From Wikipedia,
the free encyclopedia
Clinical monitoring -
Oversight and administrative
efforts that monitor a
participant's health during a
clinical trial. The government and
other
clinical trial funding
agencies require data and safety
monitoring boards to oversee
clinical trials. They want to be
certain that safety measures are
in place to protect participants.
Functions of the clinical
monitor - clinical research
associate
How to monitor a study in the
field (clinical
research associate must travel
from your company to the study
site) 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 for different programs and
sites. It will depend on the
technologies available, sponsor
and site Standard Operating
Procedures (SOPs) and personal
preference, both at the site and
at the sponsor company. 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
presented 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 he or she will need to be
there and make appropriate
arrangements.
Sometimes a CRA is the sole
monitor for a site, while at other
times the CRA will team monitor
with other CRAs. Establishing who
will monitor requires
consideration of the sponsor’s
SOPs for field monitoring, the
complexity of the protocol, the
condition being studied, the
experience of the investigator and
his or her 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 subject
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 their
frequency. The more activities
that are required during a study
visit, the more monitoring will be
required. The disease being
studied also dictates the
frequency of visits. If, for
example, 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 subject or
two 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 wok 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
clinical research associate
should visit a site regularly even
through 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 CRA
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 call it
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
their 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
Standard operating procedures 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 speed put over the course of
long-term studies and require less
review; for example, weekly visits
may be required initially,
followed by monthly, and perhaps
even quarterly, visits 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 he or she has monitoring
responsibility. There is always
the chance that the CRA simply
cannot physically visit the sites
as often as he or she 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
clinical research associate
should schedule four hours at the
very least for a site visit. With
the complexity of protocols,
regulatory requirements and good
monitoring practice, the CRA 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 twelve to eighteen 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 simply
impossible to be able to visit
sites with the degree of frequency
necessary for good monitoring,
this should be discussed with his
or her supervision.
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 a site 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
problem is the list of activities
that receive the most deficiencies
during FDA 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
most recent top five deficiency
categories for site inspections,
as reported in 2001 Report to the
Nation, are:
- 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 CROs need to
spend enough time with sponsors’
representatives to clearly
understand those expectations.
