Appendix II Examples of Serious Breaches Notified to MHRA (this is not an exhaustive list), the Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol Version 6, 08 Jul 2020, MHRA

Notifier

Details of Breach Reported

Is this a Serious Breach?

Sponsor

Dosing errors reported:

1) A subject was dosed with the incorrect IMP, which was administered via the incorrect route (the IMP used was from a completely different clinical trial to the one the subject was recruited to).
 

2) A subject was dosed with IMP from the incorrect treatment arm. In addition, some months later, the subjects in an entire cohort were incorrectly dosed with IMP three times daily when they should have been dosed once daily.

3) One subject was administered 6 additional doses of IMP. The subject was to receive IMP on day 1 and 8 but instead received IMP on days 1 to 8. The subject experienced a severe adverse event as a result.

4) A subject took IMP that had expired two days ago. The subject did not experience any adverse events and this issue was not likely to affect the data credibility of the trial.

Yes, there was significant potential to impact the safety or physical or mental integrity of trial subjects.

Yes,

• there was impact on the safety or physical or mental integrity of trial subjects or on the scientific value of the trial • this issue was systematic and persistent leading to a constant breach of the conditions and principles of GCP in connection with that trial or the trial protocol

• this issue persisted despite the implementation of a corrective and preventative action plan.

Yes, there was impact on the safety or physical or mental integrity of trial subjects and on the scientific value of the trial.

No, there was no impact on the safety or physical or mental integrity of the trial subject or on the scientific value of the trial. In addition, the assessment of the breach identified this as a single episode and a detailed corrective and preventative action plan was implemented.

Sponsor

IMP temperature excursions reported.

Yes, if the situation was not managed and subjects were dosed with IMP assessed as unstable, which resulted in harm/potential to harm subjects.

No, if the excursions had been managed appropriately (e.g. IMP was moved to alternative location/quarantined as necessary and an assessment (by qualified personnel) illustrated that there was no impact on subject safety and data integrity.

Sponsor

Multiple issues with the Interactive Response Technology (IRT) system across several clinical trials leading to the dispensing of expired IMP and a shortage of IMP at investigator sites in time of subject visits.

Yes, there was impact on the safety or physical or mental integrity of trial subjects and this issue persisted leading to a constant breach of the conditions and principles of GCP in connection with that trial or the trial protocol, despite the implementation of a corrective and preventative action plan.

Sponsor

On two separate occasions the Sponsors identified issues with the same organisation. First with consenting and then with potential fraud in recruitment and consenting. However, there was not unequivocal evidence of fraud at the time of reporting. One of the studies involved paediatric subjects.

Yes, this subsequently led to enforcement action against the organisation in question.

Sponsor

Concerns were raised during monitoring visits about changes to source data for a number of subjects in a trial, which subsequently made subjects eligible with no explanation. An audit was carried out by the Sponsor and other changes to source data were noted without explanation, potentially impacting on data integrity. Follow-up reports sent to MHRA confirmed the Sponsor concerns over consenting and data changes made to source without an adequate written explanation.

Yes.

Note: not all of the information was provided in the original notification, the Sponsor provided follow-up updates.

Sponsor

A clinical trial subject attended A&E who attempted to contact the pharmacy department (using the phone number listed on the emergency card issued to the subject) in order to break the unblinding code. Pharmacy were unable to code break in a timely manner, as a result, the subject withdrew from the clinical trial feeling unhappy that the pharmacy was not available in an emergency situation. CRO A

Yes, as this had significant potential to harm the subject if unblinding would have affected the course of treatment.

CRO

A cohort had invalid blood samples as they were processed incorrectly. As a result one of the secondary endpoints could not be met. Therefore, a substantial amendment was required to recruit more subjects to meet the endpoint. Subjects were dosed unnecessarily as a result of this error.

Yes

CRO

Subject safety was compromised because repeat ECGs were not performed, as required by the protocol. Also, there was inadequate QC of the interim safety reports used for dose escalation which has potential for stopping criteria to be missed.

Yes

Contractor

The Investigator failed to report a single SAE as defined in the protocol (re-training provided)

No, if this did not result in other trial subjects being put at risk, and if it was not a systematic or persistent problem. In some circumstances, failure to report a SUSAR could have a significant impact on trial subjects. Sufficient information and context should be provided for the impact to be assessed adequately.

Identified during inspection

Investigator site failed to reduce or stop trial medication, in response to certain laboratory parameters, as required by the protocol. This occurred with several subjects over a one-year period, despite identification by the monitor of the first two occasions. Subjects were exposed to an increased risk of thrombosis.

Yes

Identified during inspection

A potential serious breach was identified, but not reported (documentation in the Sponsor’s TMF identified that there may have been fraud at an investigator site, re-use of previous time point data in later time points). The Sponsor had investigated and the issue was subsequently found to be a genuine error and not fraud.

No, on this occasion. However, had this been identified as fraud impacting on the integrity of the data, then this serious breach would not have been notified within the regulatory timeframe (i.e. 7 day window).

Sponsor

Patient Information Leaflet and Informed Consent updated, but at one trial site this was not relayed to the patients until approximately 2-3 months after approval. More information on the potential consequences of the delay should have been provided.

No, if this was not a systematic or persistent problem and if no harm to trial subjects resulted from the delay.

Yes, if there was a significant impact on the integrity of trial subjects (e.g. there was key safety information not relayed to subjects in a timely manner).

Sponsor

Visit date deviation. A common deviation in clinical trials.

No, a minor protocol deviation, which does not meet the criteria for notification.

MHRA (CTU)

The GCP Inspectorate was notified that a substantial amendment had been submitted regarding changes to dosing on a first in human study, as a result of an SAE after dosing the initial subject. The sponsor had temporarily halted the trial and only after further investigation had assigned the SAE as unrelated. The sponsor had not notified the CTU of the “urgent safety measure” implemented or reported the SAE as a potential SUSAR.

Yes

NRES

The early destruction of investigator site files (i.e. one study had only been completed a year earlier and one study was still ongoing).

Yes

Member of public

A member of public received a named invite to be a volunteer in a clinical trial (no specific trial mentioned). However, this person was not on the organisation’s volunteer database and had not participated previously in a study. On further investigation by MHRA, it was revealed that the organisation had contracted the use of a mail shot organisation to send a generic mail shot to a list of people in a specific location, over a certain age. This had been approved by the REC.

No