Risk Based Management and Monitoring of Clinical Trials

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 which is detailed below (please expand section):

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.

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.

 

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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.

The table outlining these categories can be found below (please expand section):

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 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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