Mitigating the Effects of Nonadherence in Clinical Trials

Abstract

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.

Keywords: adherence; clinical trials; duplicate subjects; nonadherence; professional subjects.

Figure 1

The impact of noninformative subjects on study power. If noninformative data are not excluded, then a study intended to be powered at 90% would have an actual power between 50% and 87% depending on the percentage of subjects (10%–40%) contributing noninformative data. A study intended to be powered at 80% would have an actual power between 39% and 72%.

Figure 2

Increase in sample size necessary to recover power lost from noninformative data. As a greater percentage of subjects contribute noninformative data, the increased sample size required to maintain study power increases in a nonlinear fashion. When noninformative data are not excluded, the sample size required to maintain study power is greatly increased.

Figure 3

Impact of professional subjects who appear to achieve treatment success (A‐C) or treatment failure (D‐F) on an efficacy trial with a binary success/failure outcome. A and D: Apparent success rate, with success of appropriate subjects set at 15% for active medication (filled circles) and at 5% for placebo (open circles). B and E: Number of subjects/group required to achieve 80% power in detecting a significant treatment effect (α = 0.05; 2‐sided). C and F: Apparent effect size (odds ratio); in all cases there is an equal distribution of professional subjects among the placebo and active medication groups. This figure was reproduced from McCann et al¹¹ with permission of the publisher.

Figure 4

Where to act to account for and/or reduce nonadherence. Steps may be taken to address nonadherence during the prescreen process, before and after randomization, and during post hoc analysis. Discontinuing subjects prior to the first efficacy measurement may allow subjects to be excluded from the ITT.

Figure 5

Different dosing patterns for study participants over the course of the trial. Patient A demonstrated appropriate adherence. Patient B demonstrated a highly variable dosing regimen. Patient C discontinued medication after a few months. Patient D demonstrated variability in dosing and periods of extended nonadherence during the study. AiCure data.52