Safety Monitoring and Reporting

In November 2016, the National Health and Medical Research Council (NHMRC) released new guidance on Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods (the Guidance). The Guidance replaces the 2009 Australian Health Ethics Committee (AHEC) Position Statement on safety reporting. The Guidance will streamline clinical trial safety reporting and monitoring for Australia. NSW Public Health Organisations (PHOs), including Concord Hospital, have been implementing the new safety reporting guidelines from 3 October 2017.

The new reporting requirements have been implemented for new clinical trial applications and existing clinical trials with ethical approval and governance authorisation; and for therapeutic goods and non-therapeutic goods trials.

KEY CHANGES
• HRECs will no longer receive:
     - Single case Adverse Events (AEs)
     - Serious Adverse Events (SAEs)/Serious Adverse Reactions (SARs)
     - Suspected Unexpected Serious Adverse Reactions (SUSARs)* or device/non-therapeutic good trial equivalents or six monthly line listings.
• HRECs will receive:
     - All Significant Safety Issues (SSIs)
     - Annual safety reports and Investigator’s Brochure (IB) updates.
These should be submitted to the HREC by the Sponsor (or the sponsor's delegate e.g. Coordinating Principal Investigator, Principal Investigator, Contract Research Organisation)
• Research Governance Officers (RGO) will no longer receive:
     - Any IB updates
     - Any single case AEs, SAE/SARs, external SUSARs or device/non-therapeutic good equivalents
     - Six monthly line listings
• RGOs will receive:
     - All significant safety issues (SSIs)
     - Any local Suspected Unexpected Serious Adverse Reactions (SUSARs)
     - Unanticipated Serious Adverse Device Effects (USADEs)
     - Unexpected and Related Serious Adverse Event (URSAEs)

Any of the above arising from the site and any research-related events that meet the definition of an incident should be submitted by the investigator to the local RGO.

Definitions
• Adverse Event: Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and that does not necessarily have a causal relationship with this treatment.
• Adverse Reaction: Any untoward and unintended response to an investigational medicinal product related to any dose administered. All adverse events judged by either the reporting investigator or the sponsor as having a reasonable possibility of a causal relationship to an investigational medicinal product would qualify as adverse reactions.
• Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both serious and unexpected in a medicines or biological trial.
• Unanticipated Serious Adverse Device Effects (USADEs): A serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report (and/or Investigator’s Brochure/Instructions for Use).
• Urgent Safety Measure (USM): A measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety.
• Significant Safety Issue (SSI): A safety issue that could adversely affect the safety of participants or materially impact on the continued ethical acceptability or conduct of the trial.
• Unexpected & Related SAEs (URSAE): An adverse event in any other interventional trial (e.g. cognitive, surgical trials) that is:
     o Serious – meets the definition of a serious adverse event
     o Related – resulted from administration of the trial intervention
     o Unexpected – the event is not described in the protocol as an expected occurrence.

The safety monitoring and reporting responsibilities of the Sponsor, Coordinating Principal Investigator, and Principal Investigator to the HREC and RGO are outlined in the below tables and flowcharts. Reporting forms are available below as well as in Forms and Templates:

NB: The below tables only show the events that should be reported to the HREC and RGO. For further details on the safety monitoring/reporting responsibilities of the HREC, Principal Investigator, TGA, Institution and the Sponsor please refer to the guidelines here.

Summary of safety notifications (therapeutic goods trials)

Reporting pathway for therapeutic good trials

Summary of safety notifications (non-therapeutic goods trials)

Reporting pathway for non-therapeutic good trials

SERIOUS BREACHES IN CLINICAL TRIALS

Serious breaches should be reported in accordance with NHMRC Guidelines document: Reporting of Serious Breaches of Good Clinical Practice (GCP) or the Protocol for Trials Involving Therapeutic Goods 2018.

A serious breach is a breach of Good Clinical Practice or the protocol that is likely to affect to a significant degree:

• The safety or rights of a trial participant, or
• The reliability and robustness of the data generated in a clinical trial.

The NHMRC guidelines does not use the terms Protocol Deviation or Protocol Violation

Serious breaches should be reported to the reviewing HREC, usually by the Sponsor within 72 calendar days of confirming a serious breach has occurred. The HREC will review the serious breach to evaluate its impact on the continued ethical acceptability of the study and to satisfy itself that the serious breach is managed appropriately.

It is the responsibility of the Principal Investigator to (i) report any suspected breach to the sponsor within 72 hours of becoming aware of it and (ii) to report to their institution (via the Research Governance Officer) within 72 hours any serious breach that has been confirmed by the sponsor as occurring at their site.