A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another dru...

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Autores principales:	José L. Jiménez, Julia Niewczas, Alexander Bore, Carl-Fredrik Burman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/98d03a501324445bad80af254aa1364b
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spelling	oai:doaj.org-article:98d03a501324445bad80af254aa1364b2021-11-25T05:54:23ZA modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching1932-6203https://doaj.org/article/98d03a501324445bad80af254aa1364b2021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592474/?tool=EBIhttps://doaj.org/toc/1932-6203In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.José L. JiménezJulia NiewczasAlexander BoreCarl-Fredrik BurmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q José L. Jiménez Julia Niewczas Alexander Bore Carl-Fredrik Burman A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
description	In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.
format	article
author	José L. Jiménez Julia Niewczas Alexander Bore Carl-Fredrik Burman
author_facet	José L. Jiménez Julia Niewczas Alexander Bore Carl-Fredrik Burman
author_sort	José L. Jiménez
title	A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
title_short	A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
title_full	A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
title_fullStr	A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
title_full_unstemmed	A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
title_sort	modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/98d03a501324445bad80af254aa1364b
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A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

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