Background Clinical trials are widely considered
the gold standard in comparative effectiveness research (CER) but the high cost
and complexity of traditional trials and concerns about generalizability to
broad patient populations and general clinical practice limit their appeal.
Unsuccessful implementation of CER results limits the value of even the highest
quality trials. Planning for a trial comparing two standard strategies of
insulin administration for hospitalized patients led us to develop a new method
for a clinical trial designed to be embedded directly into the clinical care
setting thereby lowering the cost, increasing the pragmatic nature of the
overall trial, strengthening implementation, and creating an integrated
environment of research-based care.
Purpose We describe a novel randomized clinical
trial that uses the informatics and statistics infrastructure of the Veterans
Affairs Healthcare System (VA) to illustrate one key component (called the
point-of-care clinical trial – POC-CT) of a ‘learning healthcare
system,’ and settles a clinical question of interest to the VA.
Methods This study is an open-label, randomized
trial comparing sliding scale regular insulin to a weight-based regimen for
control of hyperglycemia, using the primary outcome length of stay, in non-ICU
inpatients within the northeast region of the VA. All non-ICU patients who
require in-hospital insulin therapy are eligible for the trial, and the
VA’s automated systems will be used to assess eligibility and present
the possibility of randomization to the clinician at the point of care.
Clinicians will indicate their approval for informed consent to be obtained by
study staff. Adaptive randomization will assign up to 3000 patients,
preferentially to the currently ‘winning’ strategy, and all care
will proceed according to usual practices. Based on a Bayesian stopping rule,
the study has acceptable frequentist operating characteristics (Type I error
6%, power 86%) against a 12% reduction of median length
of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation
of a successful treatment strategy.
Limitations Despite clinical equipoise, individual
healthcare providers may have strong treatment preferences that jeopardize the
success and implementation of the trial design, leading to low rates of
randomization. Unblinded treatment assignment may bias results. In addition,
generalization of clinical results to other healthcare systems may be limited by
differences in patient population. Generalizability of the POC-CT method depends
on the level of informatics and statistics infrastructure available to a
Conclusions The methods proposed will demonstrate
outcome-based evaluation of control of hyperglycemia in hospitalized veterans.
By institutionalizing a process of statistically sound and efficient learning,
and by integrating that learning with automatic implementation of best practice,
the participating VA Healthcare Systems will accelerate improvements in the
effectiveness of care.