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Methods of evaluation of performance of adaptive designs on treatment effect intervals and methods of designing two-stage winner designs with survival outcomes
Descriptive
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Text
TitleInfo
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Title
Methods of evaluation of performance of adaptive designs on treatment effect intervals and methods of designing two-stage winner designs with survival outcomes
Identifier
ETD_2879
Identifier
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http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000056339
Language
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Statistics and Biostatistics
Subject
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(authority = ETD-LCSH)
Topic
Sampling (Statistics)
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Drugs--Testing
Subject
(ID = SBJ-4);
(authority = ETD-LCSH)
Topic
Drug development
Abstract
The accuracy of the treatment effect estimation is crucial to the success of phase 3 studies. The calculation of fixed sample size relies on the estimation of the treatment effect and cannot be changed during the trial. Oftentimes, with limited efficacy data available from early phase studies and relevant historical studies, the sample size estimation may not accurately reflect the true treatment effect. Several adaptive designs have been proposed to address this uncertainty in the sample size calculation. These adaptive designs provide the flexibility of sample size adjustment during the trial by allowing early trial stopping or sample size re-estimation at the interim look(s). The use of adaptive designs can optimize the trial performance when the treatment effect is an assumed constant value. However in practice, the treatment effect is more reasonable to be considered within an interval rather than as a point estimate. Proper selection of adaptive designs will decrease the failure rate of phase 3 clinical trials and increase the chance for new drug approval. This dissertation proposes an optimal design based on an interval using the "regret concept". A mathematical framework is developed to evaluate the adaptability of different designs. In addition, this dissertation identifies the factors that may affect the performance of adaptive design and derives the expected sample size for two-stage sample size re-estimation designs. In drug development, a phase 2 trial may not be feasible due to long follow-up or lack of resources. So it may necessary to evaluate several promising regimens in the confirmatory phase 3 trial. In this case, an interim analysis is often used to drop the inferior arms and to avoid the high cost, long term trial conduction, and exposure to ineffective treatment. This approach is considered as combining the two phases into one study: phase 2 portion will be carried out by the interim analysis. When appropriate surrogate endpoints exist, such as progression free survival in oncology trials, they can be used at the interim analysis to accelerate the drug development process. The statistical frameworks are available in the literature for designs with continuous endpoints. However, it is very challenging to derive the correlation between log-rank statistics at interim and final analysis when survival endpoints are used. An asymptotic correlation of log-rank statistics is developed and the features for a two-stage design survival trial using same or different endpoint at interim analysis is explored.
PhysicalDescription
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electronic resource
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xix, 219 p. : ill.
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Note
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Ph.D.
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Includes bibliographical references
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Includes vita
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(type = statement of responsibility)
by Fang Fang
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Fang
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Fang
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1971-
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Fang Fang
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LIN
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YONG
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chair
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YONG LIN
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Shih
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Weichung Joe
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Weichung Joe Shih
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Lu
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Shou-En
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Shou-En Lu
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Lan
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K.K. Gordon
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K.K. Gordon Lan
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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school
OriginInfo
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2010
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2010-10
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xx
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier
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doi:10.7282/T3PV6K41
Genre
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ETD doctoral
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Rights
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder
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(type = personal)
Name
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Fang
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Fang
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DateTime
2010-09-20 10:42:01
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Fang Fang
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Rutgers University. Graduate School - New Brunswick
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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DateTime
2010-10-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 30th, 2012.
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