The FDA has released its long awaited update and replacement
to the outdated 1988 guidance on clinical monitoring. The draft guidance
for industry on Oversight
of Clinical Investigations - A Risk Based Approach to Monitoring is
early evidence that the findings and recommendations of the Clinical Trials Transformation
Initiative (CTTI), FDA's public-private partnership with Duke
University among others, are beginning to take hold in practice in the clinical
trials domain.
According to a CTTI survey, clinical trial sponsors are
successfully employing a range of monitoring modalities, such as centralized
monitoring by biostatistical and data management personnel, targeted on-site
visits to higher risk sites as well as frequent on site visits to all sites by
clinical monitoring personnel. Yet historically, industry sponsors have
rarely relied on any mechanism other than comprehensive
all-site monitoring performing 100% source data verification, every
four to six weeks. It is a well-understood, costly and time consuming
method of monitoring that the industry perceives is preferred
by FDA. Yet, given the vast changes in the clinical trial landscape in
the decades since the FDA's previous 1988 guidance and the regulations covering
sponsor obligations, including the increase in the number and complexity of
clinical trials, investigator experience, changes in ethical oversight,
treatment options, and geographical dispersion of clinical trial sites, the FDA
now calls on the industry to employ new and more effective methods for
monitoring clinical trials.
This is big news. As in the recent final
rule on safety reporting, which requires sponsors to make judgments about
whether a single case is instructive enough to warrant reporting to the
authorities, FDA here is encouraging sponsors to reduce their reliance on a
one-size-fits-all, on-site, 100% source data verification comprehensive
monitoring approach in favor of a more diversified, horses-for-courses
approach, building monitoring plans and employing monitoring modalities based
on multiple factors such as:
·
type or study and endpoints (whether objectively
or subjectively derived)
·
disease state of patient population
·
sponsor experience with investigator and
investigator experience with research
·
complexity of protocol, such as adaptive
designs, stratified designs, complex dose titrations, etc.
·
availability of EDC to facilitate centralized
monitoring
Throughout the guidance, the FDA continually refers to the
prevalence of electronic data capture (EDC) that allows for centralized and
risk-based monitoring. It appears that their expectation is that EDC
usage is now or very soon will be the norm rather than the exception.
This is certainly one of the most important advancements in clinical trials
technology that allows for alternatives to comprehensive on-site 100%
monitoring and indicates that despite its earlier struggles for acceptance
during the 1990s, remote data capture is here to stay at last.
While this is a draft guidance, the FDA is putting teeth
into it by:
·
withdrawing the extremely outdated 1988 guidance
·
ensuring that BIMO guidance manuals are
compatible with the recommendations
·
ensuring affected areas of FDA are aware of the
goals of the guidance
·
will consider establishing processes within CDER
for sponsors to voluntarily submit feedback on proposed monitoring plans.
It will be interesting to watch how sponsors and CROs
implement this new guidance. Having traditionally supported comprehensive,
frequent on-site monitoring methodology, CROs will have to develop new pricing
models other than X monitors spending Y days onsite every Z weeks.
Sponsors by their turn will have to revise their SOPs and employ
different kinds of training to use centralized electronic monitoring
methods efficiently.
This post was published at the Clinical Leader site. I am grateful to Rob Wright, Chief Editor of Life Science Leader magazine for his support.
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