Associate
How to monitor a study in the field requires considerable thought. 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.
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.
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. Catching and
solving problems early will save a lot of extra work as the study progresses.
The rate of enrolment 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. A less experienced
site may require more or longer monitoring visits, especially at the beginning of
the study. Once the site has demonstrated the ability to do the study well, the
CRA may be able to space the monitoring visits further apart.
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. The more
experience the CRA has, the easier making this determination will be.
Another factor that has an impact on CRA visits frequency 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 your
travel itinerary is a must. It helps to use the “loop method” for travel, where the
sites closest together are linked in your itinerary for a single trip.
As a general rule, a good CRA should be able to effectively monitor five to ten
sites. The number will change depending on the complexity of the study, site and
CRA experience and locations. If the CRA is in a situation where it is not
plausible to visit sites with the degree of frequency necessary for safe monitoring,
it should be discussed with their superior.
Monitoring activity
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 you
should monitor 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:
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.
_ Notify the site well in advance when they plan to visit them, how long they
expect to take, what resources they will need, and what they intend to
accomplish during the visit.
_ Communicate privately with the Visit Coordinator about any issues.
_ Use discretion so as to not create issues or extra work for the Principal
Investigator.
_ Do not interview site personnel without previously notifying the Visit
Coordinator and their Contact Person at that site.
_ The Sponsor or CRO provides a written request for the Site Monitor to
make changes to CRFs
_ The CRO or sponsor provides an SOP detailing who, how and when it may
be done
_ The Director of Regulatory Affairs approves it for a specific study
_ The Site Monitor signs the Signature Log and initials and dates all changes.
_ Changes are made on unseparated NCR copies
_ Changes are self-evident, e.g., to correctly enter data that was entered
below rather than above a line.
_ Changes do not require review of medical records at the site
_ Changes do not require the concurrence or signature of study personnel
_ Changes are not important enough to justify investment of time by study
personnel
Sponsor personnel (who are not involved in site monitoring or other quality
control activities for the site) may assist study personnel in completing CRFs
to meet a deadline.
Phase IV studies, often called Post Marketing Surveillance Trials, are conducted
after a drug or device has been approved for consumer sale. Pharmaceutical
companies have several objectives at this stage: (1) to compare a drug with other
drugs already in the market; (2) to monitor a drug's long-term effectiveness and
impact on a patient's quality of life; and (3) to determine the cost-effectiveness of a
drug therapy relative to other traditional and new therapies. Phase IV studies can
result in a drug or device being taken off the market or restrictions of use could be
placed on the product depending on the findings in the study.