CT SOP version no 1.1.

Main changes from 1.0: Improved wording. No major changes.

Sponsor

The sponsor has overall responsibility for ensuring that clinical trials are monitored. The sponsor should determine the appropriate extent and nature of monitoring based on identified risks. The sponsor’s responsibilities shall be described in the governing documents (quality system) of the individual institution.

Only tasks, not responsibilities, may be delegated. The delegation of tasks shall be documented, for example in written agreements.

Principal Investigator

The principal investigator should make all requested trial-related records available for direct access. The principal investigator should be available for discussions with the monitor and facilitate monitoring visits by providing office space, access to trial documents, source data and other relevant documents and equipment required for the trial. The principal investigator is responsible for making corrections and following up on deviations and actions identified in the monitoring report, or in other documents, within the reported timelines.

Monitor

The monitor is acting on behalf of sponsor and should ensure that monitoring  is performed according to the monitoring plan and applicable monitoring procedures. The monitor should also watch for signs of changing risks and inform the coordinating investigator/sponsor if these risks increase or decrease in a manner that could warrant a change in the Monitoring Plan.

Selection and qualifications of monitors

The sponsor should utilise appropriately qualified individuals to monitor the trial. Monitors should not be involved in the clinical conduct of the trial at the site being monitored. In national and international trials with several monitors involved, a lead monitor will often be appointed.

The lead monitor will be the liaison between the sponsor and the monitors. Sponsor should clarify with the lead monitor the responsibilities for sharing relevant trial information, such as (updated) protocols and informed consent forms, with the other monitors before and during the trial.  

The monitor should have relevant knowledge about the trial, including the Investigational Medicinal Product (IMP), the trial protocol, informed consent form(s), ICH-GCP and applicable laws and regulations. Their qualifications (current CV) must be documented in the Trial Master File (TMF).

Monitors should follow the procedures described in the monitoring plan. If the monitor is not employed at the sponsor institution, the coordinating investigator should ensure that a Data Processing Agreement for Monitoring Services is signed.

Extent and nature of monitoring

The coordinating investigator should involve the monitor early in the process, and at the latest when all documents are ready for initial submission to CTIS. Monitoring should be done before, during and after the trial, and may include site monitoring (on-site and/or remote) and centralised monitoring.

The extent and nature of the monitoring shall be determined by the coordinating investigator on the basis of a risk assessment (see SOP Quality and Risk Management  with attachments) and should be described in the monitoring plan.

In order to perform source data verification of selected data, the monitor should be given their own log-in credentials (read-only access) to the medical records, data acquisition tools and other essential records. If this cannot be granted, the investigator or study nurse must log in and sit together with the monitor when doing source data verification or print out all relevant medical notes to allow source document verification.

Monitoring plan

The coordinating investigator, assisted by the (lead) monitor, should develop a risk-based monitoring plan that addresses identified risks to safety, data quality, and trial reliability. This plan should define the monitoring strategy, activities, methods and the rationale for their use, ensuring appropriate site oversight while minimizing burden. The goal is to ensure appropriate site oversight while minimizing the burden. The plan should prioritize aspects critical to quality, including participant safety, and key endpoints.

Additionally, the monitoring plan should:  

• Define the timing of the first monitoring visit and the frequency of subsequent visits.
• Clearly specify key parameters and processes to be monitored at each visit, prioritizing critical data and trial risks. If applicable, the monitor should work closely with the data manager to ensure alignment between the monitoring plan and the data manager’s data quality plan.
• Outline centralised monitoring procedures if applicable and not described in the data quality plan.  
• Describe the criteria for adaptive monitoring, allowing adjustments to the monitoring strategy based on emerging trial data and risks. The coordinating investigator/sponsor can amend the monitoring plan based on, for example: 
  • Feedback from the monitor, data manager, or trial oversight personnel. 
  • SAE reporting that changes the risk-benefit ratio. 
  • New scientific evidence, including publications from relevant trials. 
  • Findings from the Data Monitoring Committee (DMC)/Data Safety Monitoring Board (DSMB). 
  • Pre-clinical or early clinical findings that impact trial safety or efficacy. 

The monitor should engage with the data manager, statistician and/or trial group to determine whether interim analysis or data monitoring committee meetings during the trial require additional monitoring activities, and if so, include this in the monitoring plan.

Monitoring of blinded studies with unblinded personnel

In blinded clinical trials where unblinded site staff (e.g. a pharmacist or a study nurse preparing the treatment) work together with site staff who must remain blinded, (e.g. the treating physician or evaluator), it is important to have procedures in place to prevent un-blinded information from being inadvertently disclosed to the blinded site staff.

To maintain blinding integrity, these studies require two monitors:

• A blinded monitor for trial data monitoring.
• An unblinded monitor reviewing IMP-logs and other unblinded information.

The monitor will schedule monitoring visits in coordination with the investigator or their designee. If applicable and as specified in the monitoring plan, additional appointments will be arranged with the pharmacy, laboratory, or other relevant units involved in the trial. After each visit, whether conducted on-site or remotely, the monitor should complete a visit report using the NorCRIN report templates from Norcrin and Metodebok.  The reports should be emailed within 14 calendar days to the coordinating investigator and principal investigator as described in more detail below.

The coordinating investigator should review and sign monitoring reports to ensure that any trial issues are followed up and site issues are noted.  A signed copy should be returned to the monitor within 14 calendar days.

Site Initiation

An initiation visit should be performed at each trial site before the trial is initiated to ensure all required documents and Investigational Medicinal Product (IMP) are in place, and to confirm that investigators and site staff have adequate qualifications, resources, and facilities to conduct the trial safely and properly. The initiation visit may be combined with the start-up meeting, see SOP Application Process and Approvals and template Start-up Meeting Agenda.    

The monitor will complete the Trial Initiation Report and decide whether the site is ready to start recruitment or not based on the issues identified and described in  Attachment 1 (Pending Issues) of the report. Examples of major issues are pending approvals or agreements, missing/incomplete delegation log, insurance certificate, trial drug or training of trial personnel. Monitor signs and sends a PDF of the report both to the sponsor and the investigator. Sponsor should review and sign reports to ensure that any trial issues are followed up and site issues are noted. A signed copy should be returned to the monitor and a copy filed in the TMF.

The investigator or designee should complete the tasks in Attachment 1 within the timeframe given and return a signed copy to the monitor. A copy of the report and signed Attachment 1 should also be filed in the Investigator’s Site File (ISF). When all major issues are resolved, the monitor informs the investigator and sponsor that recruitment can start. If applicable, the monitor will complete and sign the Green Light for Trial Site document according to trial specific procedures. document according to trial specific procedures.

Monitoring visits during trial conduct 

Monitoring visits should be performed as described in the monitoring plan. After each monitoring visit, whether conducted on-site or remotely, the monitor should complete a Monitoring Report reflecting the site’s status at the time of the visit. The report should contain information about any missing documents, deviations found between source data and Case Report Form (CRF), or any actions required to ensure the trial is run according to the trial protocol, laws and regulations and ICH-GCP. Actions to be followed up should be listed in Attachment 1 (Pending Issues).  The reporting language should be specified in the monitoring agreement (Avtale med forskningsstøtte).

A PDF of the completed report must be emailed to the sponsor within 14 calendar days following the visit. Sending Attachment 1 (PDF) to the sponsor is optional. A signed copy of the report should be filed in the TMF by the sponsor and a signed copy should be sent to the monitor. At the same time, a PDF of Attachment 1 should be emailed to the site. Sending the full report to the site is optional unless sponsor has specified otherwise. The investigator or designee must sign Attachment 1 when the issues are resolved, send a copy to the monitor and file a copy in the ISF.

Issues classified as protocol deviations must be reported according to protocol or the Protocol Deviation Handling Plan. Findings requiring escalation for action and resolution should be described in the report, when needed.

Close-out visit

A close-out visit should be performed at each site after the last participant’s last visit. Deviations from this may be applicable for trials with a long survival follow-up period and should be detailed in the Monitoring Plan. Sites which never received investigational product and never included participants can be closed without an on-site visit. The Close-out Monitoring Report will be written and signed by the monitor and coordinating investigator/sponsor. The original signed report will be filed in the TMF. 

In clinical trials, samples of biological material may be stored in freezers which are not part of an organized biobank facility. If the samples are to be stored more than 2 months, a study specific research biobank must be established. This biobank must be approved by REK through the CTIS application process.

If the samples will be used for purposes outside the scope of the specific study, they should be part of a general biobank. A general biobank must be approved through a separate application to REK. Participants must sign a separate consent form for giving samples to both research biobanks and general biobanks.

Based on the risk assessment it may be necessary to monitor the biobank sample storage. In case the monitoring plan requires monitoring of a biobank, the monitor should complete the Biobank Monitoring Report.

If monitoring responsibilities for a site are transferred to a new monitor, it must be ensured that the new monitor documents training in the study.

As a general rule, the previous monitor should inform the new monitor about the status of the site using Trial Handover Procedure and Checklist. A copy of the handover checklist should be filed together with the new monitor’s CVs in the TMF. It should also be filed as part of the new monitor’s training documentation. The sponsor and the relevant site(s) should be notified about the handover. 

Centralised monitoring is an evaluation of accumulated trial data, performed in a timely manner according to the monitoring plan or Data Quality Plan.

The use of centralised monitoring should be risk-based, considering the number of participants and site-specific risk factors. It may complement and reduce the extent and/or frequency of site monitoring.  

The trial data manager or statistician or other suitably qualified person will:

• Identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations
• Examine data trends, such as the range, consistency, and variability of data within and across sites
• Evaluate for systematic or significant errors in data collection and reporting at a site or across sites, or potential data manipulation or data integrity problems
• Analyse site performance metrics to identify sites requiring additional oversight or intervention

If centralised monitoring identifies sites with significant deviations in data patterns, performance inconsistencies or non-compliance with protocol requirements, these sites and/or processes may be selected for on-site monitoring, until their performance aligns with expected standards. Findings from centralised monitoring activities and observations will be reported using a centralised monitoring report.

The following monitoring documentation should be filed in the TMF:

• The monitoring plan
• All signed monitoring reports
• Copies of significant communication with site staff  (e.g. responses to protocol procedure inquiries, trial updates, newsletters etc.)
• Other documentation generated during monitoring activities

• Monitoring Plan - Template
• Trial Initiation Report - Template
• Monitoring Report - Template
• Close-out Monitoring Report - Template
• Biobank Monitoring Report - Template
• Query List - Template
• Trial Handover Procedure and Checklist - Template
• Green Light for Trial Site - Template
• Data Processing Agreement for Monitoring Services - Template
• Data Verification Plan - Template