What is trial monitoring?
Trial monitoring refers to the act of overseeing an ongoing clinical trial, ensuring it is conducted and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and other applicable regulatory requirements. It is an essential activity for those conducting a trial and should be planned in advance. However, the complexity of monitoring may vary greatly depending on the size and nature of the study.
Why Monitor a Clinical Trial?
- To ensure the rights of the study participants are protected.
- To ensure the safety of study participants
- To confirm the conduct of the trial is in compliance with the approved study protocol and / SOPs, GCP and other applicable regulatory requirements.
- To assess and confirm that the data reported are timely, accurate and complete.
The DSMP is a written document that guides the monitoring process. This document describes the methods, requirements, strategies, timing /frequency and assigns responsibility for monitoring trial-specific events on a pre-defined schedule. Any research proposals that present greater than minimal risk to subjects should include a DSMP. The initial DSMP is usually put together by the study sponsor. It may be subject to modifications from time to time by the Data Safety Monitoring Board (see below) when one is constituted.
The DSMB (sometime redferred to as a Data Monitoring Committee [DMC] or Data Safety Monitoring Committee [DSMC]) is made up of a group of independent clinical research experts appointed by the Sponsor to periodically assess the safety of study participants, quality of data and evaluate the progress of the study (eg. recruitment, accrual and retention of study participants, performance of trial sites, and other factors that can affect study outcomes). The DSMB provides a written report to the sponsor at intervals and recommends whether to continue, modify, or prematurely terminate a trial.
See Guideline for Good Clinical Practice for a detailed description of the role of monitoring and the roles and responsibilities of DSMB in a clinical trial.
It is the responsibility of the trial sponsor (sometimes with the help of trial steering committee) to come up with a monitoring plan (DSMP) and to appoint a safety monitoring officer or set up a DSMB for any research proposal that poses greater than minimal risk to subjects.
Though all trials need to be monitored, not all clinical trials need a DSMB, a safety monitoring officer may just suffice. For such trials the sponsor should justify in the DSMP why a DSMB is not needed, the need for a safety officer or provide a justification for why no independent safety oversight is required. See FDA guidance on the Establishment and Operation of Clinical Trial Data Monitoring Committees
Careful selection of DSMB members is very vital as poorly constituted DSMB may fail to provide the assurance of patient safety and trial integrity. Factors to consider while selecting members of a DSMB typically include
- Relevant expertise: Members selected on the DSMB should have the scientific and/or clinical knowledge needed for adequate monitoring of the trial.
The type of expertise needed for a particular DSMB is usually determined by the objectives and design of the trial. Most DSMBs are composed of clinicians with expertise in relevant clinical specialties and at least one biostatistician knowledgeable about statistical methods for and analysis of data from clinical trials. For high risk trials or trials with public health implications, an experienced medical ethicist may be required. Other scientists like a toxicologists, epidemiologists, or clinical pharmacologists could also be included in situations where such expertise are required for informed interpretation of trial results.
- Prior clinical trials and DSMBs experience:: It is highly desirable for at least some members to have prior DSMB service. Prior DSMB experience is important for the DSMB chair and the statistical DSMB member particularly if there is only one statistician serving on the DSMB
- Conflicts of Interest: Members on a DSMB must be external to the study trial. Members should not be affiliated with the sponsor, investigator(s), site(s),ethics committee(s)or other regulatory authority(ies). Individuals with vested conflicts of interest that could be affected by the outcome of the trial (especially financial interests or interest in other investigational products similar to the intervention under study) cannot be appointed into the DSMB.
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. Monitoring can be ‘on site monitoring’, centralized monitoring (CM) or a combination of the two. Today, regulators encourage the use of CM in conjunction with on-site monitoring to oversee clinical trials. The study sponsors should appoint one or more monitors (who may have other roles within the organisation conducting the research or with the DSMB). The role of monitors is to verify the activity of recruiting sites.
- On site monitoring Visit: On site monitoring is done before, during and at the close of the trial. The following are the various forms of on-site visits done.
- Site Initiation Visit: A monitoring visit that takes place before the site recruits its first participant. The central study team meet with the research team at the clinical site to review the specifics (e.g.: the science, design, procedures, case report form (CRF) completion, investigator site file etc.) of the protocol prior to site activation. The goal of this visit is to orient and train site staff on the protocol and study related processes; to confirm readiness for study implementation; and to identify additional requirements that must be satisfied prior to site activation and subject recruitment.
- Interim Monitoring Visit: These are the routine visits during the duration of the trial. At each visit, the monitor(s) ensures participant source documents and CRFs are accurate and signed off by the Investigator; Informed Consent process are according to protocol, signed and filed; investigational product(s) are dispensed to eligible trial participants according to the protocol; Serious Adverse Events, Adverse Events (AE), Unanticipated Problems in the course of the study are documented and reported correctly.
- Close Out Visit: This is an on-site visit done when a trial is completed or terminated and database is locked. The monitor(s) meet with the principal investigator and other research team to ensure verification of necessary documents and data; ensure biological samples are shipped or appropriately stored; arrange return / destruction of equipment and investigational products used in the study; ensure site delegation log is completed and signed off by the Principal Investigator and provide the Principal Investigator with the final monitor report which will be in the Investigator Site file.
- Centralized Monitoring (CM): It is a remote evaluation carried out in a timely manner by qualified and trained persons (e.g., data managers, clinical monitors, biostatisticians) at a location other than the sites at which the clinical investigation is being conducted. Analysis of data from CM can be used to examine data trends; evaluate for systematic or significant errors in data collection and reporting within and across sites; provide information about sites’ characteristics and performance metrics; and hand pick sites for targeted on site monitoring.