E. Identifying serious breaches:
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 e.g. in the case report form for the trial or 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 e.g. 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 and 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.
Examples illustrating breaches classified as serious or non-serious (this is not an exhaustive list):
1. A breach of GCP or the protocol leading to the death, hospitalisation or permanent disability of a trial subject in the UK. Please note, not every serious adverse event (SAE) or suspected unexpected serious adverse reaction (SUSAR) would routinely be classified as a serious breach, but SAEs/SUSARs resulting from a breach of the conditions and principles of GCP or a breach of the protocol may constitute a serious breach. Submission of a serious breach notification to the MHRA Inspectorate does not obviate the requirement for a SUSAR report, where applicable, to be submitted to the concerned competent authorities e.g. via the EudraVigilance database.
2. Proof of fraud relating to clinical trial records or data, if the fraud is likely to have a significant impact on the integrity of trial subjects or the scientific value of the data.
Although not a legal requirement under 29A, the MHRA GCP Inspectorate encourages the reporting of all confirmed instances of clinical trial fraud occurring at sites in the UK, which the Sponsor becomes aware of. The reason for this is that, although fraud at one particular trial site may not have a significant impact on scientific value or subject integrity for that particular trial, the MHRA would wish to assess the impact on other trials or subjects/patients at that site.
If clinical trial fraud is identified at a non-UK trial site, for a trial that is also being conducted in the UK, a serious breach notification should be submitted to MHRA if the fraud is likely to have a significant impact on the integrity of trial subjects in the UK or on the overall scientific value of the trial. A site refers to any site involved in the trial e.g. CRO or other contracted organisation and not solely to investigator sites.
3. Persistent or systematic non-compliance with GCP or the protocol that has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial. For example, widespread and uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial subjects in the UK or which has a significant impact on the scientific value of the trial. Another example would be of an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger (e.g. abnormal laboratory results) defined in the protocol.
4. Failure to control investigational medicinal product(s) such that trial subjects or the public in the UK are put at significant risk or the scientific value of the trial is compromised. If a serious breach occurs due to an IMP defect, a drug defect report may need to be submitted to the MHRA Defective Medicines Reporting Centre (DMRC), in addition to the serious breach notification.
5. Failure to report adverse events, serious adverse events or SUSARs in accordance with the legislation, such that trial subjects, or the public, in the UK are put at significant risk e.g. inadequate safety reporting in dose escalation studies may have an impact on the decision to escalate to the next dose level.
6. For trials that are on-going in the UK, should serious breaches that occur at non-UK sites be reported?
a. A serious breach is identified at an investigator site in Mexico. The breach has a significant impact on the integrity of trial subjects at the Mexican site and is likely to have a significant impact on the integrity of trial subjects in the UK. For example, the cause of the breach is such that the breach may occur at other trial sites, e.g. death of a subject due to incorrect administration of IMP resulting from erroneous reconstitution instructions in the protocol. Notify the MHRA of the serious breach (other concerned competent authorities may also need to be informed).
In relation to the example quoted, an urgent safety measure (USM) may need to be implemented to address the cause of the breach. If, in order to address the cause of a serious breach, a USM is implemented at UK sites, to amend the conduct of the trial or suspend the trial, a USM notification should be sent by the Sponsor to the MHRA Clinical Trials Unit within 3 days from the date the measures are taken (in accordance with Regulation 30), in addition to the serious breach notification to the MHRA Inspectorate.
b. A serious breach is identified at an investigator site in Mexico, which is likely to affect to a significant degree the overall scientific value of the trial. Notify the MHRA of the serious breach (other concerned competent authorities may also need to be informed).
Please see Appendix I for a selection of notifications that have been received to date that may help Sponsors when deciding whether to submit a notification of a serious breach.
This is not an exhaustive list. Other types of serious breaches may occur and it is the responsibility as Sponsor 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.