Appendix I – Examples of serious breaches: Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol

Category

Details of breach reported

Is this a serious breach?

1. IMP

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

1.1.2 A subject was systematically not administered IMP doses by mistake, what may result in disease breakthrough or relapse.

1.1.3 A subject received/was administered IMP during pregnancy without having previously performed a pregnancy test required as per protocol, what may result in embryo-foetal toxicity.

Yes, it is likely to affect to a significant degree the safety and rights of a subject in the clinical trial. Such breaches may be caused, for e.g. by lack of training and may impact other subjects as well.

1.2.1 A subject was administered the incorrect dose of IMP. In spite of CAPA implementation, 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.

1.2.2 A subject systematically did not receive essential concomitant therapy described as per protocol, what may result in higher toxicity of IMP (e.g. oncology trials).

Yes

• there was impact on the safety and rights of a trial subject or on the reliability and robustness of the data generated in the clinical trial;

• this issue was systematic and persistent leading to a breach of the Regulation and the trial protocol;

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

1.3.1 One subject was systematically administered additional doses of IMP. The subject was given instructions to take higher doses of IMP than what was stipulated in the protocol. The subject experienced a severe adverse event as a result.

1.3.2 One subject was mistakenly and repeatedly administered lower doses of IMP what may result in disease breakthrough or relapse.

Yes, there was impact on the safety and rights of a trial subject and on the reliability and robustness of the data generated in the trial. Even if the subject didn’t experience an adverse event, the case is considered a serious breach because the dosing error was systematic and has an impact on the reliability and robustness of the data.

1.4 A subject took IMP that had expired two days ago. The IMP was stable and the subject did not experience any adverse events and this was a single isolated incident.

No, there was no impact on the safety and rights of a trial subject or the reliability and robustness of the data generated in the clinical trial.

1.5 A subject was harmed due to incorrect administration of the IMP as a result of incorrect instructions in the protocol.

Yes, as it affected the safety of the subject in the clinical trial. Moreover, subjects enrolled in the trial at other sites could be equally at risk. In this case, the breach would be relevant to EU/EEA sites and should be reported as a serious breach.

2. Temperature monitoring

2.1.IMP temperature excursions reported.

2.2 Compounded sterile IMP preparations were systematically administered after been stored in inadequate conditions.

Yes, if the situation was not managed and subjects were dosed with IMP assessed as unstable or where stability cannot be verified or reasonably assumed, which resulted in harm/potential to harm subjects. This is likely to affect to a significant degree the safety and rights of a subject in the clinical trial.

No, if the excursions had been managed appropriately e.g. IMP was moved to alternative location/quarantined as necessary and a documented assessment (by qualified personnel) illustrated that there was no impact on subject safety and rights or reliability and robustness of the data generated in the clinical trial, and stability data showed it was stable.

3. IRT issues

3.1 Following a single incident of expired IMP being dispensed and in spite of CAPA implementation, multiple issues with the IRT system across several clinical trials occurred leading to the dispensing of expired IMP and a shortage of IMP at investigator sites in time of subject visits.

3.2 Due to an interactive response technologies (IRT) malfunction 50% of subjects assigned to one arm were unblinded in a blinded trial, furthermore this information was submitted to all trial staff at all investigator sites participating in the trial

Yes, there was impact on the safety and rights of trial subjects and this issue persisted leading to a constant breach of the Regulation or the trial protocol, despite the implementation of a corrective and preventive action plan.

Yes, this impacts the reliability and robustness of the data generated.

4. Potential fraud

4.1 On two separate occasions the sponsor identified issues with the same investigator site. First with consenting and then with suspected 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 is potential fraud that requires assessment and should be reported as a serious breach and investigation should continue in parallel to determine whether the fraud is confirmed. In this example, this breach subsequently led to legal action against the organisation in question.

5. Source data

5.1 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 in the subject notes. 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 confirmed the sponsor concerns over consenting and data changes made to source without an adequate written explanation.

Yes, and this needs to be reported when, based on the concerns raise, the minimum information to assess that the case was a serious breach, were obtained.

6. Emergency unblinding

6.1 A clinical trial subject attended the emergency department, that attempted to contact the investigator site (using the phone number listed on the emergency card issued to the subject) in order to break the unblinding code. The unblinding process did not allow to code break in a timely manner.

Yes, as this is likely to affect to a significant degree the safety and rights of the subject if unblinding would have affected the course of treatment.

7. Sample processing

7.1 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 modification was required to recruit more subjects to meet the endpoint.

Yes, it is likely to affect to a significant degree the safety and rights of a trial subject as further additional subjects had to be dosed unnecessarily as a result of this error.

8. Protocol compliance

8.1 Subject safety was compromised because repeat electrocardiograms (ECGs) were consistently not performed, as required by the protocol. The ECGs were required as part of the safety monitoring due to the pharmacology of the IMP. Also, there was inadequate quality control (QC) of the interim safety reports used for dose escalation which has potential for stopping criteria to be missed if adverse event (AEs) were not transcribed from the source to the safety report.

Yes, as it is likely to affect to a significant degree the safety and rights of a trial subject or on the reliability and robustness of the data of the clinical trial.

8.2 The thrombosis risk of an IMP was monitored by some laboratory parameters. Investigator site failed to reduce or stop trial medication, in response to altered values of these 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.

Yes, it is likely to affect to a significant degree the safety and rights of a trial subject as subjects were exposed to an increased risk of thrombosis.

8.3 Major visit date deviation, based on impact assessment of trial participants safety and wellbeing and/or clinical trials data robustness and reliability (depending on the protocol).

8.4 Minor visit date deviation. A common deviation in clinical trials.

Yes, as this may have an impact on the trial participants safety and wellbeing and/or clinical trials data robustness and reliability.

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

8.5 According to the protocol, a brain CT scan should be performed in the selection visit in order to exclude brain metastasis (exclusion criteria). The site used a previous version of the protocol where the CT scan wasn’t required so 6 patients out of 10 were included without brain CT.

Yes, because it shows lack of safety data collection. This exclusion criteria could potentially affect patients safety and rights and would affect the reliability and robustness of the data if the majority of patients were ineligible.

9. SAE reporting

9.1 The investigator failed to report a single serious adverse event (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 SAE and as a consequence, failure of the sponsor to report a SUSAR could have a significant impact on trial subjects. Sufficient information and context should be documented for the impact to be assessed adequately.

9.2 The sponsor was not clear on the reporting requirements for the trial and was incorrectly classifying events as expected, as they were common events seen with that particular disease.

Yes, under-reporting of large numbers of SUSARs due to incorrect understanding of expectedness.

9.3 The investigator was not documenting all the AEs associated with the trial.

Yes, depending on the type of trial, for example inadequate safety reporting in dose escalation studies may impact on the decision to escalate to the next dose level.

10. Consent

10.1 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.

Yes, if there was a systematic or persistent problem and/or if it has a significant impact on the safety and rights of a trial subjects (e.g. there was key safety information not relayed to subjects in a timely manner).

11. Access to data

11.1 The investigator would not allow sponsor/CRO access to the trial participants’ notes.

Yes, it is likely to affect the safety and rights of a trial subject and the reliability and robustness of the data generated in the trial as the data could not be verified. The protocol should contain a clause to state that Sponsor representative and Regulatory authorities will have access to the data, and this is also reflected in the informed consent.

11.2 Loss of data.

Yes, it is likely to affect the safety and rights of a trial subject and the reliability and robustness of the data generated in the trial. Clinical trial sponsors and vendors should have agreements in place addressing business continuity and ensuring that clinical trials data are retrievable at any point in time.

12.Randomisation/ stratification errors

12.1 Patients incorrectly randomized/stratified according to the protocol.

Yes, as this will be likely to have a significant impact on rights of the subjects or the reliability and robustness of the generated data.

13. DSMB/DMC

13.1 The Data and Safety Monitoring Board (DSMB)/ Data Monitoring Committees (DMC), which should be implemented according to the protocol and the clinical trial authorisation in a blinded trial, has in fact not been implemented.

Yes, the missing implementation of the DSMB/DMC is likely to affect to a significant degree the safety and rights of trial subjects and the reliability and robustness of the data generated in the trial.

14. Privacy

14.1 The Sponsor contracted a CRO to build an e-CRF – the eCRF contained patient identifiable information. Both the Sponsor and CRO had access to all this information.

Yes, it affects to a significant degree the rights of a trial subject as it affects their privacy. Trial participant’s confidentiality is a fundamental right by national requirements, by ICH-GCP and by ethical principles, which needs to be respected.

14.2 A coordinating investigator site was sending follow-up questionnaires to trials subjects of other investigator sites (to save the other sites the extra work). For this they had the names and addresses of trial subjects of other investigator sites. The trial subjects were not informed about this and had not given consent for this. This does not affect subject safety but it does affect the privacy of trial subject.

Yes, it is likely to affect to a significant degree the rights of a trial subject as it affects their privacy.

14.3 During an inspection, it was observed that the informed consent forms from trial subjects of one investigator site were being kept at another investigator site (also being the sponsor of the trial because it was an investigator initiated trial). The trial subjects affected were not informed about this and had not given consent for it.

Yes, it is likely to affect to a significant degree the rights of a trial subject as it affects their privacy.