Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio

by Mark Chang

Overview

This book introduces pharmaceutical statisticians, scientists, researchers, and others to ExpDesign Studio software for classical and adaptive designs of clinical trials. It includes the Professional Version 5.0 of ExpDesign Studio software that frees pharmaceutical professionals to focus on drug development and related challenges while the software handles the essential calculations and computations. After a hands-on introduction to the software and an overview of clinical trial designs encompassing numerous variations, Classical and Adaptive Clinical Trial Designs Using ExpDesign Studio: Covers both classical and adaptive clinical trial designs, monitoring, and analyses, Explains various classical and adaptive designs including group sequential, sample-size reestimation, dropping-loser, biomarker-adaptive, and response-adaptive randomization designs, Includes instructions for over 100 design methods that have been implemented in ExpDesign Studio and step-by-step demos as well as real-world examples, Emphasizes applications, yet covers key mathematical formulations, Introduces readers to additional toolkits in ExpDesign Studio that help in designing, monitoring, and analyzing trials, such as the adaptive monitor, graphical calculator, the probability calculator, the confidence interval calculator, and more, Presents comprehensive technique notes for sample-size calculation methods, grouped by the number of arms, the trial endpoint, and the analysis basis. Written with practitioners in mind, this is an ideal self-study guide for not only statisticians, but also scientists, researchers, and professionals in the pharmaceutical industry, contract research organizations (CROs), andregulatory bodies. It's also a go-to reference for biostatisticians, pharmacokinetic specialists, and principal investigators involved in clinical trials.

About the Author:
Mark Chang, PhD, is a Scientific Fellow at Millennium Pharmaceuticals. He has extensive experience with IND and NDA submissions. His involvement in drug development includes both strategic and methodological aspects. Dr. Chang is an Associate Editor for the Journal of Biopharmaceutical Statistics

Product Details

ISBN-13:	9780470438565
Publisher:	Wiley
Publication date:	06/15/2010
Sold by:	JOHN WILEY & SONS
Format:	eBook
Pages:	280
File size:	25 MB
Note:	This product may take a few minutes to download.

About the Author

Mark Chang, PHD, is a Scientific Fellow at Millennium Pharmaceuticals. He has extensive experience with IND and NDA submissions. His involvement in drug development includes both strategic and methodological aspects. Dr. Chang is an Associate Editor for the Journal of Biopharmaceutical Statistics.

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Table of Contents

Preface     xiii
Self-Study and Practice Guide     xvii
ExpDesign Studio     1
Introduction     1
How to Design a Trial Using ExpDesign Studio     3
How to Design a Classical Trial     4
How to Design a Group Sequential Trial     4
How to Design an Adaptive Trial     5
How to Run Adaptive Trial Simulations     7
How to Design a Multistage Trial     9
How to Design a Dose-Escalation Trial     10
ExpDesign Menus     11
Clinical Trial Design     14
Introduction     14
Classical Clinical Trial Design     14
Substantial Evidence     15
Clinical Trial Endpoint     15
Confirmatory Trials     15
Exploratory Trials     16
Multicenter Trials     16
Trials to Show Superiority     16
Trials to Show Equivalence or Noninferiority     16
Trials to Show a Dose-Response Relationship     17
Parallel Design     17
Crossover Design     17
Factorial Design     18
Selection of a Trial Design     18
Balanced Versus Unbalanced Designs     18
Crossover Versus Parallel Designs     19
Dose Escalation Versus Titration Designs     21
Bioavailability Versus Bioequivalence Designs     21
Equivalence Versus Bioequivalence     22
Sample-Size Determination     23
Adaptive Clinical Trial Design     23
Group Sequential Design     24
Sample-Size Reestimation Design     25
Drop-Loser Design     25
Response-Adaptive Randomization Design     25
Adaptive Dose-Escalation Design     26
Biomarker-Adaptive Design     26
Multistage Design of Single-Arm Trials     26
Classical Trial Design     27
Introduction     27
Hypothesis Test     27
Importance of Sample-Size Calculation     28
Factors Affecting Sample Size     29
Avoiding Under- or Overpowered Designs     29
How to Calculate Sample Size Using ExpDesign     30
Testing the Mean Difference Between Two Groups     30
Testing the Proportion Difference Between Two Groups     30
Testing the Survival Difference Between Two Groups     31
Testing the Survival Difference with a Follow-up Period     32
Exact Test for a One-Sample Proportion      33
McNemar's Test for Paired Data     35
Noninferiority Test for Two Means     35
Bioequivalence Test for Two Means     36
Bioequivalence Test for Two Means of Lognormal Data     37
Equivalence Test Based on the Ratio of Two Means     38
Precision Method for the Mean Difference for a Paired Sample     39
Mantel-Haenszel Test for an Odds Ratio with Two Strata     39
Pearson's Chi-Square Test for Rate Difference     41
One-Way ANOVA for Parallel Groups     41
Dose-Response Trial for a Myocardial Infarction     42
Mathematical Notes on Classical Design     43
Large-Sample-Size Calculation for Classical Design     43
Commonly Used Terms and Their Mathematical Expressions     45
Relationship Between Enrollment Rate and Number of Events     48
Group Sequential Trial Design     51
Introduction     51
Basics of Group Sequential Design     51
How to Design Sequential Trials Using ExpDesign     53
Design Featuring Early Efficacy Stopping for Two Means     54
Design Featuring Early Futility Stopping for a Proportion     56
Design Featuring Early Stopping for a Survival Endpoint     58
Design Featuring Early Stopping for Paired Proportions     60
How to Monitor a Group Sequential Trial Using ExpDesign     62
Need for Trial Monitoring     62
Techniques for Monitoring a Sequential Trial     63
How to Monitor a Trial Using ExpDesign     64
Mathematical Notes on Sequential Trial Design     68
Unified Formulation for Sequential Trial Design     68
Calculation of Conditional Probability     72
Conditional and Predictive Power and RCI for Trial Monitoring     73
Bias-Adjusted Estimates     74
Adaptive Trial Design     75
Introduction     75
Basics of Adaptive Design Methods     75
How To Design a Sample-Size Reestimation Trial Using ExpDesign     77
Sample-Size Adjustment Based on the Effect-Size Ratio     78
Sample-Size Adjustment Based on Conditional Power     78
Adaptive Design for an Acute Ischemic Stroke Trial     78
Adaptive Design for an Asthma Study     81
Adaptive Design for an Oncology Trial     84
Noninferiority Design with a Binary Endpoint     86
How to Design a Drop-Loser Trial Using ExpDesign     90
Drop-Loser Mechanism     90
Seamless Design of an Asthma Trial      90
How to Design a Trial Using a Classifier Biomarker     93
Biomarker Classifications     93
Biomarker-Adaptive Design     94
How to Design a Play-the-Winner Trial Using ExpDesign     95
Randomized Play-the-Winner Design     96
Adaptive Randomization with a Normal Endpoint     98
Adaptive Trial Monitoring     103
Introduction     103
Error-Spending Approach     103
How to Recalculate Stopping Boundaries Using ExpDesign     105
Conditional Power and the Futility Index     109
How to Reestimate Sample Size Using ExpDesign     112
Calculating Conditional Power Using ExpDesign     112
Reestimating Sample Size Using ExpDesign     113
Trial Examples     114
Changes in Number and Timing of the Analyses     114
Recursive Two-Stage Adaptive Design     119
Conditional Power and Sample-Size Reestimation     119
Oncology Adaptive Trial Design     123
Multistage Trial Design     123
Introduction     123
How to Design a Multistage Design Using ExpDesign     124
Dose-Escalation Trial Design     129
Introduction     129
Bayesian Continual Reassessment Method     134
How to Design a Dose-Escalation Trial Using ExpDesign     135
Dose-Escalation Trial Monitoring Using CRM     141
Mathematical Notes on Multistage Design     143
Decision Tree for a Multistage Trial     143
Two-Stage Design     144
Three-Stage Design     145
Mathematical Notes on the CRM     146
Probability Model for Dose-Response     146
Prior Distribution of a Parameter     147
Likelihood Function     147
Reassessment of a Parameter     147
Assignment of the Next Patient     147
Adaptive Trial Simulator     149
Adjusting the Critical Region Method     149
Classical Design with Two Parallel Treatment Groups     151
Flexible Design with Sample-Size Reestimation     157
Design with Random-Play-the-Winner Randomization     160
Group Sequential Design with One Interim Analysis     161
Design Permitting Early Stopping and Sample-Size Reestimation     162
Classical Design with Multiple Treatment Groups     165
Multigroup Trial with Response-Adaptive Randomization     165
Adaptive Design Featuring Dropping Losers     166
Dose-Response Trial Design     168
Dose-Escalation Design for an Oncology Trial     168
Further Assistance from ExpDesign Studio     172
ExpDesign Probability Functions     172
Virtual Trial Data Generation Using ExpDesign Randomizor     177
Random Number Generation Using ExpDesign     177
How to Generate a Random Univariate Using ExpDesign     177
How to Generate a Random Multivariate Using ExpDesign     179
How to Generate a Random Multibinomial Using ExpDesign     181
ExpDesign Toolkits     182
Graphic Calculator     183
Statistical Calculator     185
Confidence Interval Calculator     185
Classical Design Method Reference     187
Single-Group Design     187
One/Paired-Sample Hypothesis Test for the Mean     187
One/Paired-Sample Hypothesis Test for the Proportion     189
One/Paired-Sample Hypothesis Test for Others     190
Paired-Sample Equivalence Test for the Mean     192
Paired-Sample Equivalence Test for the Proportion     193
One-Sample Confidence Interval for the Mean     193
One-Sample Confidence Interval for the Proportion     195
One-Sample Confidence Interval for Others      196
Two-Group Design     196
Two-Sample Hypothesis Test for the Mean     196
Two-Sample Hypothesis Test for the Proportion     199
Two-Sample Hypothesis Test for Others     202
Two-Sample Equivalence/Noninferiority Test for the Mean     205
Two-Sample Equivalence/Noninferiority Test for the Proportion     207
Two-Sample Equivalence/Noninferiority Test for Survival     207
Two-Sample Confidence Interval for the Mean     208
Two-Sample Confidence Interval for the Proportion     208
Multigroup Trial Design     209
Multisample Hypothesis Test for the Mean     209
Multisample Hypothesis Test for the Proportion     211
Multisample Hypothesis Test for Others     212
Multisample Confidence Interval for Others     213
Afterword     214
Validation of ExpDesign Studio     215
Validation Process for ExpDesign Studio     216
Algorithm Validation     216
Statistical Outcome Validation     216
Criteria for Passing Validation     217
Input and GUI Validation     217
Validation of the Classical Design Module     217
Validation of the Group Sequential Design Module     221
Stopping Boundary and Type I Error Rate Validation     221
Power and Sample-Size Validation     221
Validation of the Adaptive Design Module     224
Stopping Boundary and Type I Error Rate Validation     224
Validation of Adaptive Design Monitoring     226
Validation of the Multistage Design Module     226
Validation of the Traditional Dose-Escalation Design Module     228
Validation of the Traditional Escalation Rule     228
Validation of the Bayesian Continual Reassessment Method     228
Validation of the Trial Simulation Module     228
Validation of the Randomizor     228
Validation of the ExpDesign Toolkits     229
Computer Programs for Validations     231
SAS Macro for Three-Stage Design Validation     231
Traditional 3 + 3 Escalation Design Validation     232
SAS Program for CRM Validation     232
Sample-Size Calculation Methods: Classical Design     235
References     240
Index     251
System Requirements, Software Installation, and Software License Agreement     259

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“This book has been selected for The First Clinical Research Bookshelf. Essential reading for clinical research professionals” (Journal of Clinical Research Best Practices, June 2009)

Editorial Reviews

This book has been selected for The First Clinical Research Bookshelf. Essential reading for clinical research professionals” (Journal of Clinical Research Best Practices, June 2009)

From the Publisher