CT SOP version no 1.1.

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

The sponsor has overall responsibility for ensuring that clinical trials are monitored.

Tasks can be delegated. The delegation of tasks shall be documented, for example in written agreements.

All staff who are involved in monitoring of clinical trials must possess the necessary qualifications for the task.

If monitoring is performed by a third-party vendor, in whole or part, this shall be specified in the written agreement between the sponsor and the third party. The agreement will specify activities to ensure that the sponsor’s requirements for quality are fulfilled.

Sponsor

The sponsor’s responsibilities shall be described in the governing documents (quality system) of the individual institution.

Coordinating Investigator

The coordinating investigator has the responsibility for ensuring that monitoring is carried out according to the requirements of this SOP.

The coordinating investigator will assign monitoring tasks to qualified monitors.

Principal Investigators

Principal investigators should be available for discussions with monitor and facilitate monitoring visits by providing office space, access to study documents, source data and other relevant documents and equipment required for the trial.

Principal investigators are responsible for making corrections and following up on deviations and actions identified in the monitoring report, or in other documents including, but not limited to, notes to file.

Selection and qualifications of monitors

The sponsor shall appoint monitors with suitable scientific and/or clinical knowledge to monitor the study satisfactorily.

Monitor qualifications (CV) must be documented in Trial Master File (TMF).

The monitor should be independent, i.e. the monitor must not be a direct report, a close colleague or in any other way have a close relationship to the site staff.

If the monitor is not employed at the sponsor institution, the coordinating investigator should ensure a Data Processing Agreement for Monitoring Services - Template is signed.

Extent and nature of monitoring

Site monitoring should be done before, during and after the trial. For some trials, centralised monitoring with reduced numbers of on-site visits may be appropriate.

The extent and nature of the monitoring shall be determined by the coordinating investigator on the basis of a risk assessment (see Quality and Risk Management - SOP 1.10.a with attachments) that takes into consideration all characteristics of the clinical trial, including but not limited to the following:

• Whether the clinical trial is a low-intervention clinical trial.
• The objective and methodology of the clinical trial.
• The degree of deviation of the intervention from normal clinical practice.

Monitoring plan

The coordinating investigator should in collaboration with the monitor prepare the monitoring plan, which will include procedures to mitigate any risks (see Quality and Risk Management - SOP 1.10.a with attachments), before the first monitoring visit takes place.

The monitoring plan should define when the first monitoring visit is to take place and the frequency of the subsequent visits. Usually, the first monitoring visit will take place shortly after inclusion of the first trial subjects.

The monitoring plan should clearly define what to monitor during monitoring visits.

If centralised monitoring will be performed, the process will be described in the monitoring plan and the data management plan.

The coordinating investigator can amend the monitoring plan based on, for example:

• Feedback from the monitor or data manager.
• SAE reporting leading to change in the risk-benefit ratio.
• Publications from relevant studies.
• Report from Data Monitoring Committee (DMC).
• Findings from pre-clinical studies.

Monitors should be familiar with the investigational product, trial protocol, patient information and consent form, ICH GCP and applicable laws and regulations.

Monitors shall follow the procedures described in the monitoring plan.

The principal investigator should give the monitor access to source data in the medical records in accordance with the hospital’s procedures. The monitor should be given their own log-in credentials to the medical records (read only access) if possible. 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.

After each on-site monitoring visit, the monitor should complete a visit report. The report should be completed and forwarded to the coordinating investigator as a PDF-document within 14 calendar days. Attachment 1 with the action list for the site should be attached. At the same time, the action list should be sent to the site, as a PDF-
document. The complete report can be sent to the site, as well, but this is not mandatory, except for the initiation visit report, which should be filed in the Investigator Site File (ISF).

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

The actions to be followed up will be listed in an attachment to the report and forwarded to the principal investigator and other relevant site staff by the monitor within 14 calendar days after a monitoring visit. The principal investigator or designated site staff should complete the tasks within the timeframe given and return a signed copy of the attachment to the monitor.

Issue management include deviation management will be handled as described in the SOP issue management.

Initiation visit

An initiation visit must take place at each trial site before the start of the trial (that is before investigational product is sent to the site, or before the first patient is recruited).

Monitors will contact the principal investigators at each trial site to arrange the time and place for initiation visits. Monitors will visit other facilities involved in the trial (e.g. pharmacies, laboratories etc.) as specified in the monitoring plan.

The Trial Initiation Report - Template will be written and signed by the monitor and coordinating investigator. The original signed report will be filed in the TMF.

The monitor will decide whether the site is ready to start enrollment or not, based on the issues found. Examples of major issues are pending approvals or agreements, missing/incomplete delegation log, insurance certificate, study drug or training of study personnel. The principal investigator must confirm that all major issues are
resolved before enrolment can start.

If applicable, the monitor will complete and sign the Green Light for Trial Site - Template according to study specific procedures.

Monitoring visits

The first monitoring visits are usually carried out at each trial site as early as possible after inclusion of the first subjects. The frequency of the monitoring visits should be risk based and specified in the monitoring plan.

Monitors shall inform the principal investigators of any CRF entry error, omission, or illegibility. The monitor should check that corrections, additions, or deletions are made, explained (if necessary), and initialled and dated by the principal investigator or by a member of the site staff authorised to make CRF changes. Monitor cannot
make any corrections or changes to the CRF data.

In case deviations from source data are not entered directly into an eCRF as queries, the deviations should be listed in the report or on a Query List - Template.

The Monitoring Report will be written and signed by the monitor and coordinating investigator. The original signed report will be filed in the TMF.

Close-out visit

Trial close-out visits should be done at each trial site at the end of the trial.

The Close-out Monitoring Report - Template will be written and signed by the monitor and coordinating investigator. The original signed report will be filed in the TMF.

Sites which never received investigational product and never included subjects can be closed without an on-site visit.

In clinical trials samples of biological material may be stored in freezers which are not a part of an organized biobank facility. 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 - Template.

In blinded clinical trials where un-blinded site personnel, e.g. a pharmacist or a study nurse preparing the treatment, work together with personnel that should be kept blinded, e.g. the treating physician or evaluator, it is important to have procedures in place to ensure that no un-blinded information is disclosed to the blinded site
staff. In these studies, it is required to have two monitors, one blinded monitor for study data monitoring and one un-blinded monitor reviewing the IMP-logs and other un-blinded information.

If there is a change in monitor for a study at a site, the outgoing monitor should inform the new monitor about the monitoring status of the site using a Trial Handover Procedure and Checklist - Template. A copy of the handover checklist should be filed as part of the new monitor’s training documentation, together with the monitor’s CV in the TMF, to document monitor’s qualifications.

Trials may be monitored using centralised monitoring based on a risk assessment. Centralised monitoring can be used in addition to on-site visits. For low-intervention trials centralised monitoring may replace on-site monitoring visits.

Centralised monitoring will be performed by remote evaluation of accumulating data as defined in the monitoring plan. In addition, details of data evaluation carried out by data managers or statisticians may be included in the data management plan.

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 characteristics and performance metrics.

If there are sites which are not producing data consistent with most other sites or are not performing in the same way as the majority of sites, these sites and/or processes will be selected for on-site monitoring, until they are functioning as expected.

Centralised monitoring activities and observations will also be reported using the monitoring report template. If a different report template will be used this will be described in either the monitoring plan or the data management plan.

The following should be filed in the TMF:

• The monitoring plan.
• All signed monitoring reports.
• Notes to file, if applicable.
• Copies of significant communication with site staff (e.g. answers to questions about protocol procedures, 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