Experimental Studies and Trials Randomized Clinical Trials Randomized controlled trials remain the gold standard for evaluating the efficacy and safety of treatments or interventions see
Trang 1■ Is the relationship specific for the risk factor and outcome of interest?
■ Is the relationship consistent across variations in study populations, settings and investigators, and design?
■ Is the relationship free of known and potential confounding?
■ Is the relationship free of systematic and random measurement error?
■ If an intervention is successful in reducing or eliminating the risk factor, does this alter the outcome in a consistent and predicted manner?
Experimental Studies and Trials
Randomized Clinical Trials
Randomized controlled trials remain the gold standard for evaluating the
efficacy and safety of treatments or interventions (see Table 24.2) The principle
of a randomized controlled trial is simple A group of subjects is randomly
assigned to an experimental arm (or arms) or to a comparison arm The
comparison arm can be placebo or an active control (such as the standard-of-care medication for the condition being treated) Randomization markedly reduces the risk of systematic differences in characteristics at baseline between the
groups Any outcomes observed during the period of follow-up, therefore,
should be attributable to the treatment alone and not to underlying differences in subjects
Randomized clinical trials provide the highest grade of evidence, particularly regarding establishing a causal relationship between an intervention and an
outcome This is true for two primary reasons First, randomization provides the best chance that the groups chosen for study will be equivalent at baseline
regarding both measured and unmeasured characteristics Any differences would
be attributed to chance or random error The larger the population studied, the less likely random maldistributions are to occur Strategies can be used to ensure
equal numbers of subjects in groups, so-called block randomization, and to
ensure that key characteristics are equivalent in groups, so-called stratified
randomization When assessing the success of randomization by comparing
measured characteristics at baseline, it is important to note clinically meaningful differences between groups rather than statistically significant differences If the sample is large, small and unimportant differences may be statistically
significant If the sample is small, large and important differences may not be
Trang 2The second feature of randomized clinical trials that contributes to providing high-quality evidence is that all clinical trials are based on prospectively and concurrently collected data Thus there is opportunity for standardization of definitions, methodology, measurements, reporting, and implementation of
measures for the control of quality, such as adjudication An important aspect of assessment is the concept of blinding or masking, whereby the subjects, the investigators, other study personnel, and those analyzing the data have no
knowledge of the randomized assignment of the subjects This ensures that the protocol is implemented identically in all groups Additionally, even the most well-meaning assessors may interpret subjective tests differently if they think that they know the assignment of the subject It may not be feasible for some interventions to be blinded completely For instance, for a trial of surgical versus transcatheter closure of septal defects, it would be obvious to patients and
providers which treatment a patient received In this case, however, some
blinding could still be used, as measurements, assessments, and analysis of the data can almost always remain blinded
There are multiple phases in clinical trials depending on the amount of
previous knowledge available regarding a specific intervention Also, there are different types of clinical trial approaches to be used depending on the aim to be achieved Clinical trials can be divided into four phases based on their aims Phase I trials establishes the safety of the intervention, phase II trials establish therapeutic effects, phase III trials are a full-scale evaluations of an intervention
by comparing the intervention to a control and establishing relative benefit and risks, and phase IV trials evaluate the long-term effects of an intervention, often called postmarketing trials.46,47 Prior to performing a clinical trial, it is important
to determine which phase of the intervention the trial will represent and what evidence will be needed The first and second phases are often small trials, using fewer than 50 patients, and aimed at establishing safety and therapeutic effect For drug trials, they often also incorporate assessments of pharmacokinetics and pharmacodynamics They rarely contribute to major changes in clinical practice The third and fourth phases strive to compare the intervention with a standard-of-care practice, a placebo, or a nonintervention These trials are the driving force behind changes in clinical practice and important components of the
evidence base supporting guidelines
Since the methodology for designing, performing, analyzing, and reporting clinical trials is fairly standardized, this makes them easier to appraise In the
Trang 3past 10 years, many biomedical journals have adopted the CONSORT guidelines for the standardized reporting of clinical trials in the scientific literature.48
Meta-Analyses
Meta-analyses and systematic reviews, in an effort to raise the certainty of a finding, pool data from multiple clinical studies to try to establish whether
multiple studies of a topic actually have similar findings (see Table 24.2 ) Meta-analyses identify a problem of interest and compile all studies, whether
observational or a randomized clinical trial, whether producing positive or
negative results, and whether published or not, that have previously studied the issue at hand Results from each study are then critically appraised and compiled and a summary conclusion is achieved.49,50 Meta-analyses are used to decrease the effect of studies with limited validities that might have inconsistent results Statistical analysis of meta-analyses is highly complex and beyond the scope of
this chapter Peer-reviewed meta-analyses are published in The Cochrane
Review, a repository of meta-analyses and systematic reviews, which is a high-quality reference on which to base changes in clinical practices