Monitoring, audit and their reports
A sponsor checks its own trial while it runs through quality assurance and quality control: monitoring oversees the trial's progress against a risk-based plan and reports what it finds, and an audit independent of the monitoring examines whether the processes behind the trial are fit to ensure compliance.
Quality assurance and quality control
The sponsor is responsible for establishing, implementing and maintaining appropriate quality assurance and quality control processes and documented procedures, so that trials are conducted and data are generated, recorded and reported in compliance with the protocol, GCP and the applicable regulatory requirements. Quality assurance is all the planned and systematic actions established to ensure that the trial is performed and the data are generated, recorded and reported in compliance with GCP and the applicable regulatory requirements. Quality control is the operational techniques and activities undertaken to verify that the requirements for quality of the trial-related activities have been fulfilled.
Quality assurance should be applied throughout the trial, and it includes risk-based strategies for identifying potential or actual causes of serious noncompliance with the protocol, GCP or applicable regulatory requirements, so that corrective and preventive actions can be taken. Quality control should be applied using a risk-based approach at each stage of data handling, so that data are reliable and have been processed correctly. Within a trial, the main quality control activities are monitoring and data management, and where appropriate quality control may also be applied to facilities outside investigator sites, such as central image reading facilities.
Monitoring
Monitoring is the act of overseeing the progress of a trial and ensuring that it is conducted, recorded and reported in accordance with the protocol, standard operating procedures, GCP and applicable regulatory requirements. Its aim is to ensure participants' rights, safety and well-being and the reliability of the results as the trial progresses, and it is one of the principal quality control activities.
Monitoring may include site monitoring, performed on-site, remotely or both, and centralised monitoring, depending on the monitoring strategy and the design of the trial. The sponsor should determine the appropriate extent and nature of monitoring from the identified risks, considering factors such as the objective, purpose, design, complexity, blinding, number of participants, investigational product, current knowledge of the safety profile and endpoints of the trial.
Site monitoring may cover the trial activities at the sites, including their pharmacies and local laboratories as appropriate. Its frequency should also be determined from identified risks, and both the activities and their frequency should be modified as appropriate using the knowledge gained. It may be performed on-site, remotely or both, depending on the nature and objectives of the activity, and it may include remote and secure, read-only direct access to source records, other data acquisition tools and essential record retention systems.
Centralised monitoring is an evaluation of accumulated data, performed in a timely manner, by the sponsor's qualified and trained people, such as a medical monitor, a data scientist or data manager, or a biostatistician. It provides additional capabilities that can complement site monitoring and reduce its extent or frequency, or it can be used on its own. Centralised data analytics can help identify systemic or site-specific issues, including protocol noncompliance and potentially unreliable data, and centralised monitoring may support the selection of sites or processes for targeted site monitoring.
Monitoring involves a broad range of activities, including but not limited to communication with investigator sites, verification of the qualifications of the investigator and site staff and of the site's resources, training, and review of trial documents and information, using a range of approaches including source data review, source data verification, data analytics and visits to institutional facilities undertaking trial-related activities. Some activities, such as centralised monitoring, may be conducted by different methods and by people in different roles, such as a data scientist, but monitoring should be performed by persons not involved in the clinical conduct of the trial at the site being monitored. The monitoring approach should take account of the activities and services involved, including decentralised settings, and should be included in the monitoring plan. Monitors and other trial staff should adhere to data protection and confidentiality requirements in accordance with applicable regulatory requirements, institution policy and established data security standards.
The monitoring plan
A monitoring plan is a document describing the strategy, methods, responsibilities and requirements for monitoring the trial. The sponsor should develop one tailored to the identified potential safety risks, the risks to data quality, other risks to the reliability of the results, or any combination of these. Particular attention should be given to procedures relevant to participant safety and to the trial endpoints.
The plan should describe the monitoring strategy, the monitoring activities of all the parties involved, the various monitoring methods and tools to be used, and the rationale for using them. The strategy should ensure appropriate oversight of trial conduct while considering site capabilities and the potential burden. The plan should focus on the aspects that are critical to quality and should reference the sponsor's applicable policies and procedures. It should also address the monitoring of important data and processes performed outside the investigator site, such as those related to primary and key secondary endpoints and processes intended to ensure participant safety, performed for example at central image reading facilities and central laboratories. The people performing monitoring should follow the sponsor's monitoring plan and applicable monitoring procedures.
One speaker on quality in clinical development held in 2021 that good clinical practice requires a section of the monitoring plan on the monitoring strategy, saying what type of monitoring is being done and why, and that not many companies were writing it. In his account, the regulators expect the section to be transparent about the consequence of the choice: a sponsor doing only central monitoring says so, what impact that will have and what it expects to miss, and one doing all on-site monitoring says what impact that will have. During COVID-19, when sponsors could not get on site and were doing only centralised monitoring, the regulators asked again for the logic behind the choice, and many companies did not give it, stating only that they were monitoring centrally. The regulators expect the justification, and they expect sponsors to be honest and transparent about what they do. He found them not yet too harsh about it in 2021, and expected them to get tough in time and not let sponsors go without it for much longer.
Monitoring activities
Monitoring conducted to the sponsor's requirements and the monitoring plan should generally include a defined set of activities across the trial life cycle, as applicable.
The first is communication with the parties conducting the trial. It means establishing and maintaining a line of communication between the sponsor and the investigator and the other parties and individuals involved, such as those in centrally performed activities, and in general each site should have an assigned monitor as its contact point. It also means informing the investigator and others of relevant deviations from the protocol, GCP and applicable regulatory requirements and, if necessary, taking action to prevent recurrence, and important deviations should be highlighted and be the focus of remediation as appropriate. Likewise, it means informing them of entry errors or omissions in source records or data acquisition tools and ensuring that corrections, additions or deletions are made as appropriate, dated, explained where necessary, and with the approval of the change properly documented. Actions taken over deviations, errors or omissions should be proportionate to their importance.
The second covers site selection, initiation, management and close-out, and includes:
- Select the site and confirm that the investigator and the individuals or parties involved have adequate qualifications, resources and facilities, including laboratories, equipment and site staff, to conduct the trial safely and properly.
- Confirm, with their delegated activities and experience in mind, that the investigator, site staff and others involved are adequately informed about the trial and follow the current approved protocol and other protocol-related documents, such as the current investigator's brochure and relevant information on the investigational product.
- Confirm that the investigator is maintaining the essential records.
- Confirm that informed consent was obtained before participation for the participants at the site.
- Determine whether adverse events are appropriately reported within the periods required by the protocol, GCP and applicable regulatory requirements.
- Confirm the protocol requirements for source records and where the site keeps them.
- Verify that blinding is maintained, where applicable.
- Review and report participant recruitment and retention rates.
- Confirm that the investigator provides the required reports, notifications or other information in accordance with the protocol and trial procedures.
- During site close-out, confirm the arrangement for retaining the essential records and the final accountability of the investigational product, such as return and destruction or alternative disposition where appropriate.
The third is monitoring of investigational product management, which confirms that storage conditions are acceptable and in accordance with what the protocol or other relevant documents specify; that supplies are sufficient throughout the trial and used within their shelf life; that the correct products are supplied only to eligible participants at the protocol-specified doses and, where appropriate, in accordance with the randomisation procedures; that participants, the investigator, site staff and other relevant parties are given the necessary instruction on storing, using, handling, returning and destroying or otherwise disposing of the product; that receipt, storage, use, handling, return and destruction or alternative disposition are controlled and documented adequately; and that the disposition of unused product complies with applicable regulatory requirements and the sponsor's requirements. Where a product available on the market is dispensed and used in accordance with applicable regulatory requirements, some of these considerations may not apply.
The fourth is monitoring of the trial data, which verifies that the investigator is enrolling only eligible participants. It checks the accuracy, completeness and consistency of the reported data against the source records and other trial-related records, and whether they were reported in a timely manner. That check can be done on samples and supported by data analytics as appropriate, and the sample size and the types of data or records may need adjusting in the light of previous monitoring results or other indications of insufficient data quality. Within it, monitoring should verify that the data required by the protocol and identified in the monitoring plan as of higher criticality are consistent with the source; identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations; and examine data trends such as the range, consistency and variability of data within and across sites. Monitoring of the data also identifies significant errors in data collection and reporting at a site or across sites, potential data manipulation and data integrity problems.
Monitoring reports
A monitoring report is a documented report following site or centralised monitoring activities. It should include a summary of what was reviewed, a description of the significant findings, the conclusions and the actions required to resolve them, and follow-up on their resolution, including findings not resolved in previous reports. The requirements for monitoring reports, including their content and frequency, should be described in the sponsor's procedures.
Reports of site and centralised monitoring should be provided to the appropriate sponsor staff, as the sponsor's procedures describe, in a timely manner for review and follow-up. When needed, the report should describe findings requiring escalation for action and resolution. The sponsor should then decide on the appropriate action, and those decisions and, where needed, the resolution of the actions involved should be recorded.
Audit
An audit is a systematic and independent examination of trial-related activities and records, performed by the sponsor, a service provider including a contract research organisation, or the institution, to determine whether the evaluated activities were conducted and the data recorded, analysed and accurately reported according to the protocol, applicable standard operating procedures, GCP and applicable regulatory requirements.
A sponsor's audit is independent of and separate from routine monitoring or quality control functions, and its purpose is to evaluate whether the processes put in place to manage and conduct the trial are appropriate to ensure compliance with the protocol, GCP and applicable regulatory requirements. When performed, audits should be proportionate to the risks associated with the conduct of the trial.
The sponsor should appoint auditors who are independent of the trial or processes being audited, and should ensure they are qualified by training and experience to conduct audits properly.
The sponsor should ensure that auditing follows its documented procedures on what to audit, how to audit, on-site, remotely or both, the frequency of audits, and the form and content of audit reports. The audit plan, programme and procedures for a trial should be guided, for example, by the importance of the trial to regulatory submissions, the number of participants, the type and complexity of the trial, the level of risk to participants, and any identified problems. The auditors' observations and findings should be documented. An audit report is a record describing the conduct and outcome of the audit.
To preserve the independence and value of the audit function, regulatory authorities should not routinely request audit reports. They may seek access to one on a case-by-case basis, when evidence or suspicion of serious GCP noncompliance exists or in the course of legal proceedings. When applicable regulatory requirements call for one, the sponsor should provide an audit certificate, a declaration of confirmation by the auditor that an audit has taken place.