Practical considerations for optimal designs in clinical dose finding studies
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TLDR
Practical considerations for establishing efficient study designs to estimate relevant target doses are considered and optimal designs for estimating both the minimum effective dose and the dose achieving a certain percentage of the maximum treatment effect are considered.Abstract:
A key objective in the clinical development of a medicinal drug is the determination of an adequate dose level and, more broadly, the characterization of its dose response relationship. If the dose is set too high, safety and tolerability problems are likely to result, while selecting too low a dose makes it difficult to establish adequate efficacy in the confirmatory phase, possibly leading to a failed program. Hence, dose finding studies are of critical importance in drug development and need to be planned carefully. In this paper, we focus on practical considerations for establishing efficient study designs to estimate relevant target doses. We consider optimal designs for estimating both the minimum effective dose and the dose achieving a certain percentage of the maximum treatment effect. These designs are compared with D-optimal designs for a given dose response model. Extensions to robust designs accounting for model uncertainty are also discussed. A case study is used to motivate and illustrate the methods from this paper.read more
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Optimal designs for estimating the interesting part of a dose-effect curve
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Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).
Flora T. Musuamba,Efthymios Manolis,Nicholas H. G. Holford,S. Y. A. Cheung,Lena E. Friberg,Kayode Ogungbenro,Martin Posch,James W.T. Yates,Scott Berry,Neal Thomas,Solange Corriol-Rohou,Bjoern Bornkamp,Frank Bretz,Andrew C. Hooker,P H van der Graaf,Joseph F. Standing,Justin L. Hay,Susan Cole,Valeria Gigante,Kristin E. Karlsson,Thomas Dumortier,Norbert Benda,F. Serone,Shampa Das,A. Brochot,Falk Ehmann,Robert Hemmings,I. Skottheim Rusten +27 more
TL;DR: Some methodologies that could constitute a toolkit for drug developers and regulators were presented and the added value and limitations of these methods as well as challenges for their implementation are discussed.
References
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Book
Optimal Design of Experiments
TL;DR: Experimental designs in linear models Optimal designs for Scalar Parameter Systems Information Matrices Loewner Optimality Real Optimality Criteria Matrix Means The General Equivalence Theorem Optimal Moment Matrices and Optimal Designs D-, A-, E-, T-Optimality Admissibility of moment and information matrices Bayes Designs and Discrimination Designs Efficient Designs for Finite Sample Sizes Invariant Design Problems Kiefer Optimality Rotatability and Response Surface Designs Comments and References Biographies Bibliography Index as discussed by the authors
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