The effects of non-compliance on intent-to-treat analysis of equivalence trials
ABSTRACT The standard approach for analysing a randomized clinical trial is based on intent-to-treat (ITT) where subjects are analysed according to their assigned treatment group regardless of actual adherence to the treatment protocol. For therapeutic equivalence trials, it is a common concern that an ITT analysis increases the chance of erroneously concluding equivalence. In this paper, we formally investigate the impact of non-compliance on an ITT analysis of equivalence trials with a binary outcome. We assume 'all-or-none' compliance and independence between compliance and the outcome. Our results indicate that non-compliance does not always make it easier to demonstrate equivalence. The direction and magnitude of changes in the type I error rate and power of the study depend on the patterns of non-compliance, event probabilities, the margin of equivalence and other factors.
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ABSTRACT: In the presence of dropout, intent(ion)-to-treat analysis is usually carried out using methods that assume a missing-at-random (MAR) dropout mechanism. We investigate the potential bias caused by assuming MAR when the dropout is related to unobserved compliance status. A framework to assess the magnitude of bias in the context of pre- and post-test design (PPD) with two treatment arms is presented. Scenarios with all-or-none and partial compliance level are investigated. Using two simulated data sets and actual data from an e-mental health trial, we demonstrate the utility of sensitivity analyses to assess the bias magnitude and show that they are plausible options when some knowledge of compliance behaviour in the dropout exists. We recommend that our approach be used in conjunction with methods of analysis which assume MAR in estimating the ITT effect.Statistics in Medicine 04/2008; 27(8):1164-79. DOI:10.1002/sim.3025 · 2.04 Impact Factor
- Clinical Infectious Diseases 05/2008; 46(8):1152-6. DOI:10.1086/533442 · 9.42 Impact Factor
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ABSTRACT: Poor adherence to antihypertensive medication is one of the major problems in the treatment of hypertension. Electronic monitoring is currently considered to be the gold standard for assessing adherence, but it may trigger patients to open the pill bottle without taking medication or to take out more than prescribed. In adjunct to electronic monitoring, pill count could be a valuable tool for exploring adherence patterns, and their effects on blood pressure reduction. Among a total of 228 patients with mild-to-moderate hypertension, adherence to treatment was measured by means of both the Medication Event Monitoring System (MEMS) and pill count. Patients were followed-up for seven visits over a period of 1 year. At each visit to the physician's office, patient's adherence was assessed by both methods. Adherence is defined as the percentage of days with correct dosing; median adherence according to MEMS was lower than median adherence according to pill count (91.6 vs. 96.1; P < 0.001). Both methods agreed in defining patients as adherent in 107 (47%) and nonadherent in 33 (14%) patients. Thirty-one (14%) patients were adherent only by MEMS and 59 (25%) patients only by pill count. At the end of the study, patients in the four categories reached comparable blood pressure values and reductions. Pill count could be a useful adjunct to electronic monitoring in assessing adherence patterns. Although deviant intake behavior occurred frequently, the effect on achieved blood pressure and blood pressure reduction was not remarkable.American Journal of Hypertension 11/2009; 23(2):149-54. DOI:10.1038/ajh.2009.207 · 3.40 Impact Factor