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Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this...

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Autores principales: Petit, Caroline, Samson, Adeline, Morita, Satoshi, Ursino, Moreno, Guedj, Jérémie, Jullien, Vincent, Comets, Emmanuelle, Zohar, Sarah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958415/
https://www.ncbi.nlm.nih.gov/pubmed/27705884
http://dx.doi.org/10.1177/0962280216671348
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author Petit, Caroline
Samson, Adeline
Morita, Satoshi
Ursino, Moreno
Guedj, Jérémie
Jullien, Vincent
Comets, Emmanuelle
Zohar, Sarah
author_facet Petit, Caroline
Samson, Adeline
Morita, Satoshi
Ursino, Moreno
Guedj, Jérémie
Jullien, Vincent
Comets, Emmanuelle
Zohar, Sarah
author_sort Petit, Caroline
collection PubMed
description The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose–toxicity and dose–efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.
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spelling pubmed-59584152018-05-25 Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies Petit, Caroline Samson, Adeline Morita, Satoshi Ursino, Moreno Guedj, Jérémie Jullien, Vincent Comets, Emmanuelle Zohar, Sarah Stat Methods Med Res Articles The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose–toxicity and dose–efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children. SAGE Publications 2016-10-05 2018-06 /pmc/articles/PMC5958415/ /pubmed/27705884 http://dx.doi.org/10.1177/0962280216671348 Text en © The Author(s) 2016 http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Articles
Petit, Caroline
Samson, Adeline
Morita, Satoshi
Ursino, Moreno
Guedj, Jérémie
Jullien, Vincent
Comets, Emmanuelle
Zohar, Sarah
Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title_full Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title_fullStr Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title_full_unstemmed Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title_short Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
title_sort unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958415/
https://www.ncbi.nlm.nih.gov/pubmed/27705884
http://dx.doi.org/10.1177/0962280216671348
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