Introduction to Statistical Methods for Clinical Trials C0005_FM.indd 1 10/17/07 9:36:34 AM CHAPMAN & HALL/CRC Texts in Statistical Science Series Series Editors Bradley P. Carlin, University of Minnesota, USA Julian J. Faraway, University of Bath, UK Martin Tanner, Northwestern University, USA Jim Zidek, University of British Columbia, Canada Analysis of Failure and Survival Data Elements of Simulation P. Morgan The Analysis and Interpretation of Epidemiology — Study Design and Multivariate Data for Social Scientists Data Analysis, Second Edition D.
Galbraith Essential Statistics, Fourth Edition The Analysis of Time Series — D. Rees An Introduction, Sixth Edition Extending the Linear Model with R: C. Chatfield Generalized Linear, Mixed Effects and Applied Bayesian Forecasting and Time Series Nonparametric Regression Models Analysis J. Harrison A First Course in Linear Model Theory Applied Nonparametric Statistical Methods, N.
Dey Fourth Edition Generalized Additive Models: P. Smeeton An Introduction with R Applied Statistics — Handbook of GENSTAT S. Wood Analysis Interpreting Data — A First Course E. Simpson in Statistics Applied Statistics — Principles and Examples A.
Snell An Introduction to Generalized Bayes and Empirical Bayes Methods for Data Linear Models, Second Edition Analysis, Second Edition A. Louis Introduction to Multivariate Analysis Bayesian Data Analysis, Second Edition C. Stern Introduction to Optimization Methods and and D. Rubin Their Applications in Statistics B.
Everitt Beyond ANOVA — Basics of Applied Statistics Introduction to Randomized Controlled R. Clinical Trials, Second Edition J. Matthews Computer-Aided Multivariate Analysis, Fourth Edition Introduction to Statistical Methods for A. Clark Clinical Trials Thomas D.
Cook and David L. DeMets A Course in Categorical Data Analysis T. Leonard Large Sample Methods in Statistics P. da Motta Singer A Course in Large Sample Theory T.
Ferguson Linear Models with R J. Faraway Data Driven Statistical Methods P. Sprent Markov Chain Monte Carlo — Stochastic Simulation for Bayesian Inference, Second Edition Decision Analysis — A Bayesian Approach D. Smith Mathematical Statistics Elementary Applications of Probability K.
Knight Theory, Second Edition H. Tuckwell Modeling and Analysis of Stochastic Systems V.indd 2 10/17/07 9:36:35 AM Modelling Binary Data, Second Edition Statistical Methods for Spatial Data Analysis D. Gotway Modelling Survival Data in Medical Research, Statistical Methods for SPC and TQM Second Edition D. Collett Statistical Methods in Agriculture and Multivariate Analysis of Variance and Repeated Experimental Biology, Second Edition Measures — A Practical Approach for R.
Hasted Behavioural Scientists Statistical Process Control — Theory D. Taylor and Practice, Third Edition Multivariate Statistics — A Practical Approach G. Riedwyl Statistical Theory, Fourth Edition Practical Data Analysis for Designed B. Lindgren Experiments Statistics for Accountants B.
Letchford Practical Longitudinal Data Analysis Statistics for Epidemiology D. Jewell Practical Statistics for Medical Research Statistics for Technology — A Course in D. Altman Applied Statistics, Third Edition Probability — Methods and Measurement C. O’Hagan Statistics in Engineering — Problem Solving — A Statistician’s Guide, A Practical Approach Second Edition A.
Chatfield Statistics in Research and Development, Randomization, Bootstrap and Second Edition Monte Carlo Methods in Biology, R. Caulcutt Third Edition Survival Analysis Using S —Analysis of B. Manly Time-to-Event Data Readings in Decision Analysis M. French Time Series Analysis Sampling Methodologies with Applications Henrik Madsen P.
Rao The Theory of Linear Models Statistical Analysis of Reliability Data B.indd 3 10/17/07 9:36:35 AM C0005_FM.indd 4 10/17/07 9:36:35 AM Texts in Statistical Science Introduction to Statistical Methods for Clinical Trials Edited by Thomas D. DeMets Boca Raton London New York Chapman & Hall/CRC is an imprint of the Taylor & Francis Group, an informa business C0005_FM.indd 5 10/17/07 9:36:35 AM CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2008 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U. Government works Version Date: 20110713 International Standard Book Number-13: 978-1-4200-0996-5 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use.
The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.com (http://www.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.com and the CRC Press Web site at http://www.com Contents List of figures xi List of tables xv Preface xix Author Attribution xxiii 1 Introduction to Clinical Trials 1 1.1 History and Background 3 1.2 Ethics of Clinical Research 5 1.3 Types of Research Design and Types of Trials 9 1.4 The Need for Clinical Trials 15 1.5 The Randomization Principle 18 1.6 Timing of a Clinical Trial 18 1.8 Protocol and Manual of Operations 22 1.10 Overview of the Book 26 2 Defining the Question 29 2.2 Elements of Study Question 40 2.3 Outcome or Response Measures 44 2.4 The Surrogate Outcome 56 2.7 Problems 73 3 Study Design 75 3.1 Early Phase Trials 76 3.2 Phase III/IV Trials 85 3.3 Non-inferiority Designs 101 3.4 Screening, Prevention, and Therapeutic Designs 106 3.6 Conclusions 112 vii viii CONTENTS 3.7 Problems 112 4 Sample Size 115 4.1 Sample Size versus Information 116 4.2 A General Setup for Frequentist Designs 118 4.3 Loss to Follow-up and Non-adherence 122 4.6 Tests for Interaction 136 4.7 Equivalence/Non-inferiority Trials 137 4.1 The Role of Randomization 141 5.2 Fixed Randomization Procedures 148 5.3 Treatment- and Response-Adaptive Randomization Procedures 155 5.4 Covariate-Adaptive Randomization Procedures 161 5.5 Summary and Recommendations 165 5.6 Problems 168 6 Data Collection and Quality Control 171 6.1 Planning for Collection of Clinical Trial Data 172 6.2 Categories of Clinical Data 185 6.3 Data Quality Control 194 6.4 Conclusions 199 7 Survival Analysis 201 7.2 Estimation of Survival Distributions 203 7.3 Comparison of Survival Distributions 213 7.7 Problems 229 8 Longitudinal Data 231 8.1 A Clinical Longitudinal Data Example 232 8.2 The Subject-specific Model 234 8.3 Two-stage Estimation 237 8.4 The Random-effects, Subject-specific Model 242 8.5 The Population-average (Marginal) Model 246 8.6 Restricted Maximum Likelihood Estimation (REML) 252 8.8 Testing 255 CONTENTS ix 8.9 Additional Levels of Clustering 258 8.10 Generalized Estimating Equations for Non-normal Data 260 8.12 Summary 264 9 Quality of Life 267 9.2 Types of QoL Assessments 268 9.3 Selecting a QoL Instrument 271 9.4 Developing a QoL Instrument 273 9.5 Quality of Life Data 273 9.6 Analysis of QoL Data 275 9.7 Summary 286 10 Data Monitoring and Interim Analysis 289 10.1 Data and Safety Monitoring 290 10.3 The Repeated Testing Problem 293 10.4 Group Sequential Tests 299 10.7 Inference Following Sequential Tests 322 10.9 Problems 336 11 Selected Issues in the Analysis 339 11.1 Bias in the Analysis of Clinical Trial Data 339 11.2 Choice of Analysis Population 340 11.5 Multiple Testing Procedures 370 11.7 Problems 376 12 Closeout and Reporting 377 12.1 Closing Out a Trial 377 12.2 Reporting Trial Results 378 12.3 Problems 392 A Delta Method, Maximum Likelihood Theory, and Informa- tion 393 A.2 Asymptotic Theory for Likelihood Based Inference 393 A.4 Computing the MLE 399 x CONTENTS A.6 Brownian Motion 403 References 405 Index 427 List of figures 1.1 The research triangle.3 Industry-modified NIH model.1 Populations for which clinical trial inference is conducted.2 Normal probability plot of change in LDL in TNT.3 Causal pathway diagram for valid surrogate outcome.4 Reasons for failure of surrogate endpoints.5 Cumulative all-cause mortality in NOTT.1 Schematic of phase I trial.2 Example schematic of a phase II trial.3 All-cause mortality in PRAISE I and PRAISE II.4 Cancer and heart disease deaths.5 Parallel group design.6 Run-in design.8 Two-period crossover design.9 Balanced 2 × 2 factorial design.10 Non-inferiority design.1 Fundamental principle underlying sample size calculations.2 Grapical representation of equation (4.1 Population sampling models.2 Randomization distribution of the mean in one treatment group of size five randomly drawn observations.3 Diagram of a simple example of stratification.1 Sample CRF page header.2 Examples of different types of coded fields.1 Estimated survival from data in Example 7.2 Cumulative mortality from BHAT.1 Longitudinal data for which equation (8.1) does not hold. 234 xi xii LIST OF FIGURES 8.2 Ramus height of 3 boys measured at 8, 8.5 years of age.3 Ramus height of 3 boys.4 Ramus height of all 20 boys.5 Marginal and conditional residuals.6 Ramus height data, random effects fitted coefficients β̂ + b̂i .7 Ramus height data, standardized conditional residuals.8 Ramus height data and fitted curves for conditional indepen- dence model.9 Ramus height data and fitted curves for general conditional correlation model.10 Bone density measured at 10 or 11 times per subject.1 Minnesota Living with Heart Failure Questionnaire (MLHF).2 Profile plots of individual subjects’ global MLHF scores from the VesT trial.3 Profile plots of means of the global MLHF scores in VesT.4 Path diagram for measurement model for MLHF instrument.5 Partitioned survival curve for Q-TWiST.6 Threshold utility analysis.1 Pocock and O’Brien-Fleming boundaries with α = 0.2 Emerson and Fleming boundary with early stopping in favor of H0 .3 Group sequential monitoring in BHAT.4 Cumulative probabilities of rejecting H0 for Pocock and O’Brien-Fleming tests.5 Pocock and O’Brien-Fleming type alpha spending functions with α = 0.6 Stopping boundaries for continuous monitoring based on the triangular test.7 Triangular test with “Christmas tree” adjustment.8 Triangular test in MADIT.9 Conditional power computed using B-value in Example 10.10 Conditional power boundaries for O’Brien-Fleming boundary.11 Bias in maximum likelihood estimates following sequential testing.12 Comparison of (one-sided) monitoring boundaries.1 Cumulative survival rates for intention to treat analysis in the VA CABG study.2 Cumulative survival rates for “Treatment Received” and “Adherers Only” in the VA CABG study.3 Sensitivity analysis for hypothetical result from Table 11. 359 LIST OF FIGURES xiii 12.1 CONSORT diagram from MERIT-HF study report.2 Composite outcome figure from MERIT-HF study report.3 Subgroup analyses figure from MERIT-HF study report.1 Graphical illustration of likelihood ratio test.2 Illustrations showing Wald and score tests as quadratic approximations to the likelihood ratio test.3 A sample Brownian motion path.
404 List of tables 1.1 Nuremberg Code principles.2 Principles established in the Belmont Report.3 Eight basic elements of informed consent.4 Types of research.6 Clinical trial phases.8 ICH7 efficacy guidance documents.1 Baseline and three-month LDL levels in TNT for subjects with values at both time points.2 Differences in three-month LDL levels in TNT as a function of baseline LDL.3 Power for Wilcoxon and t-test for LDL change in TNT.4 Simple example of interaction between treatment, mortality, and a nonfatal outcome.5 Simple example of interaction between treatment, mortality, and a nonfatal outcome.6 Asymptotic variances for three approaches to the use of baseline values.7 Power for treatment difference in TNT using 6 different analyses.1 Probabilities corresponding to the regions in Figure 3.2 Sources of bias as a function of the control group.3 Possible bias in the estimation of treatment effects for published trials.4 Results related to the OPTIMAAL trial.1 Impact of non-adherence and loss to follow-up on required sample size.1 Probabilities of imbalance for complete randomization.1 CRF pages typical in cardiovascular studies and when they may be completed.