SOP for Safety Data Monitoring and Reporting Requirements for Clinical Trials

Purpose

To describe the procedures and requirements related to the safety data collection, verification and reporting requirements for clinical trials involving Investigational Medicinal Products (IMP) and Investigational Medicinal Devices (IMD). This also includes post registration/post marketing surveillance studies.

Scope

This SOP applies to all health employees including, but not limited to, visiting health professionals, contractors, consultants and volunteers who propose to undertake, administrate, review and/or govern human research involving patients/participants, facilities and/or staff. All study personnel involved in the clinical study must operate within their scope of practice.

Procedure

Where a Satellite Site(s) is/are involved, staff will report safety issues directly to the Sponsor as per the timelines specified in the Protocol and the safety monitoring plan or similar document in the same way as the Primary Site. Certified copies of the relevant safety reports/documentation generated at the Satellite Site will be sent to the Primary Site for filing in the SMF. The rules will be pre-determined as per SOP for the Study Master File and as documented in the Supervision Plan.

NOTE: where a Sponsor delivers Suspected Unexpected Serious Adverse Reactions (SUSARs), analyses of accumulating safety data, annual safety reports and other safety communication through a web portal delivery system or via e-mail, as opposed to paper reports, acknowledgement of receipt by the Investigator/HREC/Institution/TGA of such information will be required by the Principal Investigator (PI), but only after the Sponsor confirms that the report has no bearing on participant safety or trial conduct. There is no longer a requirement for Investigators to print, review and file these reports. See NHMRC Safety Monitoring and Reporting In Clinical Trials Involving Therapeutic Goods.

Sponsor Responsibilities

The documents NHMRC Safety Monitoring and Reporting In Clinical Trials Involving Therapeutic Goods give clear direction to Sponsor responsibilities.

A Sponsor:

• Must be identified for all clinical trials.
• Has ultimate responsibility for the ongoing safety evaluation of the IMP/IMD.
• Is responsible for generating and disseminating all safety communications.
• Must ensure that the trial Protocol has clear sections describing:

1. the assessment and management of risk (if not in an alternative document)
2. safety reporting definitions, procedures, responsibilities and reporting timelines, and
3. any serious adverse events that do not require immediate reporting.

• Must ensure the conduct of the trial, including the monitoring of safety and reporting of adverse outcomes, complies with the study Protocol as well as applicable guidelines.
• May delegate functions and duties to individuals or third parties, such as a Contract Research Organisation (CRO), Data Safety Monitoring Board (DSMB) provided arrangements are in place for oversight of the delegated functions and duties, to ensure the integrity of the functions and duties performed and any data generated.
• Should evaluate and categorise all safety information that is reported by Investigators as well as safety information received from other sources.
• Keep detailed records of all reported adverse events and maintain up-to-date tabulations and/or line listings.
• Review the Investigational Brochure (IB)/Instruction for Use or Clinical Investigation Plan (CIP) at least annually and update it when new and relevant information becomes available.
• Prepare and submit to relevant parties an annual safety report/Development Safety Update Report (DSUR).

Safety Data Monitoring

• The Sponsor’s plans for safety data monitoring should be documented in a Safety Monitoring Plan or similar document and be given to the PI prior to the commencement of the clinical trial. It must be continually reviewed and updated during the trial, as real-time assessments of safety data are performed, and outcomes are made available.
• A Sponsor may utilise an independent safety monitoring committee (e.g. Data Safety Monitoring Board) or independent individuals (e.g. a medical monitor) to:

1. Review accruing trial safety data in either an unblinded or blinded manner to assess treatment exposure.
2. Access, assess and review emerging efficacy data for the trial.
3. Assess the balance of risks and benefits within the trial.
4. Document the outcome of these reviews.

Sponsor Reporting Requirements

• The outcome of various safety reviews is reported directly to HRECs, the Investigator and the Therapeutic Goods Administration (TGA), by the Sponsor and must indicate the impact of each report on patient/participant safety, trial conduct or trial documentation. The reporting of safety reviews by the Sponsor should be as per NHMRC Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods or as detailed in the Protocol. The safety reporting requirement in the Protocol cannot be less than that required by the NHMRC.
• Sponsor to provide to Investigator:

1. Updated IB at least annually.
2. Spontaneous reports of significant safety issues i.e. an issue that could adversely affect the safety of participants or materially impact on the continued ethical acceptability or conduct of the trial.
3. Outcomes of analyses of accumulating safety data.
4. Significant safety issues: those that meet the definition of an Urgent Safety Measure (i.e. a measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety measure) must be notified within 72 hours, and all other significant safety issues must be notified within 15 calendar days of the Sponsor instigating or being made aware of the issue.

Sponsor to provide to Therapeutic Goods Administration:

• Significant safety issues that meet the definition of an Urgent Safety Measure (i.e. a measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety measure) must be notified within 72 hours, and all other significant safety issues must be notified within 15 calendar days of the Sponsor instigating or being made aware of the issue. It is strongly recommended that the Sponsor contact the TGA within 24 hours of an Urgent Safety Measure being taken, and if initial contact is by telephone, it should be followed-up with a written notification provided by facsimile or e-mail within 72 hours.
• For fatal SUSARs, immediately, but no later than 7 calendar days after being made aware of the case, with any follow-up information within a further 8 calendar days.
• For all other SUSARs, no later than 15 calendar days after being made aware of the case.

ALSO READ: SOP for Creation, Implementation and Revision of Standard Operating Procedures

Sponsor to provide to HREC:

• Updated IB at least annually which supports trial oversight, depicts a clear picture of evolving safety profile of the trial and provides evidence that the Sponsor is conducting its safety monitoring appropriately.
• Significant safety issues: those that meet the definition of an Urgent Safety Measure (i.e. a measure required to be taken immediately in order to eliminate an immediate hazard to a participant’s health or safety measure) must be notified within 72 hours, and all other significant safety issues must be notified within 15 calendar days of the Sponsor instigating or being made aware of the issue.

Investigator’s Responsibilities

The role of the Investigator with regard to safety reporting is to:

• Provide the Sponsor with all relevant information so that an appropriate safety analysis can be performed.
• Capture and assess all local safety events and report adverse events that occur at the site as further clarified below.
• Ensure safety monitoring complies with the study Protocol, safety monitoring plan if there is one as well as Institutional and national guidelines.
• Act on any events as clinical care dictates.
• Maintain responsibility for oversight of the ongoing safety evaluation of the IMP/IMD.
• Ensure that if signing of safety documents has been delegated to another medical officer, that this is documented on the Delegation Log as per SOP for Site Staff Qualifications, Training Records and Capability.

1. Safety Data Monitoring

• Keep detailed records of safety management.
• In the instance of device trials, maintain a permanent record of participant identification, study Protocol number and device serial number or other tracking detail for the lifetime of the device, to enable a rapid response, if a device safety issues arise.
• Review the adverse outcome in the context of known information on the medicine / device and make a determination as to whether the event was drug/device-related (i.e. an adverse reaction).
• Ensure that the immediate and follow-up reports identify participant by unique code number assigned to the trial participant and not by the participant's name, personal identification number, and/or address.
• Ensure any new information regarding safety events is updated on the adverse event page in the CRF/eCRF and/or with a follow up Serious Adverse Event Form (paper or electronic), within 24 hours of the site becoming aware of the change of information and send to Sponsor.

2. Reporting Requirements

The reporting of safety reviews by the Investigator should be as per NHMRC Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods or as detailed in the Protocol. The safety reporting requirement in the Protocol cannot be less than that required by the NHMRC.

To Sponsor Within 24 hours of instigating or becoming aware of the event:

• All SAEs and SUSARs except those that are identified in the Protocol, safety monitoring plan or similar document or Investigational Brochure as not needing immediate reporting.
• Any occurrences of congenital anomaly/birth defect arising from any pregnancy of a participant (or partner).

Within 72 hours of instigating or becoming aware of the event:

• Significant safety issues which meet the definition of an Urgent Safety Measure instigated by the Investigator (i.e. a measure required to be taken immediately in order to eliminate an immediate hazard to a participant’s health or safety measure).
• All Urgent Safety Measures instigated by the site as specified in the Protocol.
• All safety critical events/laboratory abnormalities identified in the Protocol as “critical to safety evaluations”.
• Any additional requested information relating to reported deaths (e.g. autopsy reports and terminal medical reports).
• Additional requested information relating to reported deaths.

Within 15 days of instigating or becoming aware of the event:

• All other significant issues.

To Therapeutic Goods Administration

Use the Government Department of Health Report of suspected adverse reaction to medicines or vaccines commonly known as the “Blue Card”, CIOMS Form or equivalent to report to the Therapeutic Goods Administration (TGA). When submitting a SUSAR report to the TGA, submit via the TGA Business Services (TBS) ADR submission portal by email using a “Blue Card” or Sponsor provided CIOMS Form.

• Advise TGA of any safety issues which emerge during this process. Such data do not need to be submitted on a routine basis to the TGA during the trial but should be available for submission to the TGA on request, and where applicable, submitted as part of an application for registration.
• Significant safety issues: those that meet the definition of an Urgent Safety Measure (ie a measure required to be taken immediately in order to eliminate an immediate hazard to a participant’s health or safety measure) must be notified within 72 hours, and all other significant safety issues must be notified within 15 calendar days of the Sponsor instigating or being made aware of the issue.

To Institution/Research Governance Officer

• Within 72 hours of instigating or becoming aware of the event:
• Significant safety issues that meet the definition of an Urgent Safety Measure (i.e. a measure required to be taken immediately in order to eliminate an immediate hazard to a participant’s health or safety measure).
• SUSARs arising from the local site.
• Any information received from the Sponsor that may be new and have an impact on the continued ethical acceptability of the trial or may indicate the need for amendments to the trial Protocol, including monitoring of safety.

Revision History

Nil

ALSO READ: SOP for Case Report Forms and Source Documents