Abstract
BackgroundNoncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs). Intention to treat (ITT) is generally considered the best method for addressing noncompliance in RCTs. Alternatives to ITT exist, including per protocol (PP), as treated (AT), and instrumental variables (IV). These three methods define participant compliance dichotomously, but partial compliance is a common occurrence in RCTs. By defining a threshold, above which a participant is called a complier, PP, AT and IV can be used, but the resulting loss of information may affect their performance. Trials with factorial designs may experience higher rates of noncompliance due to the heavier burden that participants experience by being assigned to multiple experimental treatments.MethodsUsing simulations, we assessed the performance of ITT, PP, AT, and IV in both the partial compliance setting and in a 2-by-2 factorial design with increased participant burden for those randomized to both active treatments.ResultsThe bias, mean squared error, and type I error rates of the IV method after dichotomizing partial compliance were heavily inflated. The performance of all four methods depended on the level of noncompliance present, with higher average noncompliance leading to poorer performance. PP and AT showed improved bias and power relative to ITT without inflating the type I error beyond acceptable limits. However, the PP and AT heavily inflated the type I error rates when participant compliance was affected by the participants’ general health.ConclusionsThere are consequences for dichotomizing compliance information to make it fit into well-known methods. The results suggest the need for a method of estimating treatment effects that can utilize partial compliance information.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-1044-z) contains supplementary material, which is available to authorized users.
Highlights
Noncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs)
For the compliance distributions with a mean of 0.5, the results of the instrumental variables (IV) method are not pictured in order to keep the figure to an appropriate scale
For both distributions with mean 0.5 and all cutoff points, the type I error rate with the IV method never fell below 30 % and rose as high as nearly 85 % in the case of uniform compliance with a cutoff of 0.9
Summary
Noncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs). Alternatives to ITT exist, including per protocol (PP), as treated (AT), and instrumental variables (IV) These three methods define participant compliance dichotomously, but partial compliance is a common occurrence in RCTs. By defining a threshold, above which a participant is called a complier, PP, AT and IV can be used, but the resulting loss of information may affect their performance. Alternatives to ITT that attempt to find the true treatment effect include the per protocol (PP), as treated (AT), and instrumental variables (IV) methods. All three methods assume compliance is measured dichotomously but may be adapted for use when compliance is measured on a Merrill and McClure Trials (2015) 16:523 continuous scale Employing these methods in this manner may affect their estimation of the treatment effect
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