Statistical Methods for Evaluating Safety in Medical Product - Developmen

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

List of contents

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
 
4.6.2 Dose-escalation trial design issues 91
 
4.6.3 Precision at interim stages 93
 
4.7 Some final thoughts 94
 
4.7.1 Sharing information 94
 
4.8 Conclusions 96
 
4.9 Further reading 96
 
References 97
 
5 Phase 1 trials 99
A. Lawrence Gould
 
5.1 Introduction 99
 
5.2 Dose determined by toxicity 101
 
5.2.1 Algorithmic (rule-based) approaches 101
 
5.3 Model-based approaches 104
 
5.3.1 Basic CRM design 104
 
5.3.2 Adaptive refinement of dosage list 105
 
5.3.3 Hybrid designs 106
 
5.3.4 Comparisons with rule-based designs 107
 
5.4 Model-based designs with more than one treatment (or non-monotonic toxicity) 108
 
5.5 Designs considering toxicity and efficacy 110
 
5.5.1 Binary efficacy and toxicity considered jointly 110
 
5.5.2 Use of surrogate efficacy outcomes 112
 

Product details

• Authors: A Gould, A Lawrence Gould, A. Lawrence Gould, A. Lawrence (Merch Research Laboratories) Gould
• Assisted by: A. Lawrence Gould (Editor), Gould A. Lawrence (Editor), Lawrence Gould (Editor), A Lawrence Gould (Editor)
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 06.02.2015
• EAN: 9781119979661
• ISBN: 978-1-119-97966-1
• No. of pages: 400
• Series: Statistics in Practice; Statistics in Practice
• Subjects: Guides > Health; Natural sciences, medicine, IT, technology > Mathematics; Statistik, Medizin, Pharmakologie, Statistics, Arzneimittelsicherheit, Biostatistik, Biostatistics, Pharmacology & Pharmaceutical Medicine, Pharmakologie u. Pharmazeutische Medizin, Medical Science, Pharmazeutische Medizin, Medical Statistics & Epidemiology, Medizinische Statistik u. Epidemiologie