E. Identifying Serious Breaches, Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol Version 6, 08 Jul 2020, MHRA

Deviations from clinical trial protocols and GCP occur commonly in clinical trials. The majority of these instances are technical deviations that do not result in harm to the trial subjects or significantly affect the scientific value of the reported results of the trial. These cases should be documented (for example, in the trial case report form or the trial master file) in order for appropriate corrective and preventative actions to be taken. In addition, these deviations should be included and considered when the clinical study report is produced, as they may have an impact on the analysis of the data. However, not every deviation from the protocol needs to be reported to the MHRA as a serious breach.

What needs to be reported?

• Any serious breach of:

(a) The conditions and principles of good clinical practice in connection with that trial (as defined in UK legislation); or

(b) The protocol relating to that trial, as amended from time to time in accordance with regulations 22 to 25.

• For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a significant degree:

• (a) The safety or physical or mental integrity of the subjects of the trial (this should be relevant to trial subjects in the UK); or

(b) The scientific value of the trial.

The judgement on whether a breach is likely to have a significant impact on the scientific value of the trial 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 data to key analysis parameters, the impact of excluding the data from the analysis etc.

It is the responsibility of the Sponsor to assess the impact of the breach on the scientific value of the trial.

This assessment should be documented, as the appropriateness of the decisions taken by the Sponsor may be examined during MHRA inspections. If the Sponsor is unclear about the potential for a breach to have significant impact on the scientific value of the trial, the Sponsor should contact the MHRA to discuss the issue.

See Appendix I for further information relating to expectation for serious breach topics, this may help when deciding on whether to submit a serious breach notification. Appendix II contains examples of situations that may be considered 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.

It is also the responsibility of the Sponsor to take appropriate corrective and preventative actions in response to the serious breach, and to document these actions. Actions may also be taken by the MHRA, as described below.

What to notify (hints and tips)?

It is strongly recommended that organisations use the provided form to ensure all required information is submitted to the GCP Inspectorate and this should reduce the likelihood of additional information being requested. You do not have to wait until you have all the information, follow-up reports are acceptable. If the investigation or corrective and preventative action is on-going at the time of reporting the serious breach, it is acceptable to indicate your plans with projected timelines for completion. In such case, you should indicate in the initial report when these are expected to be completed and what follow-up reports will be provided to the Inspectorate and when.

Follow-up reports should be made in writing (the serious breaches form can also be used for this) and should:

• Be clearly identified as a follow-up report.

• Identify the unique GCP identification allocated when your initial report was acknowledged (if you are aware of this information).

• Follow-up reports should include all previously submitted information with new information added in a clear and transparent way. Each report form should be a complete record up to that point and therefore only the latest form is needed for review.

• Be forwarded to the inspector dealing with your initial notification directly or via the mailbox.

Back to the Index of the Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol Version 6, 08 Jul 2020, MHRA, Medicines & Healthcare products Regulatory Agency.