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A note on the determination of non-inferiority margins with application in oncology clinical trials()

The goal of a non-inferiority trial is to evaluate whether the effect of an experimental treatment is not inferior to that of the active control. Determination of an appropriate non-inferiority margin is critical to the demonstration of non-inferiority. A commonly used method is called the fixed-mar...

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Autores principales: Yu, Binbing, Yang, Harry, Sabin, Antony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804591/
https://www.ncbi.nlm.nih.gov/pubmed/31650074
http://dx.doi.org/10.1016/j.conctc.2019.100454
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author Yu, Binbing
Yang, Harry
Sabin, Antony
author_facet Yu, Binbing
Yang, Harry
Sabin, Antony
author_sort Yu, Binbing
collection PubMed
description The goal of a non-inferiority trial is to evaluate whether the effect of an experimental treatment is not inferior to that of the active control. Determination of an appropriate non-inferiority margin is critical to the demonstration of non-inferiority. A commonly used method is called the fixed-margin approach recommended by the FDA. The fixed-margin approach consists of two steps: first the lower limit of the [Formula: see text] two-sided confidence interval (CI) of the active-control effect versus placebo is calculated from relevant historical trials or meta-analysis; second, the non-inferiority margin is obtained as a fraction of the lower confidence limit of the control effect to preserve partial control effect. An alternative method is to use the point estimate, instead of the lower confidence limit, of the active-control effect. The fixed-margin approach based on the lower limit may be ultra-conservative with unconditional Type 1 error rate much smaller than target [Formula: see text] level, while the margin based on the point estimate is liberal. We derive the Type 1 error rate as a function of variances of the effect estimates in the historical and the current non-inferiority trials. We also propose an alternative approach for the non-inferiority margin that maintains the target Type 1 error rate. For the endpoint of landmark survival, we conduct simulations to compare the fixed-margin methods and the proposed method. For illustration, we apply the proposed method to an oncology non-inferiority clinical trial to determine an alternative non-inferiority margin.
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spelling pubmed-68045912019-10-24 A note on the determination of non-inferiority margins with application in oncology clinical trials() Yu, Binbing Yang, Harry Sabin, Antony Contemp Clin Trials Commun Article The goal of a non-inferiority trial is to evaluate whether the effect of an experimental treatment is not inferior to that of the active control. Determination of an appropriate non-inferiority margin is critical to the demonstration of non-inferiority. A commonly used method is called the fixed-margin approach recommended by the FDA. The fixed-margin approach consists of two steps: first the lower limit of the [Formula: see text] two-sided confidence interval (CI) of the active-control effect versus placebo is calculated from relevant historical trials or meta-analysis; second, the non-inferiority margin is obtained as a fraction of the lower confidence limit of the control effect to preserve partial control effect. An alternative method is to use the point estimate, instead of the lower confidence limit, of the active-control effect. The fixed-margin approach based on the lower limit may be ultra-conservative with unconditional Type 1 error rate much smaller than target [Formula: see text] level, while the margin based on the point estimate is liberal. We derive the Type 1 error rate as a function of variances of the effect estimates in the historical and the current non-inferiority trials. We also propose an alternative approach for the non-inferiority margin that maintains the target Type 1 error rate. For the endpoint of landmark survival, we conduct simulations to compare the fixed-margin methods and the proposed method. For illustration, we apply the proposed method to an oncology non-inferiority clinical trial to determine an alternative non-inferiority margin. Elsevier 2019-09-23 /pmc/articles/PMC6804591/ /pubmed/31650074 http://dx.doi.org/10.1016/j.conctc.2019.100454 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Yu, Binbing
Yang, Harry
Sabin, Antony
A note on the determination of non-inferiority margins with application in oncology clinical trials()
title A note on the determination of non-inferiority margins with application in oncology clinical trials()
title_full A note on the determination of non-inferiority margins with application in oncology clinical trials()
title_fullStr A note on the determination of non-inferiority margins with application in oncology clinical trials()
title_full_unstemmed A note on the determination of non-inferiority margins with application in oncology clinical trials()
title_short A note on the determination of non-inferiority margins with application in oncology clinical trials()
title_sort note on the determination of non-inferiority margins with application in oncology clinical trials()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804591/
https://www.ncbi.nlm.nih.gov/pubmed/31650074
http://dx.doi.org/10.1016/j.conctc.2019.100454
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