A ‘Serious Breach’ is defined as being a breach of Good Clinical Practice or clinical trial protocol which has an impact on the safety or rights of a clinical trial participant, and the reliability or efficacy of the data generated in the clinical trial. The term ‘Serious Breach’ was established by the European Union’s (EU’s) Clinical Trials Regulation (536).

The reporting guidelines for Serious Breaches and protocol deviations have been put together following a revision of the statement on the Monitoring and Reporting of Safety for Clinical Trials Involving Therapeutic Goods (2009) by the Australian Health Ethics Committee (AHEC).

Any deviations from Good Clinical Practice (GCP) or the protocol should lead to swift action by the Sponsor so that preventive action can be implemented and so analysis of the data can be studied when the clinical trial study report is complete.

Important Terms

Deviations: Any breach, divergence or departure from the requirements of GCP or the clinical trial protocol.

Suspected Breach: An event that is considered as being a possible Serious Breach but has to be formally confirmed by the trial Sponsor.

Corrective and Preventive Actions (CAPA)

Corrective Action: The identification, documentation and elimination of the root cause of an issue to prevent a problem from recurring.

Preventive Action: Aims to identify and solve a potential problem before it causes something to go wrong.

Why is a Framework for the Managing and Reporting of Serious Breaches so Important?

  • Clarifies Good Clinical Practice (GCP) guideline requirements for any reporting deviations.
  • Clarifies the roles of key stakeholders.
  • Defines standard reporting timelines.
  • Provides standard forms for serious breaches and suspected breach reporting to Human Research Ethics Committees (HRECs).

Reporting of Serious Breaches by Sponsor

Sponsors have a responsibility to determine whether a Suspected Breach can transform into a Serious Breach. The Sponsor needs to decide whether a breach will have a significant impact on the efficacy of the trial data. This depends on:

  • The clinical trial design.
  • The amount of data affected by the breach.
  • Impact of excluding data from the clinical trial analysis.

If a Sponsor is unsure whether a potential Serious Breach will have an impact on participants rights and safety, they will need to consult with the reviewing Human Research Ethics Committee (HREC).

Sponsors also need to develop documents for managing serious breaches including:

  • An assessment of whether a Serious Breach is an isolated incident or recurring.
  • The impact the Serious Breach will have on participants and the reliability of the trial data.
  • The investigation procedure.
  • Reporting procedure.
  • The management of Corrective and Preventative Action (CAPA).
  • The circulation and retention of documents relating to Serious Breaches.

Once a suspected Serious Breach has been found, Sponsors need to notify the site’s Principal Investigator within a week. A thorough analysis needs to be carried out to ensure that all corrective and preventative actions are taken.

Sponsor Reporting Guidelines

  • If a Sponsor determines that a report by the HREC implies a Serious Breach, they need to report that breach to the reviewing HREC within 7 days.
  • When a report shows that there is no Serious Breach, the reviewing HREC needs to be informed within 7 days with a justification of the decision.
  • The Therapeutic Goods Administration (TGA) and reviewing HREC needs to be notified if a Serious Breach leads to the closure of the trial site.
  • The TGA needs to be informed if a Serious Breach involves a defective product that may have serious implications for the supply chain of the marketed product.

Reporting of Serious Breaches by Third Parties

Some Serious Breaches are identified by third parties (clinical trial sites) who will report their findings directly to the reviewing HREC.

This mostly occurs when:

  • The Investigator/Institution knows that a Serious Breach has occurred but the Sponsor disagrees with the assessment and won’t notify the HREC.
  • The Serious Breach has been caused by the Sponsor.

Responsibilities of the Therapeutic Goods Administration (TGA)

The TGA assesses the impact of Serious Breaches on marketed products in Australia. They have the authority to investigate non-compliance with GCP standards for clinical trials.

Responsibilities of the Reviewing Human Research Ethics Committees (HREC)

The HREC reviews Serious Breaches and evaluates the impact of a Serious Breach on the ethical acceptability of the study. They also need to assess whether the corrective and preventative actions that have been put into place are effective and have resolved the underlying issue.

When the Sponsor has Notified the HREC of Serious Breach, the HREC Needs to:

Assess the report, including the corrective and preventive actions taken and provide feedback to the Sponsor. If a Serious Breach has led to the withdrawal of ethics approval for the trial, the HREC needs to inform the Therapeutic Goods Administration (TGA) and the Sponsor.

When a Third Party has Notified the HREC of a Suspected Breach, the HREC Should:

Let the Sponsor know about the suspected breach report. If a Sponsor challenges this finding, they need to explain (in writing) why they didn’t report the suspected breach to the HREC.

Responsibilities of the Principal Investigator

Ensure that the clinical trial staff knows how to report any Serious Breaches to a Sponsor within 72 hours. The Principal Investigator needs to provide follow up information and work alongside the Institution and Sponsor to implement any corrective and preventive actions.

Responsibilities of the Institution

Develop a clear reporting and management guideline for Investigators in the event of a Serious Breach. They also need to assess each breach to determine its impact and to facilitate the implementation of corrective and preventive actions if required by the Sponsor. The reviewing HREC gives the Institution advice and in return, the Institution needs to inform the HREC if a Serious Breach leads to the withdrawal of the site’s authorisation.

Examples of Serious Breaches

  • A participant is given the Investigational Medicinal Product (IMP) in the wrong arm.
  • Participants are given three doses a day instead of one dose.
  • The participant was administered six additional doses of IMP which results in a Serious Adverse Event.
  • Blood work is invalid due to being processed incorrectly.
  • Poor communication from a Sponsor to the trial site in a Chemotherapy trial results in the wrong equipment being used to dose a participant (participants were significantly under-dosed)

What is the Difference between a Serious Breach and a Significant Safety Issue (SSI)?

Although the definitions of a ‘Serious Breach’ and a ‘Significant Safety Issue’ (SSI) are similar, a Serious Breach is a result of a deviation from the trial protocol or GCP, while the SSI can occur in a trial without any deviation taking place.