A methodological framework to account for the impact of non-adherence on the cost-effectiveness of chronic medications

This thesis investigates the problem of estimating the effectiveness and cost-effectiveness of prescribed medications in the presence of patient non-adherence, which is a major issue when making reimbursement decisions. Poor reimbursement decisions can have significant negative consequences for both patient outcomes and costs. This research aimed to develop a methodological framework to account for the impact of non-adherence on the cost-effectiveness of chronic medications in the context of health technology assessments (HTA) using time-to-event outcomes. Such a framework did not exist when this research started. The framework put forward in this thesis was informed by four linked stages of this research: (1) a systematic review of methodological papers that identified 12 non-adherence adjustment methods and assessed their suitability for use in HTA; (2) a simulation study that assessed the performance of four adjustment methods in 90 scenarios; (3) a case study that applied two generalised methods (g-methods) to a trial of maintenance immunosuppressants in kidney transplantation in order to produce cost-effectiveness estimates based on external ‘real world’ non-adherence data; and (4) the development of an analytical framework for incorporating non-adherence into cost-effectiveness models. The review suggests that g-methods and pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis appear to be more appropriate to estimate effectiveness in the presence of real-world non-adherence. The simulation study demonstrates that g-methods and per-protocol (PP) analysis are the best-performing methods for adjusting estimates of treatment effectiveness for non-adherence compared to intention-to-treat analysis, although the PP estimand is not theoretically appropriate. The case study findings show reduced net health benefits and increased cost per patient when real-world non-adherence is taken into account. The framework provides guidance on the steps that could be followed to account for real-world non-adherence when undertaking cost-effectiveness analyses. Future research is recommended to use the framework in different case studies for evaluation.