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Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review
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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756274/ https://www.ncbi.nlm.nih.gov/pubmed/35022173 http://dx.doi.org/10.1136/bmjopen-2021-052656 |
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author | Dodd, Matthew Fielding, Katherine Carpenter, James R Thompson, Jennifer A Elbourne, Diana |
author_facet | Dodd, Matthew Fielding, Katherine Carpenter, James R Thompson, Jennifer A Elbourne, Diana |
author_sort | Dodd, Matthew |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8756274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-87562742022-01-26 Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review Dodd, Matthew Fielding, Katherine Carpenter, James R Thompson, Jennifer A Elbourne, Diana BMJ Open Research Methods 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. BMJ Publishing Group 2022-01-12 /pmc/articles/PMC8756274/ /pubmed/35022173 http://dx.doi.org/10.1136/bmjopen-2021-052656 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Research Methods Dodd, Matthew Fielding, Katherine Carpenter, James R Thompson, Jennifer A Elbourne, Diana Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title | Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title_full | Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title_fullStr | Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title_full_unstemmed | Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title_short | Statistical methods for non-adherence in non-inferiority trials: useful and used? A systematic review |
title_sort | statistical methods for non-adherence in non-inferiority trials: useful and used? a systematic review |
topic | Research Methods |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756274/ https://www.ncbi.nlm.nih.gov/pubmed/35022173 http://dx.doi.org/10.1136/bmjopen-2021-052656 |
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