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Informationen zum Autor A. Lawrence Gould, Senior Director, Scientific Staff, Merck Research Laboratories, USA. Klappentext This book gives professionals in clinical research valuable information on the challenging issues of the design, execution, and management of clinical trials, and how to resolve these issues effectively. It also provides understanding and practical guidance on the application of contemporary statistical methods to contemporary issues in safety evaluation during medical product development. Each chapter provides sufficient detail to the reader to undertake the design and analysis of experiments at various stages of product development, including comprehensive references to the relevant literature.* Provides a guide to statistical methods and application in medical product development* Assists readers in undertaking design and analysis of experiments at various stages of product development* Features case studies throughout the book, as well as, SAS and R code Zusammenfassung This book gives professionals in clinical research valuable information on the challenging issues of the design, execution, and management of clinical trials, and how to resolve these issues effectively. Inhaltsverzeichnis Preface xiii List of Contributors xv 1 Introduction 1 A. Lawrence Gould 1.1 Introduction 1 1.2 Background and context 2 1.3 A fundamental principle for understanding safety evaluation 3 1.4 Stages of safety evaluation in drug development 4 1.5 National medical product safety monitoring strategy 5 1.6 Adverse events vs adverse drug reactions, and an overall view of safety evaluation 5 1.7 A brief historical perspective on safety evaluation 7 1.8 International conference on harmonization 8 1.9 ICH guidelines 9 References 11 2 Safety graphics 22 A. Lawrence Gould 2.1 Introduction 22 2.1.1 Example and general objectives 22 2.1.2 What is the graphic trying to say? 25 2.2 Principles and guidance for constructing effective graphics 26 2.2.1 General principles 26 2.3 Graphical displays for addressing specific issues 26 2.3.1 Frequency of adverse event reports or occurrences 26 2.3.2 Timing of adverse event reports or occurrences 33 2.3.3 Temporal variation of vital sign and laboratory measurements 36 2.3.4 Temporal variation of combinations of vital sign and laboratory measurements 39 2.3.5 Functional/multidimensional data 44 2.3.6 Multivariate outlier detection with multiplicity adjustment based on robust estimates of mean and covariance matrix 48 2.3.7 Monitoring individual patient trends 53 2.4 Discussion 53 References 60 3 QSAR modeling: prediction of biological activity from chemical structure 66 Andy Liaw and Vladimir Svetnik 3.1 Introduction 66 3.2 Data 67 3.2.1 Chemical descriptors 67 3.2.2 Activity data 68 3.3 Model building 69 3.3.1 Random forests 69 3.3.2 Stochastic gradient boosting 70 3.4 Model validation and interpretation 71 3.5 Data example 74 3.6 Discussion 76 References 81 4 Ethical and practical issues in phase 1 trials in healthy volunteers 84 Stephen Senn 4.1 Introduction 84 4.2 Ethical basics 85 4.3 Inferential matters 86 4.3.1 Analysis of serious side-effects 87 4.3.2 Timing of events 87 4.4 Design for subject safety 88 4.4.1 Dosing interval 88 4.4.2 Contemporary dosing 88 4.5 Analysis 89 4.5.1 Objectives of first-in-man trials 89 4.5.2 (In)adequacy of statistical analysis plans 89 4.5.3 'Formal' statistical analyses 90 4.6 Design for analysis 90 4.6.1 Treatment assignments and the role of placebo 90
