Nonadherence is a major problem in clinical trials of new medications. To evaluate the extent of nonadherence, this study evaluated pharmacokinetic sampling from 1765 subjects receiving active therapy across eight psychiatric trials conducted between 2001 and 2011. With nonadherence defined as > 50% of plasma samples below the limit of quantification for study drug, the percentage of nonadherent subjects ranged from 12.8% to 39.2%. There was a trend toward increased nonadherence in studies with greater numbers of subjects but an association with nonadherence was not apparent for other study design parameters or subject characteristics. For two trials with multiple recruitment sites in geographical proximity, several subjects attempted to simultaneously enroll at separate site locations. The construct of “professional subjects,” those who enroll in trials only for financial gain, is gaining attention, and we therefore modeled the impact of professional subjects on medication efficacy trials. The results indicate that enrollment of professional subjects who are destined to succeed (those who will appear to achieve treatment success regardless of study drug assignment) can substantially increase both the apparent placebo response rateand the sample size requirement for statistical power, while decreasing theobserved effect size. The overlapping nature of nonadherence, professionalsubjects, and placebo response suggests that these issues should be consideredand addressed together. Following this approach, we describe a novel clinicaltrial design to minimize the adverse effects of professional subjects on trialoutcomes, and discuss methods to monitor adherence.
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