Clinical Trials Research Governance

Oversight over investigator-initiated clinical trials sponsored by UNSW has been delegated to Research Ethics & Compliance Support within the Division of Research, with the Director RECS nominated as the UNSW Sponsor's Delegate.

Oversight responsibilities include assurance that trials are covered by our insurance, have the required contracts and agreements as well as monitoring in place, and have ethics approval. The requirements for clinical trials where UNSW is to be the sponsor are included below.

Researchers from the Kirby Institute are to continue to follow the  Kirby Institute clinical trials standard operating procedures or processes put in place for establishing sponsor-related responsibilities.

Feedback on the clinical trials research governance process can be submitted by email to humanethics@unsw.edu.au or directly to the Director RECS, Dr Ted Rohr, to ted.rohr@unsw.edu.au. For further information please contact the Human Ethics Office.

Clinical Trial Definition

At UNSW Clinical Trials are defined as any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions (which may include placebo or other control) where the primary aim of the research is to evaluate the effect of the intervention on health outcomes.

The Clinical Trial Decision Tool can be used to assist researchers in determining whether research meets the definition of a clinical trial. 

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Clinical Trial Trials Involving Investigational Therapeutic Medical Products and/or Devices

An investigational medical product, device or biological is defined as follows:

  • any medicine not entered on the Australian Register of Therapeutic Goods (ARTG) or approved for use in the country that the trial is being conducted in. 
  • the use of a new formulation, strength, size, dosage form, name, indications, directions for use or type of container of a medicine already listed in the ARTG or approved for use in the country that the trial is being conducted in.
  • any medical device not entered in the ARTG or approved for use in the country that the trial is being conducted in.
  • any new design specification, model, technology, material or treatment modality of a medical device listed in the ARTG or approved for use in the country that the trial is being conducted in.
  • any biological not entered in the ARTG or approved for use in the country that the trial is being conducted in:
    • including any new applicable standards, intended clinical use or principal manufacturer of a Class 1 or 2 biological already in the ARTG or approved for use in the country that the trial is being conducted in.
    • including any new product name, dosage form, formulation or composition, therapeutic indication, type of container or principal manufacturer of a Class 3 or 4 biological already in the ARTG or approved for use in the country that the trial is being conducted in
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Clinical Trial Notification

Clinical Trials involving unapproved investigational therapeutic goods, devices or biologicals must be conducted in accordance with legislative requirements in the country that the trial will be conducted in. 

Clinical Trials Conducted in Australia

The Therapeutic Goods Administration Clinical Trial Notification process is required for trials conducted in Australia that involve the use of an unapproved investigational therapeutic medical product or device. The therapeutic goods legislation requires that the use of therapeutic goods in a clinical trial conducted under the CTN/CTX schemes must be in accordance with:

Clinical Trials Conducted in Other Countries

Where UNSW agrees to be the sponsor of the clinical trial, the Coordinating Principal Investigator is responsible for identifying the relevant regulatory requirements that involve the use of an unapproved therapeutic investigational medical product or device in other countries. Specific details need to be included in the clinical trial protocol.

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Good Clinical Practice

ICH Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

Clinical Trials Involving Investigational Therapeutic Goods

The therapeutic goods legislation requires that the use of investigational therapeutic medical products or devices in a clinical trial conducted under the CTN/CTX schemes are designed, conducted and monitored in accordance with the Guidelines for Good Clinical Practice (E6, R2), the Australian National Statement on Ethical Conduct in Human Research, and the clinical trial protocol as approved by the reviewing Human Research Ethics Committee (or Institutional Review Board as known in the US and other countries).

It is the responsibility of the Coordinating and Principal Investigators to ensure that all investigators and trial-related staff have current ICH Good Clinical Practice Training. Certificates of training completion need to be stored as an GCP essential document. According to ICH GCP, clinical trial staff are required to update their GCP training at least once every 3 years.

It is the responsibility of the Coordinating and Principal Investigators to familiarise themselves with the requirements of the Guideline for Good Clinical Practice (E6, R2).  

Other Clinical Trials

It is recommended that the requirements of GCP are met for all other trials involving human participants outside the strict definition of a clinical trial per se. The recommendation refers to researchers' recognition that best practice leads to good research outcomes.

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Clinical Trial Sponsor

The sponsor of a trial is the company, institution, or organisation which takes responsibility for the initiation, management, and/or financing of a clinical trial. 

Clinical Trials Conducted in Australia

An Australian company, institution, or organisation must act as the sponsor of clinical trials that are conducted in Australia and involve investigational medical products or devices.

Clinical Trials Conducted in Other Countries

A company, institution, or organisation in the country that the clinical trial is to be conducted must be identified as the clinical trial sponsor.

Criteria to determine whether UNSW is to be the sponsor of an investigator-initiated trial

UNSW can assume the role of clinical trial sponsor for trials conducted within Australia that meet the following criteria:

  • A UNSW staff member or student initiates the proposed research or clinical trial.
  • A UNSW staff member is the Coordinating Principal Investigator in situations where there are multiple institutions or sites involved in the undertaking of the research or the clinical trial.
  • Funding for the trial is administered by UNSW via the UNSW research grants and contracts team.

UNSW via the Coordinating Principal Investigator is responsible for:

  • the development of (a) the clinical trial protocol, (b) the design of the trial where a protocol is not required or (c) for conducting the trial where the protocol has been developed by an overseas sponsor that does not have an Australian subsidiary.
  • establishing human ethics approval, and
  • providing oversight and monitoring the conduct of the trial to ensure compliance with the protocol, Good Clinical Practice Guideline and the HREC approval.
  • UNSW is responsible for the conduct of the trial and will have the ability to vary the scope, suspend the research or clinical trial, or appoint or remove investigators.
  • UNSW will retain the financial, academic, and reputational benefits arising from the research or trial (either wholly or partially).
  • UNSW is responsible for the conduct of the trial and will have the ability to vary the scope, suspend the research or clinical trial, or appoint or remove investigators.
  • UNSW will retain the financial, academic, and reputational benefits arising from the research or trial (either wholly or partially).
  • In accordance with the Research Data Governance & Materials Handling Policy, UNSW rather than any individual or Organisational Unit is the Custodian of the data and materials and any information derived from the data. Original research data and primary materials generated in the conduct of research at the University will be owned and retained by the University subject to any contractual, statutory, ethical, and/or funding body requirements. 
  • Clinical Trial Research Agreements and any relevant research agreements list UNSW as the sponsor or the collaborative research group responsible for the clinical trial.  
  • UNSW is listed as the trial sponsor in the Human Research Ethics application, the clinical trial protocol, or any documentation to be reviewed and approved by the reviewing Human Research Ethics Committee.  
  • UNSW has confirmed its agreement to provide insurance cover for the trial.
  • The UNSW Clinical Trials Research Governance requirements are met.

Confirmation of UNSW sponsor-related responsibilities

The UNSW Sponsor’s Delegate provides written confirmation of the UNSW sponsor-related responsibilities for the trial before recruitment and data collection can commence.

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Clinical Trial Protocol

A clinical trial protocol provides the plan for the undertaking of a clinical trial. The ICH GCP-guided requirements for the development of a clinical trial protocol are outlined at this section. 

Clinical trials that require a clinical trial protocol

A clinical trial protocol that complies with the Good Clinical Practice Guideline is to be developed for:

  • Clinical trials that involve an investigational therapeutic medical product, device or biological;
  • Clinical trials that require notification via the Therapeutic Goods Administration or the relevant regulatory body within the country that the trial will be conducted in; and/or
  • Clinical trials where the trial sponsor requires a protocol.

A protocol is not required but can be submitted for:

  • Clinical trials involving a medical product, device or biological being used for the intended purpose listed in their respective Australian Register of Therapeutic Goods Public Summary or as per its conditions of approval in the country that the trial is being conducted;
  • Clinical trials that do not involve a medical product, device or biological; and/or
  • Trials that do not require notification via the Therapeutic Goods Administration Clinical Trial Notification process or the relevant regulatory body within the country that the trial will be conducted in.

Clinical Trial Protocol requirements for trials where UNSW is to be the Sponsor

The contents of the clinical trial protocol must include all items included at section 6.1 of the Guideline for Good Clinical Practice E6(R2). In particular, the following items must be included as distinct sections in the clinical trial protocol:

Risks

  • The risks relating to the investigational medical product, device, biological, trial conduct, design and methods must be defined in the clinical trial protocol.

Protocol Deviations and Serious Breaches

  • Protocol deviation and serious breach definitions, procedures for recording, reporting and developing corrective and preventative action plans must be documented in the clinical trial protocol and reflect the requirements outlined in the protocol deviations and serious breach section.

Safety Monitoring

  • Safety monitoring definitions, procedures for recording, reporting, and assessing safety monitoring reports must be documented in the clinical trial protocol and reflect the requirements outlined in the safety monitoring section. 

Delegation of duties

A delegation’s log defining the trial responsibilities of the UNSW Sponsor’s Delegate, the Coordinating Principal Investigator (s), Site Principal Investigator(s) and any trial-related personnel must accompany the clinical trial protocol.

The delegation's log must specify that the responsibilities for the conduct, oversight and monitoring for the trial are delegated to the Coordinating Principal Investigator. 

The Coordinating Principal Investigator may delegate trial-related responsibilities to the approved Principal Investigator(s) or trial related personnel. All trial-related duties delegated by the Coordinating Principal Investigator or Principal Investigator(s) and/or trial related personnel are only to be delegated to those that are qualified by experience and training.

The delegations log must specify that the UNSW Sponsor’s Delegate is notified of:

  • Protocol Deviation reports outlined in the UNSW Research Misconduct Procedure.
  • Any serious breach of Good Clinical Practice, the clinical trial protocol, the clinical trial standard operating procedures, or the human ethics approval that is likely to affect to a significant degree the safety or rights of participants or the reliability and robustness of the data generated in the clinical trial.
  • Suspected Unexpected Adverse Reactions (SUSAR) or Unanticipated Serious Adverse Device Effect (USADE) events
  • Significant Safety Issues likely to (or have the potential to) affect to a significant degree the safety or rights of participants or the reliability and robustness of the data generated in the clinical trial
  • Urgent Safety Measures implemented to remove or prevent a significant safety issue
  • Safety Reports relating to the continuation, suspension, or discontinuation of the clinical trial for safety reasons as they arise.
  • Participant complaints or concerns received in relation to the conduct of the research.
  • Any significant modifications to the clinical trial that are likely to affect to a significant degree the safety or rights of participants or the reliability and robustness of the data generated in the clinical trial.
  • Amendments to clinical trial research agreements or service level agreements.
  • Revisions to regulatory requirements including correspondence with the Therapeutic Goods Administration, clinical trial registries or the FDA.
  • Site authorisation, addition of new sites, closure of approved sites of changes to the site Principal Investigator that is responsible for a site.

Monitoring of compliance

  • Procedures for monitoring compliance must be documented in the trial protocol.
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Investigator Brochure

The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data of the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures.

Clinical trials that require an investigator brochure

An investigator brochure that complies with the Good Clinical Practice Guideline must be developed for:

  • Clinical trials that involve an investigational medical product, device or biological where this information has not been included in the clinical trial protocol.
  • Clinical trials that require notification via the Therapeutic Goods Administration or the relevant regulatory body within the country that the trial will be conducted in.
  • Clinical trials where the trial sponsor requires an investigator brochure.

Clinical trials that do not require an investigator brochure

An investigator brochure is not required but can be submitted for:

  • Clinical trials involving a medical product, device or biological being used for the intended purpose listed in their respective Australian Register of Therapeutic Goods Public Summary or as per its conditions of approval in the country that the trial is being conducted.
  • Clinical trials that do not involve a medical product, device or biological.
  • Trials do not require notification via the Therapeutic Goods Administration Clinical Trial Notification process or the relevant regulatory body within the country that the trial will be conducted in.
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Investigator Selection and Site Feasibility

The sponsor is responsible for developing procedures for identifying, assessing, and selecting the site(s), institution(s) and investigator(s) that are to participate in the clinical trial.

For trials sponsored by UNSW, the Coordinating Principal Investigator will be responsible for selection of trial sites, site principal investigator(s) and for the completion of feasibility activities.

The Coordinating Principal Investigator muar ensure that the following is in place for each participating site:

Site Principal Investigator

  • The Principal Investigator is qualified by experience and training to provide oversight and conduct the clinical trial at the site.
  • The Principal Investigator has expertise with the target population and disease area being studied.
  • The Principal Investigator has or is to be provided with protocol specific training and is aware of the requirement to conduct the trial in accordance with the protocol, HREC approved procedures and GCP.

Institution

  • The institution responsible for the site has research governance procedures in place for authorising the commencement of a clinical trial.
  • The institution responsible for the site has adequate facilities, resources, technology, and qualified personnel to conduct the trial in accordance with the protocol, HREC approval and where applicable GCP.  
  • The institution has procedures in place for facilitating the review of clinical trial research agreements, service agreements, insurance and indemnity requirements.
  • The institution responsible for the site has procedures in place for responding to participant complaints, allegations of research misconduct and/or serious breaches of GCP.

Site

  • The site has access to the target population to meet recruitment targets.

Site Personnel

  • All site personnel responsible for conducting the clinical trial in accordance with the protocol are qualified by experience and training.
  • Copies of CVs, Good Clinical Practice training certificates and records of qualifications to demonstrate experience by qualification and training are obtained and documented.  
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Human Research Ethics Committee

A trial should be conducted in compliance with the clinical trial protocol that has received prior Human Research Ethics Committee and, where applicable, overseas Institutional Review Board approval or favourable opinion.

A Human Research Ethics Committee/Institutional Review Board must be selected to complete an ethical review of the clinical trial. If the research requires the recruitment of participants from private institutions, public hospitals or in other countries, multiple HRECs or IRBs may need to be identified to review and approve a clinical trial. Trials conducted in Australia where UNSW is the sponsor must be reviewed and approved by an Australian Human Research Ethics Committee formally registered with NHMRC.

Specific detains identifying the reviewing/approving HRECs/IRBs and the sites covered by the ethics approval must be included in the clinical trial protocol.

Approvals established with an NHMRC-recognised HREC outside of UNSW must be submitted for noting via the UNSW external ethics approval process. Clinical trials conducted overseas require UNSW HREC approval before a submission is made to the in-country IRB or equivalent.

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Registration of Clinical Trial on Publicly Accessible Registry

The Coordinating Principal Investigator must register the clinical trial on a publicly accessible register complying with international standards before the recruitment of the first participant. Below are the recommended platforms to register clinical trials.  

 

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Clinical Trial Research Agreements and Other Agreements

The sponsor of a trial must enter into a clinical trial research agreement (CTRA) with each site documenting the obligations of each party with respect to the conduct of the trial and outlining any payments that will be made to the site.

  • The Medicines Australia Clinical Trial Research Agreement templates can be accessed using this link. Other templates can be requested by contacting Research Grants and Contracts.
  • Injury and Compensation Guidelines and Templates are available on the Medicines Australia and can be accessed by using this link
  • All agreements are to be negotiated with Research Grants and Contracts once the clinical trial protocol has been developed, human ethics approval has been established and, where applicable, the UNSW Clinical Trials Sponsor's Delegate has confirmed that UNSW will act as clinical trial sponsor.
  • Signed CTRAs and other agreements must be included in the list of GCP essential documents. Recruitment and data collection for a clinical trial must not commence without an executed CTRA in place.
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Insurance

Clinical trials are not automatically covered by UNSW Insurance. Advice on insurance requirements for clinical trials must be obtained by completing the Clinical Trials Spreadsheet. See the UNSW Insurance website for further advice.  

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Risk Based Management and Monitoring of Clinical Trials

The requirements for monitoring clinical trials are outlined below. 

Risk Assessment

An assessment of the investigational medical product, device, biological, intervention, trial conduct, design and methods must be conducted to determine the risk category for the clinical trial following ICH GCP guidelines.

The risk category of a particular clinical trial is determined by the nature of the monitoring requirements required for the research:

Type of Clinical Trial Risk Category

Trials involving an investigational medical product, device or biological entered onto the Australian Register of Therapeutic Goods or with regulatory approval in the country that the trial is being conducted where:

  • The medical product, device or biological is being used in the clinical for its intended purpose within the conditions of its marketing approval.
  • The medical product, device or biological is not being used for its intended purpose, outside of its marketing approval conditions where this purpose is established practice and supported by sufficient published evidence and/or guidelines.Trials involving an intervention designed to evaluate a health-related medical or behavioural outcome

Trials involving an intervention designed to evaluate a health-related medical or behavioural outcome.

Type A

Risks are comparable to standard medical care.

Trials involving an investigational medical product, device or biological entered onto the Australian Register of Therapeutic Goods or with regulatory approval in the country that the trial is being conducted where:

  • The medical product, device or biological is being used for a new indication or purpose (e.g. different patient population/disease group)
  • Substantial modifications are made to dosage or methods of administration.
  • The medical product, device or biological are to be used in combination with other medical products, devices, or biologicals where there is limited published evidence and/or guidelines on the interactions between combinations.

Trials involving an investigational medical product, device or biological not entered onto the Australian Register of Therapeutic Goods or with regulatory approval in the country that the trial is being conducted where:

  • The investigational medical product involves an active substance that is part of a medical product entered on the Australian Register of Therapeutic Goods or with regulatory approval in the country that the trial is being conducted in.

TYPE B

Risk associated with modified use of an existing product

Trials involving an investigational medical product, device or biological not entered onto the Australian Register of Therapeutic Goods or with regulatory approval in the country that the trial is being conducted.

TYPE C

Risk associated with use of an unlicensed product.

 

 

Monitoring Requirements where UNSW is the sponsor

A monitoring plan must be developed for all trials where UNSW agrees to be the sponsor. The monitoring plan must specify the risk category of the trial and the type of monitoring that is appropriate. Please note that costs associated with monitoring are to be funded via the research budget.

The following categories apply as appropriate:

  • Central monitoring involves the review of centralised data by trial oversight committees or data management personnel.
  • Remote monitoring involves the review of documents sent via secure document transfer platforms and the training of site staff via video, phone, or web-based platforms.
  • On-site monitoring involves site visits to perform checks to verify that trial documents and source data and to assess the sites compliance with the clinical trial protocol.
Type of Clinical Trial Monitoring Activities 

Risk Type: A

Monitoring Type: Central Monitoring

Intensity: Low Intensity Monitoring

Oversight of trial by a trial management group, trial safety committee, independent data safety monitoring committee or a group of investigators qualified by training and experience delegated by the sponsor.

Site initiation must occur before recruitment of the first trial participant at the site occurs. Site initiation must involve clinical trial protocol training, allocation of site personnel roles, site governance requirements, contracts, insurance, indemnity, assessment, and collection of site personnel qualifications.

Regular monitoring activities must be conducted centrally by the Coordinating Principal Investigator, Coordinating Research Personnel or as specified in the delegation log and should include:

  • Regular assessment of recruitment, screening, consent, data collection, case report forms, safety reporting, management of investigational product, dosage practices by site personnel.
  • Regular checks of documented evidence confirming that the above activities have complied with the trial protocol or procedures.
  • Assessment of CRFs (e.g. review for logical consistency, late or poor CRF completion, checks to confirm CRFs have been completed by authorised personnel).

Interim monitoring visits must be conducted centrally by the Coordinating Principal Investigator, Coordinating Research Personnel or as specified in the delegation log at defined timepoints, and should include:

  • Checks for unusual data patterns or trends (digit preference, rounding, or unusual frequency distribution – e.g. mean, variance, skewness), rates of recruitment, withdrawals, and losses to follow-up by site, missing or invalid data on the CRF (e.g. range, plausibility and consistency checks) and assessment of adverse event reporting rates compared between sites.
  • Findings of monitoring activities or visits to be communicated to the trial management group or safety committee delegated to provide oversight to the trial with a plan for corrective, preventative actions, a timeline for resolution.
  • A summary of findings and where applicable a progress report on resolution of findings that require preventative or corrective actions is to be provided to UNSW Sponsors Delegate at least annually.

Resolution of trial-related issues should be managed via telephone, email or web-based meetings that are documented by minutes.

Ongoing progress meetings should be conducted via telephone or web-based meetings that are documented by minutes.  

For cause monitoring visit to be conducted in response to a safety event or where a potential serious breach has been identified: the monitoring plan must define the criteria that will be used to determine whether for cause monitoring visits are to be conducted remotely or onsite.

Risk Type: B

Monitoring Type: Central, remote, and where necessary on-site monitoring

Intensity: Moderate Intensity Monitoring

Oversight of trial by a trial management group, trial safety committee, independent data safety monitoring committee or a group of investigators qualified by training and experience delegated by the sponsor:

Site initiation must be conducted via a remote or onsite meeting prior to the recruitment of the first trial participant at the site occurs. Site initiation must nvolve clinical trial protocol training, allocation of site personnel roles, site governance requirements, contracts, insurance, indemnity, assessment, and collection of site personnel qualifications.

Monitoring activities at defined intervals must be conducted centrally and/or remotely by the Coordinating Principal Investigator, Coordinating Research Personnel or as specified in the delegation log and should include:

  • Assessment of recruitment, screening, consent, data collection, case report forms, safety reporting, management of investigational product, dosage practices by site personnel.
  • Checks of documented evidence confirming that the above activities have complied with the trial protocol or procedures.
  • Assessment of CRFs (e.g. review for logical consistency, late or poor CRF completion, checks to confirm CRFs have been completed by authorised personnel).
  • Verification of source data.

Interim monitoring visits at defined timepoints must to be conducted by the Coordinating Principal Investigator, Coordinating Research Personnel or as specified in the delegation log at defined timepoints and should include:

  • Checks for unusual data patterns or trends (digit preference, rounding, or unusual frequency distribution – e.g. mean, variance, skewness), rates of recruitment, withdrawals, and losses to follow-up by site, missing or invalid data on the CRF (e.g. range, plausibility and consistency checks) and assessment of adverse event reporting rates compared between sites.

Findings of monitoring activities or visits must be communicated to the trial management group or safety committee delegated to provide oversight to the trial with a plan for corrective, preventative actions, including a realistic timeline for resolution.

A summary of findings and where applicable a progress report on resolution of findings that require preventative or corrective actions must be provided to UNSW Sponsor's Delegate at defined timepoints.

Resolution of trial-related issues should be managed via telephone, email or web-based meetings that are documented by minutes.

Ongoing progress meetings should be conducted via telephone or web-based meetings that are documented by minutes. 

For cause monitoring visit to be conducted in response to a safety event or where a potential serious breach has been identified: the monitoring plan must define the criteria that will be used to determine whether for cause monitoring visits are to be conducted remotely or onsite.

Risk Type: C

Monitoring Type: Central, remote and on-site monitoring.

Intensity: Higher Intensity Monitoring

The independent data safety monitoring committee or a group of investigators qualified by training and experience delegated by the sponsor act as per follows:

Site initiation must be conducted via a remote or onsite meeting and occur before recruitment of the first trial participant at the site occurs. Site initiation must involve clinical trial protocol training, allocation of site personnel roles, site governance requirements, contracts, insurance, indemnity, assessment, and collection of site personnel qualifications.

Monitoring activities at defined, regular intervals must be conducted via central or remote monitoring by the Coordinating Principal Investigator, Coordinating Research Personnel or as specified in the delegation log and should include:

  • Assessment of recruitment, screening, consent, data collection, case report forms, safety reporting, management of investigational product, dosage practices by site personnel.
  • Checks of documented evidence confirming that the above activities have complied with the trial protocol or procedures.
  • Assessment of CRFs (e.g. review for logical consistency, late or poor CRF completion, checks to confirm CRFs have been completed by authorised personnel).

Interim monitoring visits must be conducted within the first 6-8 weeks of the intervention and be conducted via remote or onsite monitoring visits by the Coordinating Principal Investigator,  Coordinating Research Personnel and include:

  • Assessment of recruitment, screening, consent, data collection, case report forms, safety reporting, management of investigational product, dosage practices by site personnel.
  • Checks for unusual data patterns or trends (digit preference, rounding, or unusual frequency distribution – e.g. mean, variance, skewness), rates of recruitment, withdrawals, and losses to follow-up by site, missing or invalid data on the CRF (e.g. range, plausibility and consistency checks) and assessment of adverse event reporting rates compared between sites.
  • Assessment of CRFs (e.g. review for logical consistency, late or poor CRF completion, checks to confirm CRFs have been completed by authorised personnel).

Each site must have an on-site monitoring visit at least annually during the active phase of the research.

In addition to the above, monitoring should include:

  • Verifying that the investigator has adequate qualifications and resources and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
  • Verifying that the adequate facilities and resources are in place for the storage and handling of investigational product.
  • Verifying that the investigational products are only provided to participants who are eligible, and it is administered as the protocol requires. Ensuring that participants are provided with instructions on how to use and handle investigational products.
  • Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.
  • Verifying that written informed consent was obtained before each participant's participation in the trial.
  • Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
  • Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution and have not delegated these functions to unauthorised individuals.

Findings of monitoring activities or visits must be communicated to the trial management group or safety committee delegated to provide oversight to the trial with a plan for corrective, preventative actions, and a timeline for resolution.

A summary of findings and where applicable a progress report on resolution of findings that require preventative or corrective actions must be provided to the UNSW Sponsor's Delegate at defined timepoints.

Resolution of trial-related issues must be managed via telephone, email or web-based meetings that are documented by minutes.

Ongoing progress meetings must be conducted via telephone or web-based meetings that are documented by minutes. 

For cause monitoring visits conducted in response to a safety event or where a potential serious breach has been identified: the monitoring plan must define the criteria that will be used to determine whether for cause monitoring visits are to be conducted remotely or onsite.

 

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Safety Monitoring Reporting - Investigational Medical Products and Devices

The requirements and definitions for safety reporting are outlined at this section. 

Safety Monitoring Reporting

Adverse Event (AE), Adverse Device Effect (ADE), Adverse Reaction (AR), Serious Adverse Event (SAE)/Serious Adverse Reaction (SAR), Serious Adverse Device Effect (SADE), Suspected Unexpected Serious Adverse Reaction (SUSAR), Unanticipated Serious Adverse Device Effect (USADE)  Significant Safety Issue (SSI), Urgent Safety Measure (USM) are to be reported by the site principal investigator to the sponsor. If UNSW is the sponsor, the site principal investigator reports must be made to the Coordinating Principal Investigator. 

Safety Monitoring Report Form

A form used to report events must be designed for the trial. Paper-based versions or electronic versions can be developed. The forms should include a mechanism for assessment of seriousness, causality, and expectedness to be made.

Assessment and Management of Safety Monitoring Reports

Procedures for assessing and classifying reports in accordance with safety reporting assessment flowchart once a report has been made must be developed and documented in the protocol before recruitment and data collection starts. If UNSW is the sponsor, the Coordinating Principal Investigator must develop the following procedures to meet these requirements.

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Adverse Event Report Assessments

Event report forms classified the safety monitoring event as “not serious” must be assessed by a Qualified Physician named in the clinical trial protocol. The Qualified Physician must use the Safety Reporting Assessment Flowchart to determine whether the event is adverse reaction or an adverse event. The Qualified Physician cannot delegate this responsibility to other research personnel. The reporting timeframes for adverse event reports from participating sites to the Coordinating Principal Investigator must be specified in the protocol. All adverse event reports must be recorded in the safety monitoring register.

Qualified Physician/Medical Expert: The medical expert who is a physician that is a listed investigator who has medical expertise in the research area that provides safety oversight, such as the ongoing monitoring of reports of adverse events (AEs) submitted by investigational sites to identify safety concerns. The Qualified Physician/Medical Expert cannot be a Principal Investigator responsible for a trial site. The name of this person must be specified in the general information section of the protocol. The role cannot be delegated to another party.

Serious Event Report Assessments

Event report forms that classify the event as “serious” must be assessed by the Sponsor’s Medical Expert. A report must be sent to the Sponsor’s Medical Expert for assessment as soon as possible and within 7 working days of receiving the report form. The following criteria classify the report as serious:

  • Fatal
  • Life-threatening illness or injury (actual risk of death at the time of the event)
  • Permanent impairment of body structure or body function
  • In-patient or prolonged hospitalisation (not for a pre-existing condition or an elective surgery)
  • Medical or surgical intervention to prevent life –threatening illness or injury or permanent impairment to a body structure or function
  • Led to fetal distress, fetal death or congenital abnormality or birth defect.

The Sponsor’s Independent Medical Expert must use the Safety Reporting Assessment Flowchart to determine whether the event is a serious adverse reaction, a serious adverse event, or a serious adverse device effect.

The Sponsor’s Independent Medical Expert cannot delegate this responsibility to other research personnel. All decisions made by the Sponsor’s Medical Expert are to be recorded.

Sponsor's Independent Medical Expert: A person independent of the listed investigators that is a qualified medical physician, who has medical expertise in the research area that provides safety oversight, such as the ongoing monitoring of reports of serious adverse events (SAEs) submitted by investigational sites to identify safety concerns and make recommendations for continuing or stopping a trial.

Serious Adverse Reaction (SAR) or Serious Adverse Device Effect (SADE)

Any serious adverse events related to the investigational medical product or device that occur and are referenced in the clinical trial protocol, the product information, referenced safety information or the investigator brochure must be classified by the Sponsors Independent Medical Expert as a SAR or a SADE.

Suspected Unexpected Adverse Reactions (SUSAR) or Unanticipated Serious Adverse Device Effect (USADE)

Any serious adverse events related to the investigational medical product or device that occur and are not referenced in the clinical trial protocol, the product information or investigator brochure must be classified by the Sponsors Independent Medical Expert as a SUSAR or USADE.

Register of Clinical Trial Safety Monitoring Reports

A register of all event reports made and assessed are to be kept by the sponsor. If UNSW is the sponsor, the Coordinating Principal Investigator (or delegated staff member as reflected in the trial delegation log) must maintain a register of safety monitoring events.

Reporting of Clinical Trial Safety Monitoring Reports

For trials where UNSW is the sponsor, single case reports of Adverse Events (AEs), Adverse Reactions (AR), Adverse Device Effect, Serious Adverse Events (SAEs) Serious Adverse Reactions (SARs), Serious Adverse Device Effect (SADE) reports do not need to be reported to the UNSW Sponsor’s Delegate. All single case reports must be recorded in a safety monitoring register and need to be reported to the UNSW Sponsor’s Delegate annually. The UNSW Safety Monitoring Register Template UNSW is provided as an example of the information to be recorded in a register. 

The Trial Management Group (TMG), Trial Safety Committee (TSC) or the Data Safety Monitoring Board (DSMB) must review the safety information to identify any serious emerging safety concerns. If safety concerns are identified, a plan to minimise the time that participants may be placed at excess risk of harm must be developed. If no emerging safety issues are identified, the TMG must provide a safety review summary. The following must be reported to the UNSW Sponsor’s Delegate via email to  humanethics@unsw.edu.au:

  • A brief analysis of the safety profile of the trial intervention(s) and its implications for participants considering all available safety data and the results of relevant clinical or non-clinical studies (annually).
  • A brief discussion of the implications of the safety data to the trial’s risk-benefit ratio
  • A description of any measures taken or proposed to minimise risks. (annually).
  • Copies all safety review summaries along with the line listings that relate to these summaries.
  • A report of emerging safety issues or where no emerging safety issues have been identified documented evidence (e.g. minutes of a meeting) confirming that a review was undertaken.
  • Plan to minimise the time that participants are placed at excess risk as a result of emerging safety issues (within 7 days of becoming aware of the safety issues).

Reporting of Suspected Unexpected Adverse Reactions (SUSAR)

Any clinical trial safety monitoring reports classified by the Sponsor’s Medical Expert as a SUSAR must be reported to the Coordinating Principal Investigator.

The Coordinating Principal Investigator must report to the TGA and the UNSW Sponsor’s Delegate:

  • Any fatal or life threatening Australian SUSARs or USADE 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.
  • All other all other Australian SUSARs or USADE, no later than 15 calendar days after being made aware of the case.

Significant Safety Issues (SSIs)

Significant safety issues are defined as any safety issue that could adversely affect the safety of participants or materially impact on the continued ethical acceptability or conduct of the trial. The following steps must be followed in situations where urgent measures are taken to eliminate an immediate hazard to a participant’s health or safety.

Principal Investigators must report significant safety issues must be reported immediately to the UNSW Sponsors Delegate. The report must be supported by advice from the principal investigator addressing the following points:

  • A description of the significant safety issue and any urgent safety measure implemented.
  • A description of any measures taken and advice on whether a temporary halt of the trial is required for safety reasons.
  • An indication of whether there is a requirement to submit an amendment of the clinical trial protocol to the approving HREC.

 ​​​​​​​UNSW Sponsors Delegate will ensure that significant safety issues meeting the urgent safety measure's definition are notified to the TGA, HREC and investigators within 72 hours. ​​​​​​​Other significant safety issues notified to the UNSW Sponsors Delegate who will then report to the TGA, HREC and investigators within 15 calendar days of the sponsor instigating or being aware of the issue.

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Safety Monitoring - Other Clinical Trials

The safety monitoring requirements for clinical trials that do not involve an investigational medical product or device are outlined at this section.

Safety Monitoring Reporting

Safety event reports are to be reported by the site principal investigator to the sponsor. If UNSW is the sponsor, the Coordinating Principal Investigator must develop the following procedures to meet these requirements. If the trial does not have any participating sites a process for recording and documenting adverse events and incidents is to be detailed as a procedure or within the HREC approved application.

Adverse Event: An adverse event is defined as any untoward occurrence (medical or other) in a clinical trial participant administered one or more of the trial interventions. All expected and/or known discomforts, harms, or affects that will be (or have the potential to be) induced by the trial procedures must be specified in the Human Ethics Application or a separate safety monitoring procedure. The safety information must also include:

  • Measures for minimising the risk of a participant experiencing an event
  • A plan for providing support of care for participants that experience an event.

Serious adverse event: A serious adverse event is any event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. The Human Ethics Application or a separate safety monitoring procedure must outline the process that the research team will follow to assess whether the event was related or unrelated to the clinical trial, its procedures or the interventions.

Significant Safety Issue:  Defined as an issue that could adversely affect the safety of participants or materially impact on the continued ethical acceptability or conduct of the trial. The human ethics application of safety monitoring procedure must specify that significant safety issues that occur are reported to the UNSW Sponsors Delegate immediately but no later than 7 days.

Urgent Safety Measure: Defined as a measure required to be taken to eliminate an immediate hazard to a participant’s health or safety. The human ethics application of safety monitoring procedure must specify that urgent safety measures that occur are reported to the UNSW Sponsors Delegate immediately but no later than 7 days.

Safety Monitoring Report Form

For multi-centre trials a form that can be used by sites to report events must be designed for the trial. Paper-based versions or electronic versions can be developed. Trials that do not have participating sites can record events in a safety monitoring register.

Register of Clinical Trial Safety Monitoring Reports

A register of all event reports made and assessed are to be kept by the sponsor. If UNSW is the sponsor, the Coordinating Principal Investigator must maintain a register of safety monitoring events. The UNSW Safety Monitoring Register Template UNSW is provided as an example of the information to be recorded in a register.

Assessment of Safety Monitoring Reports

A group or committee must be established to assess safety monitoring reports. The group or committee must include at least one person qualified by experience and training that can provide an independent assessment serious adverse event, significant safety issues, urgent safety measures.

Adverse event reports can be assessed by an investigator listed in the ethics application that is experienced by qualification and training. The investigator must be independent of the site where the event occurred.

Reporting of Safety Monitoring Reports

Adverse Events and Serious Adverse Events: For trials where UNSW is the sponsor, single case reports of Adverse Events and Serious Adverse Events reports do not need to be reported to the UNSW Sponsor’s Delegate or the HREC. All single case reports must be recorded in a safety monitoring register supported by an assessment of trial safety must be reported to the UNSW Sponsor’s Delegate annually.

Significant Safety Issues: Are to be reported immediately, but no later than 7 days via email to humanethics@unsw.edu.au.

Urgent Safety Measures: Are to be reported immediately, but no later than 7 days via email to humanethics@unsw.edu.au.

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UNSW Protocol Deviation and Serious Breaches of Good Clinical Practice

We are working on procedures to provide meaningful intersections between possible non-compliance with Good Clinical Practice, the protocols approved in the relevant HREC approvals, and definitions of breaches as defined in the Australian Code for the Responsible Conduct of Research.

Protocol Deviation 

A protocol deviation is defined as any breach, divergence or departure from the requirements of Good Clinical Practice, the clinical trial protocol, the clinical trial standard operating procedures, or the human ethics approval and does not have a significant impact on the continued safety or rights of participants or the reliability and robustness of the data generated in the research or clinical trial. Protocol deviations are events that do not occur in a persistent or systematic manner, and do not have the potential to result in participant harms. Examples of protocol deviations include but are not limited to: 

  • Deviations because of participant adherence to the protocol, including rescheduled study visits, participants refusal to complete scheduled research activities or failure to complete self-report questionnaires required by the study protocol.  
  • Blood samples obtained or clinical trial testing occurring at times close to, but not precisely at the time points specified in the protocol. 
  • The completion of consent forms, safety monitoring report, case report forms or data collection tools in a manner that is not consistent with the protocol instructions, or failure to make reports within the required reporting timeframes.  
  • Administration of the clinical trial investigational medical product, or device in a manner that is not consistent with the manufacturer’s instructions for use. 
  • Use of an unapproved version of the participant information statement or recruitment of participants using unapproved recruitment procedures.  
  • Inclusion of a participant that does not meet the inclusion criteria.  
  • An urgent safety measure implemented required to be taken to eliminate an immediate hazard to a participant’s health or safety. 

 Serious Breach  

A serious breach is defined as a breach of Good Clinical Practice, the clinical trial protocol, the clinical trial standard operating procedures, or the human ethics approval that is likely to affect to a significant degree the safety or rights of participants or the reliability and robustness of the data generated in the clinical trial. Examples of serious breaches include but are not limited to: 

  • Persistent or systematic non-compliance with the instructions for completing consent forms, safety monitoring forms, case report forms or data collection tools that results in continued missed or incomplete data collection.  
  • Failure to record or report adverse events, serious adverse events, suspected unexpected serious adverse reactions, significant safety issues where urgent safety measures were implemented.  
  • Failure to conduct clinical trial procedures in accordance with the clinical trial delegation log.  
  • Widespread and uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial subjects. 
  • Failure to report investigational medical product or device defects to the clinical trial sponsor or any relevant regulatory body. 
  • Failure to conduct research in conformity with the issued approvals, permits or licences in accordance with required laws, regulations, disciplinary standards and UNSW policies relating to the responsible and/or safe conduct of research. 
  • Concealing or facilitating breaches (or potential breaches) of the Research Code by others. 
  • Conducting research without the requisite approvals, permits or licences required by laws, regulations, disciplinary standards and UNSW policies related to the responsible and/or safe conduct of research. 
  • Failure to conduct Research as approved by an ethics review body where that conduct leads to (or has the potential to) results in participant harms. 
  • Conducting Research without ethics approval as required by the National Statement on Ethical Conduct in Human Research where that conduct leads to (or has the potential to) result in participant harms. 
  • Any breaches as outlined in the UNSW Research Misconduct Procedure or the Australian Code for responsible conduct of research that leads to (or has the potential to) result in participant harms.  

 Reporting Protocol Deviations  

Protocol deviations occurring at a site must be documented in site files and need to be reported by site principal investigator to the Coordinating Principal Investigator.

The Coordinating Principal Investigator must review the protocol deviation, along with the clinical trial protocol to establish the corrective actions and preventative steps to prevent the deviation from reoccurring. 

The protocol deviation and corrective action plan must be reported to the UNSW Sponsor’s Delegate by the Coordinating Principal Investigator or Coordinating Research Team using the protocol deviation report form.  

Reporting of a Serious Breach 

A serious breach occurring at a participating site must be reported by the site Principal Investigator to the Coordinating Principal Investigator within a specified timeframe.  

The Coordinating Principal Investigator must review the serious breach, along with the clinical trial protocol to develop a Corrective and Preventive Action (CAPA) that defines the steps to prevent the serious breach from reoccurring. 

The serious breach report and the CAPA is to be provided to the approving HREC and the UNSW sponsors delegate for review and approval.  

Reporting of Serious Breaches by Third Parties 

A Suspected Breach is a report that is judged by the reporter as a possible serious breach but has yet to be formally confirmed as a serious breach by the sponsor. 

A Suspected Breach form must be completed when a third party (e.g. individual / institution) wishes to report a suspected breach of Good Clinical Practice or the protocol. This should be reported directly to the reviewing HREC without reporting through the sponsor. 

Recording of Protocol Deviation and Serious Breach Reports  

A register of protocol deviation and serious breach reports must be recorded, written records and copies of documentation sent to the sponsor in the must be retained by in the Investigator Site File.  

Copies of protocol deviation and serious breach reports must be recorded, written records and copies of documentation sent to the sponsor, referrals made to the HREC or to establish whether a breach of the Australian Code for Responsible conduct of research  must be retained in the Master Site File.  

 Review of a Protocol Deviation and a Serious Breach 

The UNSW Sponsor’s Delegate will review reports to establish whether the event meets the definition of a protocol deviation or serious breach, to establish whether the proposed CAPA is appropriate and to establish whether there is or will be an ongoing impact on the reliability and robustness of the data generated. 

Advice from the approving HREC will be sought by the UNSW Sponsor’s Delegate on the corrective and preventive actions.

Protocol deviation and/or serious breach reports where a UNSW researcher, staff or student is responsible for the protocol deviation or the serious breach will be reviewed as per the UNSW Research Misconduct Procedure to establish whether a breach of the UNSW Research Code of Conduct has occurred. 

Protocol deviation and/or serious breach reports where the UNSW Sponsor’s Delegate determines that the site Principal Investigator(s)/ site personnel are responsible for a protocol deviation or the serious breach will be referred onto their responsible institution for review under their own Research Misconduct procedures to establish whether a breach of the Australian Research Code for the Responsible Conduct of Research has occurred.  

or site files as GCP essential documents.

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Research Governance and Site Authorisation

Site Authorisation from the responsible institution is to be obtained before recruitment and data collection commences at a site. 

The Coordinating Principal Investigator is responsible for ensuring that the following documentation is in place before recruitment and data collection at a trial site commences:

  • A letter from a person with the delegated authority for the institution responsible for the participating trial site that authorises the commencement of the trial.
  • A clinical trial research agreement signed by the trial sponsor and the delegated authority for the site.
  • CVs for all site investigators, and certificates of completed GCP training for all investigators and trial site personnel.
  • Evidence to confirm that protocol specific training for investigators and site personnel has occurred.
  • Evidence to confirm that site principal investigators and trial site staff have been made aware of the requirement to maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail)
  • Evidence to confirm that the site Principal Investigator is aware of all documents to be retained in the Investigator Site File.
  • Evidence to confirm that the current HREC approved documentation has been provided to the site.
  • Any conflict of interest disclosures has been completed and documented.
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