Defining outcome measures for medication adherence in clinical trials.

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Deviations from protocol-defined dosing regimens, in the form of variable adherence to trial medication, are prevalent and problematic. An analysis of 95 clinical studies, reported that the number of patients taking prescribed oral medication(s) decreased progressively over time, with less than 70% of patients being fully adherent to the protocol-specified dosing regimen after 100 days [https://doi.org/10.1146/annurev-pharmtox-011711-113247]. This can lead to incorrect interpretation of a medicine's efficacy, confound the selection of an appropriate dosing regimen and may mislead the attribution of safety concerns to trial medication. This is especially problematic given that the measurement of medication adherence in registration trials varies widely and is reported poorly [https://doi.org/10.1002/cpt.2709]. Under the auspices of the International Society for Medication Adherence (ESPACOMP), we have developed a consensus taxonomy for medication adherence (ABC), medication adherence reporting guidelines (EMERGE), methods for analysing adherence data (TEOS) and for assessing the risk of bias within adherence research (RoBIAS and RoBOAS tools). This PhD project will aim to further advance the methodology of medication adherence measurement and reporting in clinical trials.As an explanatory variable, adherence to trial medication is conventionally measured as the proportion of doses taken (or some variation on this); and, as an outcome variable, as the proportion of patients achieving some arbitrary threshold (usually 80%) of doses taken over a defined period of observation. Both measures conceal important differences in the nature of patients' adherence. Specifically, non-adherence includes non-initiation (which is a dichotomous outcome); poor implementation of the dosing regimen (patients who take the drug, but not according to the prescribed dosing regimen); and premature discontinuation (when they are fail to persist with treatment). The student will: (i) review the literature for measures and metrics of medication adherence; (ii) assess the risk of bias of these measures in relation to the three phases of adherence, utilising data from several thousand trial participants in whom adherence was measured electronically using the Medication Event Monitoring System (Aardex Group's Adherence Knowledge Centre database); (iii) assess different measures for their appropriateness in the context of different trial designs and objectives; and (iv) develop a core outcome set of adherence measures for use in drug trials.