Monitor’s qualifications    

Monitor should have relevant knowledge about the trial, including the Investigational Medicinal Product (IMP), the trial protocol, patient information and consent form, ICH-GCP and applicable laws and regulations.  

Monitor's tasks

The monitor should

• Facilitate a Risk Assessment with the trial team, if requested 

• Assist the trial team in developing a Monitoring Plan based on the risk assessment, if requested 

• Develop a monitoring agreement (Avtale med forskningsstøtte) with the Coordinating Investigator (CI)/sponsor, if requested. If relevant, a Data Processing Agreement for Monitoring Services should be developed 

• Develop a cost estimate for the monitoring activities in the trial, if requested 

• Facilitate the trial team in developing a Protocol Deviation Handling Plan, if requested. Statistician and data manager, if available, should be consulted 

• Present the monitoring plan at start-up meetings, if requested 

• Establish and maintain communication between the sponsor and investigator and other parties involved in trial conduct, if requested
• Perform the monitoring visits according to the Monitoring Plan, document monitoring activities in the Monitoring visit report and send to sponsor for signature
• Any findings/unresolved issues should be listed in the attachment (Pending issues) to the monitoring visit report and sent to the PI and study nurse for follow-up after the monitoring visit. The PI/SN should resolve pending issues within agreed timelines, and then sign and return the document PI/SN to the monitor who will forward the document to sponsor

Lead monitor's tasks

In multi center and multi national 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.  

In addition to the tasks for monitors listed above, a lead monitor should

• Share the risk assessment, monitoring plan, monitoring agreement and cost estimate, as applicable, with the monitors, including accounting information required for invoicing.
• Share this SOP with international monitors, if applicable.
• Clarify with the sponsor responsibilities for sharing relevant trial information with the monitors before and during the trial. This may include:
  • Protocol
  • Informed consent form(s)
  • Relevant approvals
• Assist the CI/sponsor in collecting signed Data Processing Agreement from monitors employed at other institutions than the sponsor institution
• Provide training to the monitors in the monitoring plan
• Answer questions from the monitors and others related to the monitoring in the trial
• Schedule digital meetings or other meetings with the monitors as needed for sharing of information and monitoring status follow-up

Monitoring plan

The CI, 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, and methods (such as on-site monitoring, remote monitoring, and centralised monitoring), along with the rationale for their use. 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 management plan
• Describe the monitor’s responsibility for informing the CI about the need to update the monitoring plan based on findings found

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 trials 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 endpoint evaluator), it is important to have procedures in place to prevent unblinded information from being inadvertently disclosed to the blinded site staff.

To maintain blinding integrity, these trials may require two monitors:

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

Monitor handover

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.  

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.  If the start-up meeting is held on-site, then the trial initiation visit can be performed on the same day.

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 the 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 will sign and send the reports in pdf-format to both the CI and the investigator. The CI should review and sign the reports to ensure that all 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 trial initiation visit report and the signed list of pending issues should be filed in the Investigational 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 the monitoring plan.

Monitoring

Monitoring visits should be performed as defined 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.

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 the 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 specific procedures and/or the SOP Protocol Deviation Handling. Findings requiring escalation for action and resolution should be described in the report, when needed.

Close-out

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.

After the close-out visit the monitor should complete the Close-out Monitoring Report and send copies of the report and Attachment 1 in the same manner as the Monitoring Reports described above. At the CI/sponsor’s site, the monitor should list any follow-up tasks assigned to the CI/sponsor as pending issues. Tasks that require confirmation of completion should be signed off and sent back to the monitor according to the designated timelines. Other tasks with a longer time horizon, such as the reporting of trial results and trial archiving, should remain as a checklist for the CI/sponsor and do not require confirmation of resolution by the monitor.

Remote monitoring

Remote monitoring is defined as off-site monitoring of a site by phone or through digital meetings, and/or remote evaluation of source records, data acquisition tools and other essential records. If a digital meeting is used and the monitoring plan requires verification of sensitive information- such as signed informed consent forms or source data with personal information- a secure solution approved by the site institution must be used. 

Preparations for efficient remote monitoring visits

• Prepare the site staff by emailing the investigator and study nurse in advance with information about the purpose of the visit and items to be discussed. The email should also list documents to be checked, so the site staff can ensure they are easily available during the remote monitoring.
  • Documents to be checked may include patient records, informed consent forms, as well as documents from the ISF.
• The investigator is recommended to participate, at least at a part of the visit, to ensure investigator’s oversight of the trial. 
• The monitor should also be well prepared, including selecting the patients to be source data verified, based on the monitoring plan, before the remote monitoring visit.     

Guidance for completing NorCRIN report templates

• Any cross in grey boxes in the report template should be commented on. In the comment field, please refer to the relevant section number when adding the comment. 
• Use the “not applicable” box if the topic is irrelevant for the trial (e.g. blinding in an open trial) or if the monitoring plan does not require the topic to be checked (e.g. biobank is used, but the monitor is not required to check the facilities). 
• Use the “not checked” box if the topic is relevant for the trial and/or covered in the monitoring plan, but the check was not performed during the visit. The reason must be explained in the comment field (e.g. due to time constraints the Investigator Site File (ISF) was not checked during this visit). 

• For pending issues, the monitor should set a due date which reflects the seriousness of the issue when defining necessary actions to be taken by site staff.
  • Serious deviations requiring urgent action should be resolved within a week or two.
  • Non-urgent deviations should typically be resolved within one or two months.
  • For some deviations, a solution cannot be expected until the participant returns for the next visit. In these cases, the expected date for the next visit should be used as due date.    
• All actions and corrections required should be performed and documented accordingly by the site personnel.

For remote monitoring, report templates should be used as is. Questions not being checked during the remote monitoring should be marked with a cross in “not checked”, and “remote monitoring” should be provided as reason.

Trial Initiation Report guidelines 

Section 1. Authorities’ approval

• Enter the date and version number of the current protocol and informed consent form.
• Modify the table if more than one version of the documents is in use at the same time.

Section 4. Trial staff

• CV: All trial staff members listed on the delegation log, should file a dated and signed current copy of their CV in the ISF.
• ICH-GCP: The principal investigator must document ICH-GCP knowledge, either on their CV, training log or by a training certificate. This is also recommended for other trial staff members performing trial specific tasks such as obtaining informed consents, collecting data or evaluating the trial participants.  ICH-GCP training is especially relevant for persons assisting in the trial and having delegated trial activities that go beyond their usual training and experience.
• Protocol training: All trial staff performing trial specific tasks that go beyond their usual training and experience should document that they have received protocol and procedure specific training either by a training certificate or on a trial specific training log.

Section 6. CRF and source data

• Assessments for fitness for purpose of computerised systems relates to the systems owned or deployed by the site, not the ones controlled by the sponsor (e.g. eCRF)  

Section 8. Investigational medicinal product(s)

• Specify whether an Investigator’s Brochure (IB) or a Summary of Product Characteristics (SmPC) is used as reference safety information in this trial and specify version and/or date of the current document. IBs are usually used for IMPs without marketing authorisation, while SmPCs are used for IMPs with marketing authorisation.
  • IBs should be revised annually. If there is no new information available, the marketing authorisation holder should provide a document confirming this.
  • The latest version of the SmPC for products authorized in Norway can be found at Legemiddelsøk - Legemiddelverket. If the trial includes unauthorised auxiliary medicinal products (AxMPs), the same requirements as for IMP(s) apply. 

Section 9. Facilities, lab, equipment

• Pay attention to trial specific equipment and/or equipment important to the trial’s endpoints. Ensure that appropriate routines for service, validation and/or calibration are in place.
• All lab reference values – both original and updated values - should be available as part of the trial documentation at the site.
• Documentation confirming that the lab is accredited or ISO-certified must be in place. Verify that the accreditation or ISO-certification remains valid.

Monitoring report guidelines

Section 2. Authorities’ approval

• Enter the date and version number of the current protocol and informed consent form.
• Modify the table if more than one version of the documents is in use at the same time.

Section 5. Participant information

• List the version(s) used for each trial participant, and for which participants the informed consent process was checked.
• In the participants’ medical notes, it should be stated that they have received oral and written information, had the opportunity to ask questions, had time to consider participation, and were given a copy of the dated and signed informed consent form.
• Checking informed consent form may include the following:    

• Timing: Is the informed consent form signed before any trial specific procedures have been done?
• Version Control: Is the correct version of the informed consent form used? Is version number and date present in the header or footer? Is the version approved by the authorities?
• Completeness: Are all applicable fields completed? Is the contact information (name, address and phone number) correct?
• Signatures and Dates: Have the participant (or participant’s representative) signed and dated themselves? Is the date complete (day, month and year)? If the signature is not legible, it is recommended that the name is written in typed letters as well. Did the staff member sign after the participant (or participant’s representative)? If the signature is not legible, it is recommended that the name is written in typed letters as well
• Investigator/Staff Compliance: Is the person informing the participant delegated this task on the delegation log? Is the date complete with day, month and year?

Section 6. CRF and source data

• Document for which participants inclusion and exclusion criteria have been checked.
• Document for which participants and visits source data verification (SDV) has been performed.
• If queries cannot be entered directly into an eCRF, they should be listed in the report or in Attachment 3. The list should be attached to Attachment 1 when sent to the site, and the monitor should keep a copy, to be able to verify that all queries are resolved.  

Section 7. Adverse events

• Record for which participants and visits AEs and SAEs have been checked. In case of deviations, please comment.

Section 8. Investigational medicinal Product(s)

• For trials involving shelf products, drug accountability logs should be maintained for each participant.
• For trials using a trial specific produced IMP, additional site-level drug accountability logs are required.
• Drug accountability log-templates can be found at metodebok.no
• If other templates or records are used, they should contain all required information, such as dose dispensed (to whom, when and by whom), batch number, and expiry date.  

• For trials with both a blinded and unblinded monitor
  • The blinded monitor should complete a monitoring report, excluding Section 8 (IMP).
  • The unblinded monitor completes a separate report, covering Section 8 only.
  • The blinded monitor forwards the report to the sponsor, along with Attachment 1 to the investigator.
  • The unblinded monitor forwards the Section 8 report/Attachment 1 to unblinded trial staff only and ensures they follow up on action items. The unblinded trial staff should store the report with limited access to blinded trial staff during the trial, and the unblinded monitor should keep unblinded reports electronically at a secure place with limited access to the blinded monitor.
  • When the database is locked, the unblinded reports may be filed in the site’s ISF. Issues considered protocol deviations should be reported according to protocol specific procedures keeping the blinding whenever possible. In some trials, the CI may be unblinded.

Section 9. Facilities, lab, equipment

• All lab reference values – both original and updated values- should be available as part of the trial documentation at the site.  If a check of the local biobank is part of the monitoring plan, refer to the report template for monitoring biobanks 

Section 11 At the CI’s site (not applicable to other sites)

• 11.2 Check that the annual report is sent to the authorities 1 year + up to 60 days after the approval first was given.

Section 12. Monitoring plan

• Monitoring should be risk-based. It is therefore important that the monitor informs the sponsor whenever the monitor uncovers deviations that warrant a change in the monitoring plan for the entire trial or for that specific site. This information should be highlighted in the email and the monitor should ensure that an evaluation is given by CI.   

Close-out monitoring report guidelines

Section 4. Investigational Medicinal Products (IMP)

For trials with blinded and unblinded monitors:

• The blinded monitor should complete a close-out visit report, excluding section 4.
• The unblinded monitor completes a separate report, covering section 4 only.
• The blinded monitor forwards the report to sponsor, while Attachment 1 is sent to investigator.
• The unblinded monitor forwards the report to unblinded trial staff only. The unblinded trial staff should store the report with limited access to blinded trial staff during the trial, and the unblinded monitor should keep unblinded reports electronically at a secure place with limited access to the blinded monitor.
• When the database is locked, the unblinded reports may be filed in the ISF.

Biobank monitoring report guidelines

If a check of the local biobank is part of the monitoring plan, refer to the Biobank Monitoring Report.

If samples are stored in freezers not part of a hospital’s regular sample repository, the monitor may need to confirm proper sample registration, temperature monitoring, and storage conditions.

Section 1. Storage units

• 1.1 Record contact information available for the investigator and other relevant site personnel to be contacted in case the samples must be relocated, for instance.
• 1.3 Use the comment field to describe whether a central surveillance system is used (electronically temperature surveillance) or if it is done manually. Manual surveillance is recommended daily.
• 1.4 Use the comment field to describe what happens if the temperature is outside recommended limits.
• 1.5 The department/clinic ought to have emergency equipment. The personnel should know where it is located. 
• 1.7 Check with the Technical Department responsible for setting up the storage facility.

Section 3. Handling and shipment of samples:

• 3.3 Ensure that samples are not marked with directly identifiable personal information. 
• 3.4 The samples should have labels adapted to the type of freezer and the storage duration. Labels must remain legible and should stick to the container throughout the storage period.  
• 3 6 If “No”, use the comment field to describe how the site keeps an overview of the biobank. In addition, describe whether there is a record of samples that have been taken out and refrozen.
• 3.8 The person responsible should ensure the samples are packed and shipped according to local regulations, see e.g. shipment of biological material published by “Direktoratet for samfunnssikkerhet og beredskap”.
• 3.9 Before shipping samples between sites, an agreement must be in place.
  • If both sites are participating in the trial, the shipment of samples could be described in a collaboration agreement.
  • If the samples are being shipped to a third party, a Material Transfer Agreement (MTA) is required. The person responsible for shipment must ensure that the trial participant has consented to the shipment, and the samples generally need to be de-identified before transfer.