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In deciding if a treatment is likely to work in an individual patient, clinicians need to know the effect of the intervention in patients who take the treatment as prescribed. However, participants in clinical trials may not adhere to the protocol, or clinicians may recommend withdrawal of the study medication because of apparent adverse effects. Should investigators exclude from the analysis any participants who violate the research protocol? In this article, we review how randomization reduces bias in clinical trials and then discuss the importance of including all eligible patients in the analysis, to ensure the validity of the results.
Preventing bias in randomized controlled trials
The randomized controlled clinical trial is the best way to minimize bias in ascertaining treatment effects. The intent of randomization is to establish groups of patients with similar distributions of the characteristics that could determine whether they will suffer the adverse outcome of interest. If prognostic factors are balanced in the 2 (or more) groups and if the treatment has no effect, the proportion of participants experiencing the target outcome will be similar in the arms of the study. Conversely, if differences in outcome are observed, clinicians can confidently attribute those differences to the experimental intervention.
Applying the intention-to-treat principle
How should investigators analyze study data if one or more patients have not adhered to the allocated management strategy, for whatever reason? Some investigators deal with these protocol violations by excluding the participants from the analysis. This form of analysis, known as a per protocol, efficacy, explanatory analysis, or analysis by treatment administered, describes the outcomes of the participants who adhered to the research protocol. Although investigators can use information from such an analysis to estimate the intervention's efficacy in those who actually received it in the intended intensity or dose for the intended interval, this estimate is likely to be seriously flawed.
The problem arises because the reasons for nonadherence to the protocol may be related to prognosis. Empirical evidence suggests that participants who adhere tend to do better than those who do not adhere, even after adjustment for all known prognostic factors and irrespective of assignment to active treatment or placebo.1,2 Excluding nonadherent participants from the analysis leaves those who may be destined to have a better...