Abstract
Randomized controlled trial results are needed for developing guidelines, payment
rules, and quality-of-care measures; however, 2 phenomena reduce the usefulness of
randomized controlled trial findings. First, these studies now enroll patients with
less severe disease, who are less likely to benefit from a drug or treatment. Second,
patients are living longer but, as a result, have more chronic diseases. Although
randomized controlled trials often exclude these older patients, trial findings continue
to be generalized to them. Together, these phenomena impose challenges to the usefulness
of the results of randomized controlled trials for clinical and policy applications.
The convergence of these phenomena makes the current research paradigm underlying
evidence-based medicine, guideline development and quality assessment fundamentally
flawed in 2 ways. First, the “evidence” includes patients who may have a minimal benefit
from the treatment being tested. This could reduce the power for the trial and yield
negative or null results, leading to undertreatment of a group of patients with potential
for a greater-than-observed benefit. Second, attempts to generalize the results from
positive trials to patients who have been excluded from those trials may result in
the overtreatment of those who could not benefit (e.g., because they will die from
other causes before the benefit of treatment would occur) and therefore represents
a parallel hazard. In this article, we describe sources of heterogeneity of treatment
effects (HTE) within trials, which can compromise the interpretation and generalizability
of results. We also examine strategies for understanding and managing HTE in practice,
to increase the usefulness of trial results.
Keywords
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© 2007 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
