John O'Quigley - Böcker

Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials gives a thorough presentation of state-of-the-art methods for early phase clinical trials. The methodology of clinical trials has advanced greatly over the last 20 years and, arguably, nowhere greater than that of early phase studies. The need to accelerate drug development in a rapidly evolving context of targeted therapies, immunotherapy, combination treatments and complex group structures has provided the stimulus to these advances. Typically, we deal with very small samples, sequential methods that need to be efficient, while, at the same time adhering to ethical principles due to the involvement of human subjects.Statistical inference is difficult since the standard techniques of maximum likelihood do not usually apply as a result of model misspecification and parameter estimates lying on the boundary of the parameter space. Bayesian methods play an important part in overcoming these difficulties, but nonetheless, require special consideration in this particular context. The purpose of this handbook is to provide an expanded summary of the field as it stands and also, through discussion, provide insights into the thinking of leaders in the field as to the potential developments of the years ahead. With this goal in mind we present: An introduction to the field for graduate students and novices A basis for more established researchers from which to build A collection of material for an advanced course in early phase clinical trials A comprehensive guide to available methodology for practicing statisticians on the design and analysis of dose-finding experiments An extensive guide for the multiple comparison and modeling (MCP-Mod) dose-finding approach, adaptive two-stage designs for dose finding, as well as dose–time–response models and multiple testing in the context of confirmatory dose-finding studies. John O’Quigley is a professor of mathematics and research director at the French National Institute for Health and Medical Research based at the Faculty of Mathematics, University Pierre and Marie Curie in Paris, France. He is author of Proportional Hazards Regression and has published extensively in the field of dose finding. Alexia Iasonos is an associate attending biostatistician at the Memorial Sloan Kettering Cancer Center in New York. She has over one hundred publications in the leading statistical and clinical journals on the methodology and design of early phase clinical trials. Dr. Iasonos has wide experience in the actual implementation of model based early phase trials and has given courses in scientific meetings internationally.Björn Bornkamp is a statistical methodologist at Novartis in Basel, Switzerland, researching and implementing dose-finding designs in Phase II clinical trials. He is one of the co-developers of the MCP-Mod methodology for dose finding and main author of the DoseFinding R package. He has published numerous papers on dose finding, nonlinear models and Bayesian statistics, and in 2013 won the Royal Statistical Society award for statistical excellence in the pharmaceutical industry.

Proportional hazards models and their extensions (models with ti- dependent covariates, models with time dependent regression co- cients, models with random coe?cients and any mixture of these) can be used to characterize just about any applied problem to which the techniques of survival analysis are appropriate. This simple obser- tion enables us to ?nd an elegant statistical expression for all plausible practical situations arising in the analysis of survival data. We have a single unifying framework. In consequence, a solid understanding of the framework itself o?ers the statistician the ability to tackle the thorniestofquestionswhichmayarisewhendealingwithsurvivaldata. The main goal of this text is not to present or review the very s- stantial amount of research that has been carried out on proportional hazards and related models. Rather, the goal is to consider the many questions which are of interest in a regression analysis of survival data (prediction, goodness of ?t, model construction, inference and int- pretation in the presence of misspeci?ed models) from the standpoint of the proportional hazards and the non-proportional hazards models.

Proportional hazards models and their extensions (models with ti- dependent covariates, models with time dependent regression co- cients, models with random coe?cients and any mixture of these) can be used to characterize just about any applied problem to which the techniques of survival analysis are appropriate. This simple obser- tion enables us to ?nd an elegant statistical expression for all plausible practical situations arising in the analysis of survival data. We have a single unifying framework. In consequence, a solid understanding of the framework itself o?ers the statistician the ability to tackle the thorniestofquestionswhichmayarisewhendealingwithsurvivaldata. The main goal of this text is not to present or review the very s- stantial amount of research that has been carried out on proportional hazards and related models. Rather, the goal is to consider the many questions which are of interest in a regression analysis of survival data (prediction, goodness of ?t, model construction, inference and int- pretation in the presence of misspeci?ed models) from the standpoint of the proportional hazards and the non-proportional hazards models.

Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials gives a thorough presentation of state-of-the-art methods for early phase clinical trials. The methodology of clinical trials has advanced greatly over the last 20 years and, arguably, nowhere greater than that of early phase studies. The need to accelerate drug development in a rapidly evolving context of targeted therapies, immunotherapy, combination treatments and complex group structures has provided the stimulus to these advances. Typically, we deal with very small samples, sequential methods that need to be efficient, while, at the same time adhering to ethical principles due to the involvement of human subjects.Statistical inference is difficult since the standard techniques of maximum likelihood do not usually apply as a result of model misspecification and parameter estimates lying on the boundary of the parameter space. Bayesian methods play an important part in overcoming these difficulties, but nonetheless, require special consideration in this particular context. The purpose of this handbook is to provide an expanded summary of the field as it stands and also, through discussion, provide insights into the thinking of leaders in the field as to the potential developments of the years ahead. With this goal in mind we present: An introduction to the field for graduate students and novices A basis for more established researchers from which to build A collection of material for an advanced course in early phase clinical trials A comprehensive guide to available methodology for practicing statisticians on the design and analysis of dose-finding experiments An extensive guide for the multiple comparison and modeling (MCP-Mod) dose-finding approach, adaptive two-stage designs for dose finding, as well as dose–time–response models and multiple testing in the context of confirmatory dose-finding studies. John O’Quigley is a professor of mathematics and research director at the French National Institute for Health and Medical Research based at the Faculty of Mathematics, University Pierre and Marie Curie in Paris, France. He is author of Proportional Hazards Regression and has published extensively in the field of dose finding. Alexia Iasonos is an associate attending biostatistician at the Memorial Sloan Kettering Cancer Center in New York. She has over one hundred publications in the leading statistical and clinical journals on the methodology and design of early phase clinical trials. Dr. Iasonos has wide experience in the actual implementation of model based early phase trials and has given courses in scientific meetings internationally.Björn Bornkamp is a statistical methodologist at Novartis in Basel, Switzerland, researching and implementing dose-finding designs in Phase II clinical trials. He is one of the co-developers of the MCP-Mod methodology for dose finding and main author of the DoseFinding R package. He has published numerous papers on dose finding, nonlinear models and Bayesian statistics, and in 2013 won the Royal Statistical Society award for statistical excellence in the pharmaceutical industry.

This book provides an extensive coverage of the methodology of survival analysis, ranging from introductory level material to deeper more advanced topics.