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Australian clinical trial handbook

Guidance on conducting clinical trials in Australia using 'unapproved' therapeutic goods

12 October 2018

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Safety reporting to TGA for CTN and CTX trials

Trial sponsors should refer to the NHMRC Guidance: Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods (NHMRC Guidance) for safety reporting requirements. The NHMRC guidance addresses the monitoring, collection and reporting of adverse events that occur in clinical trials involving therapeutic goods conducted under the CTN or CTX schemes. The NHMRC Guidance has aligned with the European Union's Clinical Trial Regulations: Regulation EU No 536/2014.

The NHMRC Guidance outlines the responsibilities of trial sponsors, investigators, HRECs and institutions (referred to as the approving authority in this handbook); however, it is the trial sponsor that is responsible for reporting to us.

We have adopted the CPMP/ICH/377/95 Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting in principle with annotations for local regulatory requirements. For clinical trials, we now reference the European Commission terms for categorising adverse events as they are more widely used in Australia. For example, the term Suspected Unexpected Serious Adverse Reaction (SUSAR) has replaced the term Serious and Unexpected Adverse Drug Reaction.

The term 'investigational medicinal product' in the NHMRC Guidance applies to both medicines and biologicals.

In this handbook, medicines and biologicals are referenced separately so that the differing regulatory requirements can be highlighted.

We have aligned the definitions for all safety reporting with those provided in the NHMRC Guidance.

The NHMRC Guidance outlines the trial sponsor's safety reporting responsibilities for CTN and CTX trials. We have provided further information on how the trial sponsor should notify us of all relevant safety reports for CTN and CTX trials in the following tables.

Safety reporting timeframes for CTN and CTX trials

1. Single case events from Australian sites: SUSARS and USADEs
Type of event Type of good Report format Timeframe
Suspected unexpected serious adverse reactions (SUSARs) from Australian sites only Medicines and biologicals

OR

  • Adverse event reports can be submitted using the new online reporting form. This can be accessed from the Reporting Problems page. You will be able to use your TBS credentials to log in and submit adverse event reports. If you do not have your own, individual login credentials, you will need to contact your organisation's TBS administrator, who can create your user profile.

OR

Please visit Adverse Event Management System (AEMS) for more information about reporting to the TGA.

  • For fatal or life threatening Australian 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 Australian SUSARs, no later than 15 calendar days after being made aware of the case
Unanticipated serious adverse device effects (USADEs) from Australian sites only Medical devices ul>

OR

  • For fatal or life threatening Australian USADEs, 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 Australian USADEs, no later than 15 calendar days after being made aware of the case
2. Significant safety issues* and overseas regulatory action
Type of event Type of good Report format Timeframe
Significant safety issues (SSIs) requiring implementation of urgent safety measures (USMs) All therapeutic goods In writing to the Pharmacovigilance and Special Access Branch via email to clinical.trials@health.gov.au Within 24 hours (where possible) and in any case, no later than 72 hours of the measure being taken
Action with respect to safety that has been taken by another country's regulatory agency (relevant to an ongoing clinical trial in Australia) All therapeutic goods In writing to the Pharmacovigilance and Special Access Branch via email to clinical.trials@health.gov.au Without undue delay and no later than 72 hours of the trial sponsor becoming aware of the actio
All other significant safety issues (SSIs): Notification of an amendment** Temporary halt of a trial for safety reasons Early termination of a trial for safety reasons All therapeutic goods In writing to the Pharmacovigilance and Special Access Branch via email to clinical.trials@health.gov.au Without undue delay and no later than 15 calendar days of the trial sponsor becoming aware of the issue or temporary halt or early termination

*SSIs that arise from analysis of overseas reports (relating to a clinical trial in Australia) should be reported to us as per the timeframes above.

** We should receive notification that a SSI has occurred but the amendment revising trial documentation should be submitted to the HREC only.

Note: A SUSAR or USADE may also meet the definition of an SSI.

3. Other report types
Type of event Type of good Report format Timeframe
Other single case adverse events (AEs) All therapeutic goods Up to date tabulations or line listings On our request
Annual safety reports All therapeutic goods Development Safety Update Reports (DSURs) or other annual safety reports On our request

Single case events from Australian sites: SUSARs and USADEs

Individual SUSARs and USADEs from Australian sites must be reported to us. Refer to the NHMRC Guidance for definitions of SUSARs and USADEs.

Even if initial information is limited (i.e. less than the minimum information required for expedited reporting as outlined in the CPMP/ICH/377/95 Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) these details should still be forwarded to us pending receipt and provision of further data.

Managing blinded trials

The blind should be broken with care when trial sponsors are reporting SUSARs and USADEs to us.

We recommend that the trial sponsor breaks trial code for a particular patient, even if the investigator has not unblinded the case. This may necessitate withdrawal of the subject from the trial.

It is essential that unblinded information is only accessible to sponsor staff who need to be involved in the reporting of these events to us. The blind should be maintained for persons responsible for the ongoing conduct of the trial, particularly those who are responsible for data analysis and interpretation of results.

Breaking a trial code may also be required in the interests of public safety. However, this is a serious undertaking that has the capacity to invalidate the entire clinical trial. Trial sponsors, HRECs and DSMBs are invited to consult with us if this situation arises.

We recognise that in some trials (for example, stroke trials) efficacy end-points such as mortality or serious morbidity could also be SUSARs or USADEs. As such, the trial's integrity may be compromised if the blind is systematically broken. These outcomes would be considered to be 'disease-related' and exempted from expedited reporting. However, where it becomes apparent from the trial sponsor's own monitoring and analysis of data that the number of cases of a fatal or serious nature is in excess of that which could reasonably be expected, trial sponsors should reconsider the issue of blinding and report this information to us.

The CPMP/ICH/377/95 Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting provides further information on managing blinded therapy cases.

For trials in which efficacy end-points could also be SUSARs or USADEs, the trial protocol should state explicitly when the trial will be unblinded because of safety concerns.

Reporting of overdoses and interactions between therapeutic goods

Trial sponsors should report SUSARs that occur as a result of cases of accidental or intentional overdose. This includes, for example, instances where the investigational medicinal product is suspected of causing suicidal ideation or medication errors leading to an accidental overdose. There is no requirement to report overdoses with no associated adverse reaction as SUSARs.

Any SUSAR or USADE that results from interactions between therapeutic goods should also be reported to us.

Sponsor reporting of SUSARs and USADEs to TGA (for trials conducted under the CTN or CTX schemes)

This text representation of this flowchart is provided as a list with numbered steps.

  1. Is the report from within Australia?
    1. No: not required to report to TGA, but following actions required:
      • update line listings
      • regular analysis of cumulative data
      • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
      • End flowchart
    2. Yes: go to step 2.
  2. Is the report of a serious adverse event?
    1. No: not required to report to TGA, but following actions required:
      • update line listings
      • regular analysis of cumulative data
      • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
      • End flowchart
    2. Yes: go to step 3.
  3. Is the event related to the therapeutic good?
    1. No: not required to report to TGA, but following actions required:
      • update line listings
      • regular analysis of cumulative data
      • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
      • End flowchart
    2. Yes: go to step 4.
  4. Is the event unexpected or unanticipated?
    1. No: not required to report to TGA, but following actions required:
      • update line listings
      • regular analysis of cumulative data
      • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
      • End flowchart
    2. Yes: go to step 5.
  5. Is the event fatal or life threatening?
    1. Yes: report to TGA is required:
      • Initial report to TGA within 7 calendar days, and
        • update line listings
        • regular analysis of cumulative data
        • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
        • End flowchart
      • Follow up report within further 8 calendar days, and
        • update line listings
        • regular analysis of cumulative data
        • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
        • End flowchart
    2. No: Report to TGA within 15 calendar days, and
      • update line listings
      • regular analysis of cumulative data
      • inform TGA, investigators and HREC's of significant safety issues (SSIs) that are identified from analyses
      • End flowchart
  6. End flowchart.

Refer to the NHMRC Guidance: Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods for safety reporting requirements for other stakeholders.

Significant safety issues including urgent safety measures

A significant safety issue (SSI) is a safety event that could adversely affect the safety of participants or materially impact on the continued ethical acceptability or conduct of the trial, for example by altering the risk-benefit balance of the trial. It is recommended that information regarding the trial sponsor's proposed action, reports of any similar events internationally, and information as to the proposed action of other regulators is provided with notification of an SSI.

Example significant safety issues:

A serious adverse event that could be associated with the trial procedures and that requires modification of the conduct of the trial

A hazard to the patient population, such as lack of efficacy of an investigational medicinal product used for the treatment of a life-threatening disease

A major safety finding from a newly completed animal study (such as carcinogenicity)

Recommendations of the DSMB, where relevant for the safety of participants, such as an increase in frequency or severity of an expected adverse reaction.

A single case event such as a SUSAR or USADE may also meet the definition of an SSI. If this is the case it should be reported to us as both a SUSAR or USADE and an SSI. When the event is not an Australian SUSAR or USADE (i.e. from an overseas trial), report it solely as an SSI.

Example single case event that is also a significant safety issue:

Toxic epidermal necrolysis, agranulocytosis or hepatic failure in a participant that has led to an urgent safety measure.

SSIs requiring implementation of urgent safety measures (USMs) are of greatest concern to us. An USM is a measure required to be taken in order to eliminate an immediate hazard to a participant's health or safety.

Example significant safety issue implemented as an urgent safety measure:

A chemotherapy trial requires an immediate dose reduction for all patients in response to an unacceptable level of toxicity seen in previously treated patients.

A temporary halt or early termination of a trial due to safety reasons would meet the definition of an SSI. The timelines for reporting to us would depend on whether the halt or termination required implementation of a USM.

In some trials, particularly those involving serious conditions (for example, intensive care trials), urgent actions or interventions may routinely be necessary, often as a result of the participant's clinical condition. Where these events are managed in accordance with the protocol as routine care, they are not considered USMs. USMs are significant safety issues that result from the trial and are likely to result in a temporary halt or early termination, an immediate change to trial procedures or the addition of trial procedures. In these cases, the HREC is generally notified post hoc.

When an urgent safety measure occurs, where possible, the trial sponsor should notify us within 24 hours and in any case, no later than 72 hours of the measure being taken.

Sponsor reporting of significant safety issues to TGA (for trials conducted under the CTN or CTX schemes)

This text representation of this flowchart is provided as a list with numbered steps.

Does this safety issue relate to an urgent safety measure (USM)?

  1. Yes: report to TGA within 72 hours.
    • Provide: reasons for the USM, measures taken and further actions planned.
    • End flowchart
  2. No: report to the TGA within 15 calendar days:
    • for a temporary halt of a trial: provide reasons for the halt, scope of the halt, measures taken, further actions planned and notification of the trial restarting, include evidence that it is safe to restart.
    • for a early termination of a trial: provide reasons for the early termination, measures taken and further actions planned.
    • for all other significant safety issues: provide details of the SSI and further actions planned.
    • End flowchart

SSIs that involve a SUSAR or USADE are also subject to the reporting requirements for SUSARs and USADEs.

Refer to the NHMRC Guidance: Safety Monitoring and Reporting in Clinical Trials Involving Therapeutic Goods for safety reporting requirements for other stakeholders.

Other report types

Trial sponsors must keep records of all adverse events reported to them and are expected to maintain up-to-date tabulations or line listings of these events. This information should be made available on our request.

Trial sponsors should conduct an ongoing safety evaluation of the data they have received. If new safety information that meets the definition of an SSI is discovered it should be reported to us.

When data on 'other adverse events' are requested by us, initial presentation will be accepted in a tabular format, with further clinical details available at our request. As a minimum, this should include:

  • participant identification codes, age, sex, name(s) of the therapeutic good(s) involved, dose and duration of treatment, nature of the reaction or event, condition being treated, potentially confounding factors and outcome.

Non-Australian SUSARs and USADEs

Trial sponsors are not required to routinely submit individual SUSARs or USADEs to us from outside Australia, even if a trial is ongoing at Australian sites. However, trial sponsors are required to continually monitor the safety of their clinical development program and advise us of any SSIs that arise from analysis of overseas reports. This includes a temporary halt or early termination of an overseas trial. In addition, any action with respect to safety which has been taken by another country's regulatory agency should be reported to us. This advice must include the basis for such action.

Trial sponsors must also inform the HREC(s) and investigator(s) of this information. Such information 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. We also require that trial sponsors are able to provide to us promptly the clinical details of any individual overseas adverse event reports if requested.

Reports from post-market studies

For safety reporting requirements that apply only to post-ARTG registration studies where a medicine is being used in line with the product information or label indications, refer to Pharmacovigilance responsibilities of medicine sponsors.

For safety reporting requirements that apply only to post-ARTG inclusion studies carried out in accordance with the conditions of inclusion of a biological in the ARTG, label indications or product document indications refer to Biovigilance responsibilities of sponsors of biologicals.

For post-market monitoring requirements for a medical device included in the ARTG, refer to our Medical devices safety guidance.

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