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Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review
Matthew Dodd1,2, Katherine Fielding3, James R Carpenter4,5
1Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK matthew.dodd@lshtm.ac.uk.
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.
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