Roles and responsibilities for clinical trial safety reporting of significant safety issues and urgent safety measures

This page summarises the roles and responsibilities of key stakeholders in clinical trial safety reporting of significant safety issues (SSIs) and urgent safety measures (USMs).  For complete information on safety reporting refer to the National Health and Medical Research Council (NHMRC) guidance document, Safety monitoring and reporting in clinical trials involving therapeutic goods.

Definitions 

Significant safety issues (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. 

Urgent safety measure (USM)

• a measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety. 
  • Note: this type of significant safety issue can be instigated by either the investigator or sponsor and can be implemented before seeking approval from HRECs or institutions 

Suspected unexpected serious adverse reactions (SUSAR)

• an adverse reaction that is both serious and unexpected.

Unanticipated Serious Adverse Device Effect (USADE)

• 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.

Responsibilities

Stakeholder responsibilities related to safety reporting of SSIs and USMs are summarised below. For complete information of all safety reporting responsibilities see the NHMRC guidance document; Safety monitoring and reporting in clinical trials involving therapeutic goods. The ICH GCP and ISO 14155 put the responsibility for ongoing safety evaluation of the investigational product with the sponsor.

Sponsor

In a clinical trial the sponsor is responsible for the following aspects of safety reporting of SSIs and USMs: 

• establishing safety monitoring processes that are based on the risk, size and complexity of the proposed research.
• ensuring all responsibilities for safety monitoring and reporting (e.g. reporting SSI/USMs, USADEs and SUSARs to the Therapeutic Goods Administration (TGA)) are appropriately allocated or delegated. 
• notifying the TGA, HREC and investigators of all SSIs that adversely affect the safety of participants or materially impact the continued ethical acceptability or conduct of the trial. 
  • SSIs that meet the definition of an USM are notified within 72 hours.
  • All other SSIs are notified within 15 calendar days of the sponsor instigating or being made aware of the issue. 
  • SSIs and USMs are to be notified to the TGA using the Clinical trial Significant Safety Issue/Urgent Safety Measure (SSI/USM) safety reporting form.

Principal Investigator

The role of the investigator regarding safety reporting is to provide the sponsor with all relevant information so that an appropriate safety analysis can be performed. 

In a clinical trial the principal investigator should: 

• assess all local safety events and should act on any events as clinical care dictates.

Human Research Ethics Committee

The sponsor, through their independent safety monitoring arrangement, has the primary responsibility for monitoring the ongoing safety of the investigational medicinal product. 

The HREC should be satisfied that the sponsor’s arrangements are sufficiently independent and commensurate with the risk, size and complexity of the trial. 

In a clinical trial the approving HREC should: 

• assess the safety of proposed trials, including whether the evaluation of the anticipated benefits and risks is satisfactory and ensure that the sponsor has proportionate systems in place to mitigate and manage any identified risks.
• satisfy itself that the sponsor’s ongoing safety monitoring arrangements are adequate, including the justification for appointing/not appointing a Data Safety Monitoring Board and any ‘stopping rules’ or criteria for withdrawing individual participants from the trial. 
• keep under review the adequacy and completeness of the informed consent process and documentation in the light of new information about risks and benefits. 
• assess whether changes to the risk-benefit ratio that are reported by the sponsor are compatible with continued ethical approval.
• advise the TGA, investigators and their institutions of any decision to withdraw approval. 

While HRECs must keep approvals under review in light of safety information it receives, the responsibility for proactively monitoring the ongoing risk-benefit ratio of the trial remains with the sponsor at all times.

Institution 

An institution’s responsibilities and oversight of safety information in clinical trials will differ depending on whether they are hosting externally sponsored clinical trials or sponsoring locally led non-commercial trials. In both cases they should help ensure that their site(s) understands and complies with sponsor requirements. Institutions should have oversight of any issues that may require management, such as disputes or litigation resulting from trials. Where the institution is also named as the trial sponsor, the institution will also assume the sponsor responsibilities. 

In a clinical trial the institution should: 

• assess whether any safety reports received impact on medico-legal risk, the responsible conduct of research, adherence to contractual obligations or the trial’s continued site authorisation and, where applicable, facilitate the implementation of corrective and preventative action.
• develop clear guidance for investigators detailing the requirements for safety reporting and monitoring in clinical trials. This document(s) should cover the requirements for both externally sponsored clinical trials and, if applicable, internally sponsored investigator/initiated or collaborative group trials.

Therapeutic Goods Administration

Responsibility for the regulatory control of therapeutic goods in Australia lies with the TGA.  Clinical trials of unapproved therapeutic goods are conducted in Australia under the TGA’s Clinical Trial Notification (CTN) or the Clinical Trial Approval (CTA) schemes.

The TGA may request further information after it has received a safety notification and may also;

• conduct an inspection of a clinical trial. 
• stop a trial, where that action is in the public’s interest.

Related links

• Clinical trial Significant Safety Issue/Urgent Safety Measure (SSI/USM) safety reporting form
• Clinical trials