I recently found a case study at the most interesting website crgcp.org dealing with serious breaches during a clinical trial, and the required action taken by the CRA. You may find this example at www.crgcp.org/content/2015/10/05/serious-breaches-case-study.


Serious Breaches Case Study

In the new EU Regulation on Clinical Trials which will come into force in the next couple of years there is a new requirement for reporting Serious Breaches to the regulators within 7 days of the sponsor becoming aware of the breach. The relevant section of the legislation is reproduced below.  This has been a requirement in the UK for some time and the MHRA has published additional guidance around this. (...)

Below is a scenario where there have been several issues with a clinical trial.  Which of these issues do you think would constitute a Serious Breach?

Scenario:
A monitor visited a clinical trial site and found the following:

  • The IMP had expired and was awaiting relabeling for extension of the use by date, which had been approved by the QP.  The IMP had not been quarantined as requested and had been dispensed to one patient after the expiry.
  • The monitor also noticed that the IMP from a completely different clinical trial had accidentally been dispensed to subjects in the trial.  These subjects had been withdrawn but one had suffered a severe adverse event in the meantime.
  • When reviewing source notes for one patient the monitor noticed that some changes had been made to source data which made the subject eligible when under the original data they would not have been.  The investigator was unable to provide a satisfactory explanation.
  • ECGs were required at each visit to check for changes in heart rhythm which had been identified as a marker for a potential serious adverse drug reaction.  For one subject the investigator had not performed ECGs at two separate visits because the subject was in a hurry and the investigator had performed an examination himself and in his view the heart was beating normally.
  • One patient had been in a car accident which had resulted in hospitalisation.  The investigator had failed to report this as an SAE because he only found out several weeks after the event and he considered it unrelated to the IMP.

Suggested Answer:

  • The IMP had expired and was awaiting relabeling for extension of the use by date, which had been approved by the QP.  The IMP had not been quarantined as requested and had been dispensed to one patient after the expiry.  Not a serious breach at this stage as the label extension had been approved by the QP, but the monitor should discuss with the investigator and pharmacist and stress the importance of doing this in future.  If this happened more than once it might then become a serious breach.
  • The monitor also noticed that the IMP from a completely different clinical trial had accidentally been dispensed to subjects in the trial.  These subjects had been withdrawn but one had suffered a severe adverse event in the meantime. This is a serious breach – subjects put at risk – probably also a serious breach for the other trial too!
  • When reviewing source notes for one patient the monitor noticed that some changes had been made to source data which made the subject eligible when under the original data they would not have been.  The investigator was unable to provide a satisfactory explanation. Serious Breach – compromises subject safety and data integrity.
  • ECGs were required at each visit to check for changes in heart rhythm which had been identified as a marker for a potential serious adverse drug reaction.  For one subject the investigator had not performed ECGs at two separate visits because the subject was in a hurry and the investigator had performed an examination himself and in his view the heart was beating normally. Serious Breach – subject put at risk
  • One patient had been in a car accident which had resulted in hospitalisation.  The investigator had failed to report this as an SAE because he only found out several weeks after the event and he considered it unrelated to the IMP. Probably not a serious breach but the monitor should discuss with the investigator and stress the importance of doing this in future.  If this happened more than once it would then become a serious breach.