TGA Guidance on Clinical Trial Safety Reporting: Significant Safety Significant Safety Issues and Urgent Safety Measures

1. Overview

The Therapeutic Goods Administration (TGA) outlines roles and responsibilities for reporting significant safety issues (SSIs) and urgent safety measures (USMs) in clinical trials involving unapproved therapeutic goods in Australia. This guidance, aligned with the National Health and Medical Research Council (NHMRC) document Safety monitoring and reporting in clinical trials involving therapeutic goods, ensures ongoing participant safety and ethical trial conduct. Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

Reporting focuses on issues that could adversely affect participants or the trial's ethical acceptability.

2. Key Definitions

• Significant Safety Issue (SSI): A safety issue that could adversely affect participant safety or materially impact the trial's continued ethical acceptability or conduct.
• Urgent Safety Measure (USM): A measure required to eliminate an immediate hazard to a participant’s health or safety, which can be implemented by the investigator or sponsor before approval.
• Suspected Unexpected Serious Adverse Reaction (SUSAR): A serious and unexpected adverse reaction.
• Unanticipated Serious Adverse Device Effect (USADE): A serious adverse device effect not identified in the current risk analysis report. Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

3. Sponsor Responsibilities

Sponsors bear primary responsibility for ongoing safety evaluation under ICH GCP and ISO 14155. Key duties include:

• Establishing risk-based safety monitoring processes
• Ensuring allocation of safety reporting responsibilities
• Notifying TGA, HREC, and investigators of SSIs:
  • USMs within 72 hours
  • Other SSIs within 15 calendar days
• Using the Clinical trial Significant Safety Issue/Urgent Safety Measure (SSI/USM) safety reporting form for TGA notifications Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

4. Principal Investigator Responsibilities

Investigators must:

• Assess all local safety events and provide relevant information to the sponsor
• Act on events as required by clinical care
• Implement USMs immediately if needed, then notify the sponsor Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

5. Human Research Ethics Committee (HREC) Responsibilities

HRECs:

• Assess trial safety and sponsor monitoring arrangements
• Review changes to risk-benefit ratio
• Ensure adequate informed consent in light of new risks
• Advise TGA, investigators, and institutions if withdrawing approval Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

The sponsor retains primary responsibility for proactive monitoring.

6. Institution Responsibilities

Institutions:

• Oversee safety reports for impact on medico-legal risk and site authorisation
• Provide guidance for investigators on safety reporting
• Assume sponsor responsibilities if acting as sponsor Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

7. TGA Role

The TGA:

• Receives SSI/USM notifications
• May request further information
• Can inspect trials or stop them in the public interest Source: https://www.tga.gov.au/products/unapproved-therapeutic-goods/access-pathways/clinical-trials/roles-and-responsibilities-clinical-trial-safety-reporting-significant-safety-issues-and-urgent-safety-measures

For full details, refer to the NHMRC guidance document.