/EC as of applicability date

Transition period and CTIS implementation

Although the Regulation entered into force in 2014, its application was contingent on the availability of a fully functional EU submission system. CTIS was confirmed operational in April 2021 [1], leading to a formal applicability date of 31 January 2022.

A transition period followed, during which sponsors could choose to initiate trials under either the former Directive 2001/20/EC or the new Regulation via CTIS. From 31 January 2023, all new clinical trials in the EU must be submitted exclusively via CTIS, marking the full entry into force of the Regulation.

Features of the Regulation (EU) No 536/2014

Single EU-wide authorisation process

Under the previous Directive 2001/20/EC, clinical trials conducted across multiple EU Member States required separate applications in each country, each following its own format, timelines, and national procedures.

The Regulation introduces a unified submission system through the CTIS. This allows sponsors to submit a single application for all concerned Member States, streamlining the process significantly. The application is assessed in two coordinated parts:

  1. Part I covers scientific and technical aspects (such as methodology, risk-benefit analysis, IMP quality). This part is jointly assessed by all relevant Member States.
  2. Part II addresses country-specific elements (including ethical approval, language requirements, and informed consent). Each Member State evaluates this section individually.

Although each Member State makes its own authorisation decision, the process is based on a shared evidence base. This harmonised system is particularly beneficial for multinational trials, reducing administrative duplication and enabling faster trial initiation.

Transparency provisions

The Regulation significantly strengthens transparency obligations related to clinical trial data. All submissions made via CTIS become part of a public EU database, accessible by default unless specific reasons justify confidentiality. These include:

  • protection of commercially confidential information;
  • compliance with data protection laws;
  • safeguarding confidential communications among Member States;
  • ensuring effective supervision and enforcement of clinical trials.

The public disclosure of data is intended to improve trust in the clinical research process, support secondary research, and facilitate better public awareness of ongoing and completed trials. As of 18 June 2024, updated transparency rules apply [2], supported by a revised version of the CTIS public portal.

Subject protection and Informed consent

The Regulation includes reinforced measures to protect the rights, safety, and well-being of clinical trial participants. Sponsors are required to provide clear and accessible information to participants, especially those considered vulnerable (e.g., minors, incapacitated adults, or emergency cases).

Ethical and scientific assessments must demonstrate that the benefits of the trial outweigh its risks. National authorities are responsible for ensuring that informed consent procedures meet legal and ethical standards, and that trial designs minimize harm.

Simplified safety reporting

Safety reporting procedures are streamlined under the Regulation. Sponsors may define in the trial protocol that only certain adverse events (AEs) and serious adverse events (SAEs) need to be recorded, focusing on those relevant to trial objectives.

A single annual safety report (ASR) is now sufficient for a trial involving multiple investigational medicinal products (IMPs). Suspected unexpected serious adverse reactions (SUSARs) must be reported through the EudraVigilance database.

Clinical trials conducted outside the EU

For marketing authorisation applications submitted within the EU, any clinical trials conducted in third countries must adhere to standards equivalent to those outlined in the Regulation. This includes respect for participant rights, scientific reliability, and ethical oversight.

Additionally, such trials must be registered prior to initiation in a WHO-recognised registry [3]. Data from trials conducted before the Regulation’s applicability, or published in a peer-reviewed journal, must also meet these principles to be considered valid for regulatory use.

Regulatory oversight and inspections

The European Medicines Agency (EMA) is responsible for the development, maintenance, and operation of the CTIS platform and associated EU clinical trials database.

Regulatory oversight is shared between the European Commission and Member States, which may conduct:

  • Good Clinical Practice (GCP) inspections of trial sites;
  • Good Manufacturing Practice (GMP) inspections of facilities producing investigational products.

Union controls [4] may be initiated to ensure Member State compliance with the Regulation. These controls can also assess whether third countries meet standards equivalent to EU rules, particularly in relation to participant safety and data quality.

See also

Another relevant pages

Links to this page

References and notes

  1. ↑ Clinical Trials Information System reaches major milestone towards go-live and application of the Clinical Trial Regulation, https://www.ema.europa.eu/en/news/clinical-trials-information-system-reaches-major-milestone-towards-go-live-and-application-clinical-trial-regulation Accessed Jun 2025
  2. ↑ Clinical Trials Information System (CTIS) Bitesize Talk: Revised transparency rules and the new CTIS public portal, https://www.ema.europa.eu/en/events/clinical-trials-information-system-ctis-bitesize-talk-revised-transparency-rules-new-ctis-public-portal Accessed Jun 2025
  3. ↑ International Clinical Trials Registry Platform (ICTRP) Registry Network, https://www.who.int/tools/clinical-trials-registry-platform/network Accessed Jun 2025
  4. ↑ Union controls are specific regulatory enforcement tool defined under Regulation (EU) No 536/2014. These are audits or inspections conducted by the European Commission, sometimes jointly with Member States, to ensure that the Regulation is correctly applied across the EU. Purpose of union controls are 1) to assess whether Member States are properly supervising clinical trials conducted under the Regulation and 2) to evaluate whether third countries (i.e., non-EU countries) have equivalent regulatory systems in place regarding protection of trial participants; data quality and robustness; compliance with ethical principles equivalent to EU standards.

External links


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