title: The Reporting of Treatment Nonadherence and Its Associated Impact on Economic Evaluations Conducted Alongside Randomized Trials: A Systematic Review.
abstract: OBJECTIVE
  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 nonadherence in economic evaluations.
  
  
  METHODS
  The National Health Service Economic Evaluation Database was searched for recently published trials. We extracted information on the methods used to assign shared costs in the presence of nonadherence and methods to account for nonadherence 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, whereas 66% reported treatment intensity. Most studies (23 of 31 [74%] trials and 42 of 53 [79%] trials of one-off and recurring interventions, respectively) reported strict intention-to-treat or complete case analyses. A minority (3 of 31 [10%] and 7 of 53 [13%], respectively), however, performed a per-protocol analysis. No studies used statistical methods to adjust for nonadherence 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.
  
  
  CONCLUSIONS
  Most of the trials reported a measure of adherence, but reporting was not comprehensive. A nontrivial proportion of studies report a primary per-protocol analysis that potentially produces biased results. Alongside primary intention-to-treat analysis, statistical methods for obtaining an unbiased estimate of cost-effectiveness in adherers should be considered.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK. Electronic address: sam.brilleman@monash.edu.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Brilleman
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Metcalfe
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Peters
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: William
authors.initials: W
authors.lastname: Hollingworth
mesh_terms: D003362:Cost-Benefit Analysis; D003627:Data Interpretation, Statistical; D006801:Humans; D017059:Models, Econometric; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D016903:Drug Monitoring
keywords: adherence; compliance; economic evaluation; systematic review; trial