Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review. Issue 1 (12th January 2022)

• Record Type: Journal Article
• Authors: Dodd, Matthew; Fielding, Katherine; Carpenter, James R; Thompson, Jennifer A; Elbourne, Diana
• Is Part Of: BMJ open. Volume 12:Issue 1(2022)
• Publication Date: 2022-01-12
• Subjects: statistics & research methods -- general medicine (see internal medicine) -- public health; Medicine -- Research -- Periodicals; 610.72
• DOI: 10.1136/bmjopen-2021-052656
• Languages: English
• ISSNs: 2044-6055

Abstract

Abstract : Background: In non-inferiority trials with non-adherence to interventions (or non-compliance), intention-to-treat and per-protocol analyses are often performed; however, non-random non-adherence generally biases these estimates of efficacy. Objective: To identify statistical methods that adjust for the impact of non-adherence and thus estimate the causal effects of experimental interventions in non-inferiority trials. Design: A systematic review was conducted by searching the Ovid MEDLINE database (31 December 2020) to identify (1) randomised trials with a primary analysis for non-inferiority that applied (or planned to apply) statistical methods to account for the impact of non-adherence to interventions, and (2) methodology papers that described such statistical methods and included a non-inferiority trial application. Outcomes: The statistical methods identified, their impacts on non-inferiority conclusions, and their advantages/disadvantages. Results: A total of 24 papers were included (4 protocols, 13 results papers and 7 methodology papers) reporting relevant methods on 26 occasions. The most common were instrumental variable approaches (n=9), including observed adherence as a covariate within a regression model (n=3), and modelling adherence as a time-varying covariate in a time-to-event analysis (n=3). Other methods included rank preserving structural failure time models and inverse-probability-of-treatment weighting. The methods identified in protocols and results papers were more commonly specified as sensitivity analyses (n=13) than primary analyses (n=3). Twelve results papers included an alternative analysis of the same outcome; conclusions regarding non-inferiority were in agreement on six occasions and could not be compared on six occasions (different measures of effect or results not provided in full). Conclusions: Available statistical methods which attempt to account for the impact of non-adherence to interventions were used infrequently. Therefore, firm inferences about their influence on non-inferiority conclusions could not be drawn. Since intention-to-treat and per-protocol analyses do not guarantee unbiased conclusions regarding non-inferiority, the methods identified should be considered for use in sensitivity analyses. PROSPERO registration number: CRD42020177458.