Appendix II – Points to consider for sponsors in relation to the assessment of a breach of Regulation (EU) No 536/2014 or the clinical trial protocol

The aim of this appendix is to help sponsors to adequately identify and assess suspected serious breaches.

This is not an exhaustive list.

• It needs to be considered if the breach meets the definition of serious breach according to Art. 52 of Regulation (EU) No. 536/2014. This may be difficult to determine initially and may take some time to investigate. However, if the incident is likely to affect the safety and/ or rights of a subject to a significant degree or questions the reliability and robustness of the data generated in the clinical trial, then the incident should be regarded as a serious breach and reported as a serious breach during the investigation of the incident.
  
  If there is a proper quality management system in place to ensure that:
   
• The sponsor can identify the root cause for a serious breach.
• The extent of the issue is evaluated and in case of a systematic serious breach, assessed if it can potentially affect other subjects within the same trial and/or other trials.
• There is an assessment whether it was a genuine human error, or lack of training, or failure to follow a procedure.
• If the breach is caused by a service provider, the sponsor checks whether this serious breach affects any of the sponsor’s other trials, whether open or closed, managed by the same service provider.
• If subject safety and/or rights has/have been compromised, proper risk proportional actions are taken, which may include informing the subjects affected about the serious breach.
• The CAPA plan ensures safety of the affected subjects, or the reliability of the data. It needs to be considered if the clinical trial needs to be suspended or terminated or the affected data will need to be removed from the clinical study report.
• The CAPA plan addresses the serious breach and ensures that measures are put in place in order to avoid reoccurrence.
• Internal procedures are updated, training provided, systems updated.
• The proposed timelines for the CAPAs are reasonable according to the serious breach.

© European Medicines Agency, 2021