ISBN: 978-1-118-95922-0 October 2017 928 Pages
Presents elements of clinical trial methods that are essential in planning, designing, conducting, analyzing, and interpreting clinical trials with the goal of improving the evidence derived from these important studies
This Third Edition builds on the text’s reputation as a straightforward, detailed, and authoritative presentation of quantitative methods for clinical trials. Readers will encounter the principles of design for various types of clinical trials, and are then skillfully guided through the complete process of planning the experiment, assembling a study cohort, assessing data, and reporting results. Throughout the process, the author alerts readers to problems that may arise during the course of the trial and provides common sense solutions. All stages of therapeutic development are discussed in detail, and the methods are not restricted to a single clinical application area.
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Preface to the Third Edition xxv About the Companion Website xxviii 1 Preliminaries 1 1.1 Introduction 1 1.2 Audiences 2 1.3 Scope 3 1.4 Other Sources of Knowledge 5 1.5 Notation and Terminology 6 1.6 Examples, Data, and Programs 9 1.7 Summary 9 2 Clinical Trials as Research 10 2.1 Introduction 10 2.2 Research 13 2.3 Defining Clinical Trials 19 2.4 Practicalities of Usage 29 2.5 Nonexperimental Designs 35 2.6 Summary 41 2.7 Questions for Discussion 41 3 Why Clinical Trials are Ethical 43 3.1 Introduction 43 3.2 Duality 47 3.3 Historically Derived Principles of Ethics 57 3.4 Contemporary Foundational Principles 65 3.5 Methodologic Reflections 72 3.6 Professional Conduct 79 3.7 Summary 85 3.8 Questions for Discussion 86 4 Contexts for Clinical Trials 87 4.1 Introduction 87 4.2 Drugs 91 4.3 Devices 95 4.4 Prevention 99 4.5 Complementary and Alternative Medicine 106 4.6 Surgery and Skill-Dependent Therapies 116 4.7 A Brief View of Some Other Contexts 130 4.8 Summary 135 4.9 Questions for Discussion 136 5 Measurement 137 5.1 Introduction 137 5.2 Objectives 140 5.3 Measurement Design 143 5.4 Surrogate Outcomes 162 5.5 Summary 170 5.6 Questions for Discussion 171 6 Random Error and Bias 172 6.1 Introduction 172 6.2 Clinical Bias 181 6.3 Statistical Bias 188 6.4 Summary 194 6.5 Questions for Discussion 194 7 Statistical Perspectives 196 7.1 Introduction 196 7.2 Differences in Statistical Perspectives 197 7.3 Frequentist 202 7.4 Bayesian 204 7.5 Likelihood 210 7.6 Statistics Issues 212 7.7 Summary 215 7.8 Questions for Discussion 216 8 Experiment Design in Clinical Trials 217 8.1 Introduction 217 8.2 Trials As Simple Experiment Designs 218 8.3 Goals of Experiment Design 223 8.4 Design Concepts 225 8.5 Design Features 230 8.6 Special Design Issues 237 8.7 Importance of the Protocol Document 244 8.8 Summary 252 8.9 Questions for Discussion 253 9 The Trial Cohort 254 9.1 Introduction 254 9.2 Cohort Definition and Selection 255 9.3 Modeling Accrual 264 9.4 Inclusiveness, Representation, and Interactions 267 9.5 Summary 275 9.6 Questions for Discussion 275 10 Development Paradigms 277 10.1 Introduction 277 10.2 Pipeline Principles and Problems 281 10.3 A Simple Quantitative Pipeline 286 10.4 Late Failures 292 10.5 Summary 300 10.6 Questions for Discussion 301 11 Translational Clinical Trials 302 11.1 Introduction 302 11.2 Inferential Paradigms 308 11.3 Evidence and Theory 312 11.4 Translational Trials Defined 313 11.5 Information From Translational Trials 317 11.5.6 Sample Size for Translational Trials 324 11.5.7 Validity 327 11.6 Summary 328 11.7 Questions for Discussion 328 12 Early Development and Dose-Finding 329 12.1 Introduction 329 12.2 Basic Concepts 330 12.3 Essential Concepts for Dose versus Risk 333 12.4 Dose-Ranging 338 12.5 Dose-Finding is Model Based 344 12.6 General Dose-Finding Issues 354 12.7 Summary 366 12.8 Questions for Discussion 368 13 Middle Development 370 13.1 Introduction 370 13.2 Characteristics of Middle Development 372 13.3 Design Issues 375 13.4 Middle Development Distills True Positives 379 13.5 Futility and Nonsuperiority Designs 381 13.6 Dose–Efficacy Questions 385 13.7 Randomized Comparisons 386 13.8 Cohort Mixtures 392 13.9 Summary 395 13.10 Questions for Discussion 396 14 Comparative Trials 397 14.1 Introduction 397 14.2 Elements of Reliability 398 14.3 Biomarker-Based Comparative Designs 402 14.4 Some Special Comparative Designs 408 14.5 Summary 411 14.6 Questions for Discussion 412 15 Adaptive Design Features 413 15.1 Introduction 413 15.2 Some Familiar Adaptations 418 15.3 Biomarker Adaptive Trials 423 15.4 Re-Designs 425 15.5 Seamless Designs 427 15.6 Barriers to the Use of AD 428 15.7 Adaptive Design Case Study 428 15.8 Summary 429 15.9 Questions for Discussion 429 16 Sample Size and Power 430 16.1 Introduction 430 16.2 Principles 431 16.3 Early Developmental Trials 436 16.4 Simple Estimation Designs 438 16.5 Event Rates 451 16.6 Staged Studies 455 16.7 Comparative Trials 457 16.8 Expanded Safety Trials 478 16.9 Other Considerations 481 16.10 Summary 489 16.11 Questions for Discussion 490 17 Treatment Allocation 492 17.1 Introduction 492 17.2 Randomization 494 17.3 Constrained Randomization 500 17.4 Adaptive Allocation 504 17.5 Other Issues Regarding Randomization 507 17.6 Unequal Treatment Allocation 514 17.7 Randomization Before Consent 519 17.8 Summary 520 17.9 Questions for Discussion 520 18 Treatment Effects Monitoring 522 18.1 Introduction 522 18.2 Administrative Issues in Trial Monitoring 527 18.3 Organizational Issues Related to Monitoring 537 18.4 Statistical Methods for Monitoring 545 18.5 Summary 570 18.6 Questions for Discussion 572 19 Counting Subjects and Events 573 19.1 Introduction 573 19.2 Imperfection and Validity 574 19.3 Treatment Nonadherence 575 19.4 Protocol Nonadherence 580 19.5 Data Imperfections 583 19.6 Summary 588 19.7 Questions for Discussion 589 20 Estimating Clinical Effects 590 20.1 Introduction 590 20.2 Dose-Finding and Pharmacokinetic Trials 594 20.3 Middle Development Studies 599 20.4 Randomized Comparative Trials 606 20.5 Problems With P-Values 616 20.6 Strength of Evidence Through Support Intervals 620 20.7 Special Methods of Analysis 622 20.8 Exploratory Analyses 628 20.9 Summary 639 20.10 Questions for Discussion 640 21 Prognostic Factor Analyses 644 21.1 Introduction 644 21.2 Model-Based Methods 647 21.3 Adjusted Analyses of Comparative Trials 661 21.4 PFAS Without Models 666 21.5 Summary 669 21.6 Questions for Discussion 669 22 Factorial Designs 671 22.1 Introduction 671 22.2 Characteristics of Factorial Designs 672 22.3 Treatment Interactions 675 22.4 Examples of Factorial Designs 680 22.5 Partial Fractional and Incomplete Factorials 682 22.6 Summary 683 22.7 Questions for Discussion 683 23 Crossover Designs 684 23.1 Introduction 684 23.2 Advantages and Disadvantages 686 23.3 Analysis 691 23.4 Classic Case Study 696 23.5 Summary 696 23.6 Questions for Discussion 697 24 Meta-Analyses 698 24.1 Introduction 698 24.2 A Sketch of Meta-Analysis Methods 700 24.3 Other Issues 705 24.4 Summary 707 24.5 Questions for Discussion 708 25 Reporting and Authorship 709 25.1 Introduction 709 25.2 General Issues in Reporting 710 25.3 Clinical Trial Reports 715 25.4 Authorship 726 25.5 Other Issues in Disseminating Results 731 25.6 Summary 732 25.7 Questions for Discussion 733 26 Misconduct and Fraud in Clinical Research 734 26.1 Introduction 734 26.2 Research Practices 741 26.3 Approach to Allegations of Misconduct 743 26.4 Characteristics of Some Misconduct Cases 747 26.5 Lessons 754 26.6 Clinical Investigators’ Responsibilities 757 26.7 Summary 759 26.8 Questions for Discussion 760 Appendix A Data and Programs 761 A.1 Introduction 761 A.2 Design Programs 761 A.3 Mathematica Code 763 Appendix B Abbreviations 764 Appendix C Notation and Terminology 769 C.1 Introduction 769 C.2 Notation 769 C.3 Terminology and Concepts 772 Appendix D Nuremberg Code 788 D.1 Permissible Medical Experiments 788 References 790 Index 871TABLE OF CONTENTS
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