Adaptive Dose-Response Studies
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.... Brenda Gaydos
Eli Lilly
Adaptive Dose-Response Studies
Michael Krams
Wyeth
Inna Perevazskaya Merck
Frank Bretz
Novar/is
Qing L1u
Johnson & Johnson
Paul Galla Novar/is
Dan Berry
M. D. Anderson Cancer
Insufficient exploration of the dose-response is a shortcoming of clinical drug development. andfailure to characterize dosing early is often cited as a key contributor to the high late-stage attrition rate currently faced by the industry. Adaptive methods, for example. make it feasible to design a proof-of-concept study as an adaptive dose-response trial. Efficient learning about the dose response earlier in development will ultimately reduce overall costs and provide
Center
better information on dose in the filing package. This article presents the Pharmaceutical Research and Manufacturers of America working group's main recommendations regarding adaptive dose-response studies. As background, traditional fixed and adaptive dose-response designs are briefly reviewed. Information ondeveloping a Bayesian adaptive dose design and some monitoring and processing issues are also discussed.
CI!flsty Chuang-Stein
Pfizer
JaS8 Pinheiro Novarlis
Alun Bedding
EliLilly
Key Words
Dose-response; Adaptive; Bayesian; Frequentist
Carresponde.ce Address Eli Lillyand Company. Lilly Corporate Center, Indianapolis. IN 46285.
INTRODUCTION Insufficient exploration of the dose-response is often a key shortcoming of clinical drug development. Initial proof-of-concept (PoC) studies often rely on testing just one dose level (eg, the maximum tolerated dose) without much information on which to base the decision, assuming "more is better" and hoping the "right" dose was selected. Adaptive designs (defined in Ref. 1) offer efficient ways to learn about the dose response and guide decision making on which dose to select for further development or whether to discontinue a program. It is both feasible and advantageous to design a PoC study as an adaptive dose-response trial. The continuation of a dose-response trial into a confirmatory stage in a seamless design is a further opportunity to increase information on the right dose earlier in development and reduce the total clinical development timeline: see Ref. 2. We envisage that efficient learning about the dose response earlier in development will reduce overall costs and provide better information on dose in the filing package. Our goals for the development of adaptive dose-response designs are to facilitate • more feasible approaches for gaining information on the dose-response profile earlier in development • increasing the probability of technical success by taking the correct choice of dose forward into
phase III and thereby reducing the late-stage attrition rate • reducing the clinical development timeline by stopping at the earliest possible time point for either futility or efficacy
This article paper primarily focuses on phase Ib and II study designs. using endpoints that support filing or are predictive of the filing endpoint. For example. a biomarker might be
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