The Reporting of Treatment Nonadherence and Its Associated Impact on Economic Evaluations Conducted Alongside Randomized Trials: A Systematic Review

Objectives: To review trial-based economic evaluations, identifying: 1) the proportion reporting adherence; 2) methods for assigning intervention costs according to adherence; 3) which participants were included in the economic analysis; and 4) statistical methods to estimate cost-effectiveness in those who adhered. We provide recommendations on handling non-adherence in economic evaluations.

Methods: The NHS Economic Evaluation Database was searched for recently published trials. We extracted information on the methods used to assign shared costs in the presence of non-adherence and methods to account for non-adherence in the economic analysis.

Results: Ninety-six eligible trials were identified. For one-off interventions, 86% reported the number of participants initiating treatment. For recurring interventions, 56% and 73% respectively reported the number initiating and completing treatment, whilst 66% reported treatment intensity. Most studies (23/31 [74%] trials and 42/53 [79%] trials of one off and recurring interventions respectively) reported strict intention to treat or complete case analyses. A minority (3/31 [10%] and 7/53 [13%] respectively), however, performed a per protocol analysis. No studies used statistical methods to adjust for non-adherence directly in the economic evaluation. Only 13 studies described patient-level allocation of intervention costs; there was variation in how fixed costs were assigned according to adherence.

Conclusion. The majority of trials reported a measure of adherence, but reporting was not comprehensive. A non-trivial proportion of studies report a primary per protocol analysis which potentially produces biased results. Alongside primary ITT analysis, statistical methods for obtaining an unbiased estimate of cost-effectiveness in adherers should be considered.