Model-Based Optimization of Clinical Trial Designs
General attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmac...
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Uppsala universitet, Institutionen för farmaceutisk biovetenskap
2014
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ndltd-UPSALLA1-oai-DiVA.org-uu-2334452015-01-24T04:46:11ZModel-Based Optimization of Clinical Trial DesignsengVong, CamilleUppsala universitet, Institutionen för farmaceutisk biovetenskapUppsala2014nonlinear mixed-effects modelspharmacometricslikelihood ratio testNONMEMpowersample sizestudy designproof-of-conceptdose-findingpopulation optimal designLOQBQL dataneutropeniadocetaxelmyelosuppressionthrombocytopeniaMTDBayesian methods3+3 algorithmdose escalation studyGeneral attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmacokinetic-pharmacodynamic models was identified as one of the strategies core to this renaissance. Coupled with Optimal Design (OD), they constitute together an attractive toolkit to usher more rapidly and successfully new agents to marketing approval. The general aim of this thesis was to investigate how the use of novel pharmacometric methodologies can improve the design and analysis of clinical trials within drug development. The implementation of a Monte-Carlo Mapped power method permitted to rapidly generate multiple hypotheses and to adequately compute the corresponding sample size within 1% of the time usually necessary in more traditional model-based power assessment. Allowing statistical inference across all data available and the integration of mechanistic interpretation of the models, the performance of this new methodology in proof-of-concept and dose-finding trials highlighted the possibility to reduce drastically the number of healthy volunteers and patients exposed to experimental drugs. This thesis furthermore addressed the benefits of OD in planning trials with bio analytical limits and toxicity constraints, through the development of novel optimality criteria that foremost pinpoint information and safety aspects. The use of these methodologies showed better estimation properties and robustness for the ensuing data analysis and reduced the number of patients exposed to severe toxicity by 7-fold. Finally, predictive tools for maximum tolerated dose selection in Phase I oncology trials were explored for a combination therapy characterized by main dose-limiting hematological toxicity. In this example, Bayesian and model-based approaches provided the incentive to a paradigm change away from the traditional rule-based “3+3” design algorithm. Throughout this thesis several examples have shown the possibility of streamlining clinical trials with more model-based design and analysis supports. Ultimately, efficient use of the data can elevate the probability of a successful trial and increase paramount ethical conduct. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233445urn:isbn:978-91-554-9063-8Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 192application/pdfinfo:eu-repo/semantics/openAccess |
collection |
NDLTD |
language |
English |
format |
Doctoral Thesis |
sources |
NDLTD |
topic |
nonlinear mixed-effects models pharmacometrics likelihood ratio test NONMEM power sample size study design proof-of-concept dose-finding population optimal design LOQ BQL data neutropenia docetaxel myelosuppression thrombocytopenia MTD Bayesian methods 3+3 algorithm dose escalation study |
spellingShingle |
nonlinear mixed-effects models pharmacometrics likelihood ratio test NONMEM power sample size study design proof-of-concept dose-finding population optimal design LOQ BQL data neutropenia docetaxel myelosuppression thrombocytopenia MTD Bayesian methods 3+3 algorithm dose escalation study Vong, Camille Model-Based Optimization of Clinical Trial Designs |
description |
General attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmacokinetic-pharmacodynamic models was identified as one of the strategies core to this renaissance. Coupled with Optimal Design (OD), they constitute together an attractive toolkit to usher more rapidly and successfully new agents to marketing approval. The general aim of this thesis was to investigate how the use of novel pharmacometric methodologies can improve the design and analysis of clinical trials within drug development. The implementation of a Monte-Carlo Mapped power method permitted to rapidly generate multiple hypotheses and to adequately compute the corresponding sample size within 1% of the time usually necessary in more traditional model-based power assessment. Allowing statistical inference across all data available and the integration of mechanistic interpretation of the models, the performance of this new methodology in proof-of-concept and dose-finding trials highlighted the possibility to reduce drastically the number of healthy volunteers and patients exposed to experimental drugs. This thesis furthermore addressed the benefits of OD in planning trials with bio analytical limits and toxicity constraints, through the development of novel optimality criteria that foremost pinpoint information and safety aspects. The use of these methodologies showed better estimation properties and robustness for the ensuing data analysis and reduced the number of patients exposed to severe toxicity by 7-fold. Finally, predictive tools for maximum tolerated dose selection in Phase I oncology trials were explored for a combination therapy characterized by main dose-limiting hematological toxicity. In this example, Bayesian and model-based approaches provided the incentive to a paradigm change away from the traditional rule-based “3+3” design algorithm. Throughout this thesis several examples have shown the possibility of streamlining clinical trials with more model-based design and analysis supports. Ultimately, efficient use of the data can elevate the probability of a successful trial and increase paramount ethical conduct. |
author |
Vong, Camille |
author_facet |
Vong, Camille |
author_sort |
Vong, Camille |
title |
Model-Based Optimization of Clinical Trial Designs |
title_short |
Model-Based Optimization of Clinical Trial Designs |
title_full |
Model-Based Optimization of Clinical Trial Designs |
title_fullStr |
Model-Based Optimization of Clinical Trial Designs |
title_full_unstemmed |
Model-Based Optimization of Clinical Trial Designs |
title_sort |
model-based optimization of clinical trial designs |
publisher |
Uppsala universitet, Institutionen för farmaceutisk biovetenskap |
publishDate |
2014 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-233445 http://nbn-resolving.de/urn:isbn:978-91-554-9063-8 |
work_keys_str_mv |
AT vongcamille modelbasedoptimizationofclinicaltrialdesigns |
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1716728426079977472 |