Monitoring of clinical trials
Current section refers to the item 5.18 Monitoring of the INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2). It contains the E6(R2) Addenda, and provides an overview of the scope of, requirements to clinical trial monitoring process, as well as responsibilities of all participants.
The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
5.18.3 Extent and Nature of Monitoring The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
On-site monitoring is performed at the sites at which the clinical trial is being conducted. Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians).
Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.
Review, that may include statistical analyses, of accumulating data from centralized monitoring can be used to:
- 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.
- analyze site characteristics and performance metrics.
- select sites and/or processes for targeted on-site monitoring.
5.18.4 Monitor's Responsibilities.
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:
- Acting as the main line of communication between the sponsor and the investigator.
- Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) 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, for the investigational product(s):
- That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
- That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
- That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
- That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
- That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
- Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
- Verifying that written informed consent was obtained before each subject's participation in the trial.
- Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
- Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.
- 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 unauthorized individuals.
- Verifying that the investigator is enroling only eligible subjects.
- Reporting the subject recruitment rate.
- Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
- Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
- Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:
- The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
- Any dose and/or therapy modifications are well documented for each of the trial subjects.
- Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
- Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
- All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.
- Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
- Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
- Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).
- Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.
5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
5.18.6 Monitoring Report
- The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.
- Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
- Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.
- The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.
- Reports of on-site and/or centralized monitoring should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow up. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Reporting of centralized monitoring activities should be regular and may be independent from site visits.
5.18.7 Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures.
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