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Functions of the clinical monitor - Clinical Research

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.

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 your 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. 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:

 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.

SITE MONITOR RESPONSIBILITIES


By Norman M. Goldfarb

Before a visit, monitors:

_ Identify the site's Visit Coordinator.


_ Obtain the address, telephone number, map, directions and Contact Person
for all locations they will visit.
_ Tell the site, in as much detail as possible, what they want to accomplish
during their visit, what resources they will need, what records they want to
review, and how much time they expect each activity to take.
_ With the site, establish a schedule for their visit, accommodating, as much
as possible, the site’s other priorities. They should allow enough time to stay
on schedule.
_ Make sure the contact people at all locations know and accept their visit
schedule.
_ Confirm the above information in a timely letter to the site.
_ Know all aspects of the Study and any other instructions or clarifications
that have been communicated to the site.

Monitor visit objectives may include:

_ Confirming that subject enrollment and visits are on schedule.


_ Confirming that study personnel are complying with the protocol.
_ Reviewing signed informed consent forms.
_ Verifying that most current informed consent form is being used.
_ Reviewing 100% or a sampling of CRF pages, and collect all completed CRF
pages.
_ Reviewing source documents for CRF support, unscheduled visits and
adverse events.
_ Reviewing the regulatory binder.
_ Reviewing protocol deviation and SAE reporting.
_ Reviewing study logs and Temperature Logs.
_ Inspecting investigational articles and clinical supplies; assess storage
facilities.
_ Reconcile drug accountability records.
_ Inspect randomization code materials.
_ Reviewing blinding and dispensing procedures.
_ Assessing the adequacy of the facilities.
_ Assessing whether equipment is properly maintenance maintained and
calibrated.
_ Verifying that laboratory certifications and other documentation is current.
_ Checking inventory levels of study drugs, clinical supplies and blank
documents such as CRFs.
_ Verifying that drug expiration dates have not been exceeded.
_ Assessing investigator’s involvement in the study.
_ Assessing study personnel’s knowledge of GCP and the protocol.
_ Sharing the experience of other sites, e.g., in recruiting.
_ Training site personnel on who to contact with specific questions
_ Reviewing status of study and site with central and/or local IRB

During a visit, monitors:

_ Keep their Contact Person informed of their activities.


_ Review and collect all completed CRF pages. Flag pages with questions or
problems and review them with the Study Coordinator.
_ If they handle medications or other supplies, replace them exactly as they
found them.
_ Do not interrupt site personnel when they are with a patient, on the
telephone or in a conversation; instead, ask their Contact Person or someone
at the front desk to help them.
_ Bring an organized set of the study forms and documents.
_ If they identify a potential issue, discuss it as soon as possible with the site
during their visit, providing details and referencing the pertinent passages in
the study documents.
_ Ensure, to the extent practical, that issues flagged in CRFs are resolved
during the visit.
_ Mark the place in the Regulatory Binder where he/she stopped his/her
review.
_ When raising an issue about the contents of the study documents,
specifically identify the pertinent passages.
_ If his/her schedule changes, notify everyone who may be affected.
_ At the end of their visit, meet with the Principal Investigator to discuss
findings and next steps.

Monitors review CRFs for:


_ Missing entries
_ Incomplete entries
_ Illegible entries
_ Data recorded in the wrong field
_ Illogical data
_ Inconsistent data
_ Ambiguous data
_ Entries that demonstrate protocol violations or deviations
_ Missing signatures
_ Missing dates

When visiting a subinvestigator or other satellite site, monitors:

_ 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.

After a visit, monitors:

_ Communicate significant problems to the site immediately, before small


problems become big ones.
_ Transmit their report to the site as soon as possible.

Any significant deviations from these expectations should be documented


and discussed with the Site Monitor, or their supervisor if necessary.

Site Monitors generally may not write on original CRF pages.


Exceptions may be made only if all of the below apply:

_ 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.

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