5. Reporting serious breaches – Points to consider: Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol

5.1. What needs to be reported?

Any breach of:

The Regulation (EU) No 536/2014.
or
The clinical trial protocol version applicable at the time of the breach.
which is likely to affect to a significant degree:
The safety of a trial participant.
and/or
The rights of a trial participant.
and/or
The reliability and robustness of the data generated in the clinical trial.

is serious and should be notified.

In line with Article 47 of the Regulation (EU) No 536/2014, the sponsor of a clinical trial and the investigators shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice.

The judgement on whether a breach is likely to affect the reliability and robustness of the trial data depends on a variety of factors, for example: the design of the trial, the type and extent of the data affected by the breach, the overall contribution of the affected data to key analysis parameters, the impact of excluding the data from the analysis etc. It should be noted that mitigation actions undertaken to remediate the occurrence of the serious breach do not negate the fact that a breach occurred and should be treated according to the legal requirements.

In the same way, if a systematic and/or significant mis-dosing occurred, this would still meet the criteria for a serious breach regardless of whether or not the trial participant(s) suffered adverse reactions as a result of that mis-dosing.

It is the responsibility of the sponsor to thoroughly perform a root cause analysis to identify the cause of the serious breach and to assess the impact of the breach on the reliability and robustness of the trial data as well as the impact on a trial participant’s safety and/or rights.

This assessment should be documented, as the appropriateness of the decisions and actions taken by the sponsor may be examined during any process triggered by the notification of the serious breach for example during GCP inspections.

Where the tasks of the sponsor have been delegated to a party, and a disagreement rises on classification/assessment of the breach between the sponsor and the delegated party resulting in no notification of a serious breach, the related communication between sponsor and delegated party should be documented. In particular, their respective individual position on whether or not a serious breach occurred should be recorded. In addition, the sponsor’s reasons for not proceeding with the notification, whilst taking into account the views of the delegated party, should be documented.

Section 7 on ‘General considerations for serious breaches’ provides further information related to expectations for serious breach topics. This may help when deciding on whether to consider a breach as serious. Appendix I contains examples of situations that may be considered as serious breaches depending on the context of the situation. This list is not exhaustive and other types of serious breaches may occur. It is the sponsor’s responsibility to assess the information and ensure appropriate reporting. Appendix II contains points to consider for sponsors in relation to the assessment of a breach.

Deviations from clinical trial protocols, good clinical practice (GCP) and/or European or national legislation may occur in clinical trials and where these are considered important, as defined by the ICH E3 guideline on the structure and content of clinical study reports, they should be described in the clinical study report (CSR). It is important to underline that an important deviation as defined in the ICH guideline E3 questions and answers (R1) is not equivalent to the definition of a serious breach and therefore an important deviation is not necessarily also a serious breach and vice versa. Nevertheless all serious breaches should be included in the corresponding clinical study report. Deviations that do not significantly affect the safety and/or the rights of a trial participant or the reliability and robustness of the data generated in the trial should be documented (for example, in the trial case report form or the clinical trial master file) in order for appropriate corrective and preventive actions to be taken.

In addition, deviations considered important as defined by the ICH E3 guideline, even if they are not considered serious breaches, should be included in the clinical study report, as they may have an impact on the analysis of the data. However, not every (important) deviation from the protocol needs to be reported through the CTIS as a serious breach.