Medication adherence in clinical research and associated methodological challenges

Poor adherence to medication wastes resources and can lead to reduced exposure to and effectiveness of pharmacological treatments. Poor adherence to medication in clinical research can dilute treatment effects, obscuring the true benefits that medication can provide. The study of medication adherence comprises significant methodological challenges. The aim of my thesis was to investigate several methodological challenges encountered when studying medication adherence in clinical research using data from five clinical studies. Several methods for measuring adherence were compared using both correlation and agreement approaches. I proposed extensions to data visualisation techniques for comparing agreement. As an alternative to reporting summary measures, I explored the use of advanced modelling techniques to model adherence data collected via electronic monitors. I also moved beyond comparisons of measures and investigated approaches for predicting disagreement and calibration techniques. I investigated various methods for modelling the determinants of adherence, considering determinants according to type of measure used, type of condition being studied, different study designs, and different conceptualisations of adherence. I explored, quantitatively, the extent to which the treating clinician influenced whether a patient adhered to their treatment. I also established the feasibility of calculating randomisation-based efficacy estimators in randomised controlled trials with non-adherence, scrutinising the implementation of these approaches during placebo-controlled trials and non-inferiority trials involving two active treatments. My findings emphasise the need for considering the impact of medication adherence when designing a study, rather than leaving it as an afterthought, as it would appear to be much of the time. Such considerations include selecting an appropriate mode (or modes) of medication adherence ascertainment, agreeing adherence definitions of interest, measuring variables that are likely to be associated with adherence, and, particularly for trials, determining whether it is feasible to adjust findings for non-adherence while maintaining a comparison of groups as randomised