Monitoring in clinical trials
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Clinical monitoring is the oversight and administrative efforts that monitor a participant's health during a clinical trial. The government and clinical trial funding agencies require data and safety monitoring boards to oversee clinical trials.
Functions of the clinical monitor
Monitors may be referred to by many different titles. Some of the most common are Clinical Research Associate, Clinical Research Monitor, Study Site Monitor and Quality Specialist.
Almost all field monitoring requires regular visits to the site by the clinical research associate throughout the period of the study. On very rare occasions, an extremely simple, low risk study might be monitored almost exclusively by telephone except for the startup and closeout visits. Since the concept of "low risk" is subjective, this definition should be established in internal policies and procedures.
A clinical research associate (CRA) must determine how to integrate telephone, email, fax and regular mail communications into a monitoring strategy. This will differ among programs and sites depending on available technology, sponsor and site standard operating procedures (SOPs) and personal preference. In monitoring, like any business, many problems can be traced back to a lack of communication, inappropriate communication and/or unclear communication. A good communication strategy should have a high priority in a monitoring plan.
The intensity of monitoring
The intensity of monitoring will vary across studies and among sites. Must or should the CRA be present while the site is seeing study subjects? Will the CRA have any interaction with study subjects? In early phase I studies, the CRA may be required to be present during all or part of a subject's treatment. Therefore, the CRA must determine how long they must be there and make appropriate arrangements.
Sometimes a CRA is the sole monitor for a site, while other times the CRA will co-monitor with other CRAs. Establishing who will monitor requires consideration of the sponsor's SOPs, the complexity of the protocol and the condition being studied, the experience of the investigator and staff, and the training and experience of the CRA.
The Clinical Research Associate's overall monitoring plan should remain fairly consistent, but the strategy for individual sites may change considerably during the course of the study depending on study conditions and site performance.
Frequency of monitoring visits
Another key determination in a monitoring plan is the frequency with which the CRA will visit each site. There are a number of factors that must be considered in making this decision:
- Complexity of the protocol
- Disease being evaluated
- Experience of the investigator/staff
- Number of study subjects enrolled at the site
- Rate of enrollment
- Site performance
- Sponsor monitoring SOPs
- CRA experience and effectiveness
The protocol dictates the conduct of the study by establishing the procedures that subjects must undergo and a schedule of assessments. The more activities that are required during a study visit, the more monitoring will be required. The disease being studied is also a factor. For instance, if the CRA is monitoring an infectious disease study, the course of the therapy will probably be complete for each subject in about ten days. This requires a different frequency of visits than a cholesterol-lowering study with a treatment period of one or two years.
All sites should be visited soon after the first subjects are enrolled just to be sure the site understands and is correctly following protocol procedures.
The rate of enrollment will also affect monitoring frequency. Generally speaking, the more subjects a site has, the more frequently the CRA will have to visit. The faster a site enrolls and the more data generated, the more frequently the site will need monitoring.
The CRA should visit a site regularly even though enrollment may be slow or non-existent. Slow subject enrollment may include a lack of enthusiasm on the part of the site personnel regarding the study. In that case, a bit of encouragement may help, which will probably involve visits. Site personnel often view frequent visits by the CRA as an indication of the importance of their study to the sponsor. Not only that, but seeing the CRA walk through the door reminds the site of their commitment to enroll subjects and complete the study on time. Call it encouragement or guilt, it generally works. Sometimes a few extra visits are all that is necessary to get a study back on track or to re-establish priorities at the site.
The frequency and duration of monitoring visits will also vary from site to site depending on the experience of the investigator and staff. In some instances, sponsor SOPs dictate the frequency of monitoring visits. If so, the SOP normally establishes a minimum schedule, e.g., "all sites must be visited every six weeks or less". In this case, the CRA must adjust the visit schedule to ensure compliance with the SOP.
The frequency of monitoring visits may change as the study progresses. Some sites will do a better job complying with GCPs than others and may need less frequent monitoring. Subject enrollment may complete or level off after a period of time, allowing for more time between monitoring visits. Subject visits may spread out over the course of long-term studies and require less review. Initially, weekly visits may be required, followed by monthly, and perhaps even quarterly as the study progresses. In short, a CRA must visit each site often enough to stay on top of the activities that are required for good monitoring.
Another factor that affects the frequency of CRA visits is the number and location of sites for which they have monitoring responsibility. There is always the chance that the CRA simply cannot physically visit the sites as often as they would like to or need to because of travel time and the actual number and location of sites. Here again, the CRA will have to spend some time integrating travel requirements with the experience and study complexity.
The CRA should schedule a minimum of four hours for a site visit. With the complexity of protocols, regulatory requirements and good monitoring practice, they will need to spend a day or more at most sites. Creative scheduling of a travel itinerary is a must. It helps to use the "loop method" for travel, where the sites closest together are linked in the itinerary for a single trip.
The CRA should have a general plan for what will be monitored at each site visit. Most sponsors have a site visit or monitoring report that the CRA completes during and after the visit. This report is a standard document that a CRA will use for all field monitoring visits. It serves as both a checklist for the CRA and as documentation of the visit. However, the CRA must not view this as the only list of activities that must be done.
To be successful as a CRA, it is important to develop a sense for what should be monitored at each site and how much attention should be given to each activity. It helps to be aware of where problems are most likely to arise during the conduct of a study. A good indication of potential problems is the list of activities that received the most deficiencies during U.S. Food and Drug Administration audits. This list is published annually by the Center of Drug Evaluation and Research (CDER) and has remained essentially unchanged for over a decade. The top five deficiency categories for site inspections as reported in the 2001 Report to the Nation are as follows:
- Failure to follow the protocol
- Failure to keep adequate and accurate records
- Problems with the informed consent form
- Failure to report adverse events
- Failure to account for the disposition of study drugs
These areas, in addition to the things the sponsor wants emphasized, should receive specific attention during monitoring visits. Sponsor expectations for studies are important. Independent CRAs and those employed by contract research organizations need to spend enough time with sponsors' representatives to clearly understand those expectations.
- Data monitoring committee
- Drug development
- European Medicines Agency
- Safety monitoring
- U.S. Food and Drug Administration (FDA)