Guidelines For Notification of Serious Breaches of Regulation (EU) No. 536/2014

Marie Carroll from our regulatory team looks at the steps that need to be taken when there is a serious breach of EU regulation No. 536/2014.  The European Medicines Agency describes the regulation as:

The goal of Clinical Trial Regulation EU No. 536/2014 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. 

Firstly, what is Clinical Trial Regulation EU No. 536/2014?  The European Clinical Trials framework will undergo a major change when the Clinical Trials Regulation 536/2014 comes into application towards the end of 2018. The legislation becomes a regulation, rather than a directive, which will ensure key aspects have identical rules throughout the EU.

The guideline was adopted by the GCP Inspectors Working Group (GCP IWG) on the 30/01/2017 and by the Clinical Trial Facilitation Group (CTFG) on the 31/01/2017. The public consultation on the guideline ended on the 22/08/2017. The guideline was drafted to provide practical advice on how to handle the requirements of Article 52 of Regulation (EU) No. 536/2014.

The Main Characteristics of Regulation (EU) 536/2014

  • A single set of documents to be prepared and submitted for the clinical trial application (CTA).
  • A streamlined application procedure via a single entry point, the EU portal.
  • 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, which means the countries where the trial is intended to be conducted. Part II is assessed by each Member State concerned separately.
  • 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 agreement which will give sponsors increased legal certainty.
  • Streamlined safety 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.

Regulation (EU) No. 536/2014 Article 52 states:

“The sponsor shall notify the member states concerned about a serious breach of this Regulation or of the version of the protocol applicable at the time of breach through the EU portal without undue delay but not later than seven days of becoming aware of that breach”


“For the purposes of this Article, “a serious breach” means a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial”.

The Aim of the Draft Guidance

The aim of the draft guideline is to provide advice on the practical arrangements for notification of serious breaches, classification of breaches and what possible actions might be taken by the member states concerned in response to notifications of serious breaches. A “Who, How, When and What” approach is used to outline the requirements.

Appendix I of the guideline provides examples of serious breaches. It is expected that a documented root cause analysis is carried out to identify the cause of the serious breach and to assess the impact of the breach on the trial and the impact on the subject’s safety and rights. Appendix II outlines points to be considered during the assessment process.

A number of groups have engaged with the consultation process on the draft guideline and have provided extensive feedback to the EMA. The need for a guideline was generally accepted, however, it was found that many of the points made could be enhanced to improve the in-use effectiveness of the guideline.

If you would like to have a discussion with us about the new regulations or any other clinical trial related issue then please feel free to call us on 00353 52 61 76706 or simply complete the webform below and we will call you back.

About the Author
Marie Carroll
Regulatory Affairs Advisor
Marie Carroll is a Regulatory Affairs Advisor with Acorn Regulatory and focuses on issues relating to Chemistry, Manufacturing and Controls. Prior to joining the company she spent over 15 years in senior roles with a large pharmaceutical company. You can read other articles by Marie Carroll by clicking the link below.
Other articles by Marie Carroll