Exposure-Response Based Trial Simulations to Assess Adaptive Designs in Phase II Clinical Trials

Speaker: Simon Zhou, Ph.D., Director of Clinical Pharmacology, Wyeth Research

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Adaptive design enables clinical trials to adapt to evolving information. It is more powerful and cost effective than traditional design based on formal hypothesis in defining dose response curve and identifying optimal dose in exploratory drug development aiming to learn about pharmacology. When multiple adaptive designs are plausible, clinical trial simulation is a powerful tool to evaluate and differentiate potential outcome of individual adaptive design. It can model complicated dynamic process to evaluate key assumptions in trial design and their impacts on trial outcome. Various types of clinical trial simulations may be conducted to visualize the dynamic trial process from patient recruitment, drug distribution, treatment administration to biomarker, PK/PD and clinical responses.

Integrated with cumulative knowledge of PK/PD and biomarkers, Exposure Response (ER) based trial simulation could assess the validity and robustness of efficacy and safety findings, anticipate problems, project trial outcome. In this presentation, advantages of exposure-response based trial simulations in dosing range phase II studies will be discussed via a case study. Incorporating prior exposure variability and PK/PD information, trial simulations were conducted to (1) evaluate potential adaptive designs via traditional statistical and exposure-response analysis; (2) determine sample size and associated power in demonstrating either utility or futility; (3) define decision criteria based on multiple endpoints; (4) evaluate the robustness of efficacy and safety signals at various stages of study.

Simon Zhou holds Bachelor and Master degrees in Chemistry, a Ph.D. in Pharmaceutics and a Graduate Certificate on Modeling of Complex System from the University of Michigan. Dr. Zhou is currently a director in the department of clinical pharmacology at Wyeth Research in Collegeville, PA. Prior to his current position, he has worked in preclinical and clinical drug development functions addressing biopharmaceutical and trial design issues at Pfizer and Bristol-Myers Squibb. He is experienced in kinetic/dynamic and statistical modeling and simulation to integrate and mine voluminous and complex data from clinical trials. He has published manuscripts in biopharmaceutics, drug delivery and pharmacokinetic and pharmacodynamic modeling.

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