Clinical Trials: A Methodologic Perspective, 3rd Edition

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thumbnail image: Clinical Trials: A Methodologic Perspective, 3rd Edition

 

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.

The authors bases current revisions and updates on his own experience, classroom instruction, and feedback from teachers and medical and statistical professionals involved in clinical trials. The Third Edition greatly expands its coverage, ranging from statistical principles to new and provocative topics, including alternative medicine and ethics, middle development, comparative studies, and adaptive designs. At the same time, it offers more pragmatic advice for issues such as selecting outcomes, sample size, analysis, reporting, and handling allegations of misconduct. Readers familiar with the First and Second Editions will discover revamped exercise sets; an updated and extensive reference section; new material on endpoints and the developmental pipeline, among others; and revisions of numerous sections.

In addition, this book:

• Features accessible and broad coverage of statistical design methods—the crucial building blocks of clinical trials and medical research -- now complete with new chapters on overall development, middle development, comparative studies, and adaptive designs

• Teaches readers to design clinical trials that produce valid qualitative results backed by rigorous statistical methods

• Contains an introduction and summary in each chapter to reinforce key points

• Includes discussion questions to stimulate critical thinking and help readers understand how they can apply their newfound knowledge

• Provides extensive references to direct readers to the most recent literature, and there are numerous new or revised exercises throughout the book

Clinical Trials: A Methodologic Perspective, Third Edition is a textbook accessible to advanced undergraduate students in the quantitative sciences, graduate students in public health and the life sciences, physicians training in clinical research methods, and biostatisticians and epidemiologists.

This book is accompanied by downloadable files available below under the DOWNLOADS tab. 

These files include:

  • MATHEMATICA program – A set of downloadable files that tracks the chapters, containing code pertaining to each.
  • SAS PROGRAMS and DATA FILES used in the book.

The following software programs, included in the downloadables, were developed by the author, Steven Piantadosi, M.D., Ph.D:

  • RANDOMIZATION – This program generates treatment assignments for a clinical trial using blocked stratified randomization.
  • CRM – Implements the continual reassessment methods for dose finding clinical trials.
  • OPTIMAL – Calculates two-stage optimal phase II designs using the Simon method.
  • POWER – This is a power and sample size program for clinical trials. 

Executables for installing these programs can also be found at https://risccweb.csmc.edu/biostats/.

Steven Piantadosi, MD, PhD, is the Phase One Foundation Distinguished Chair and Director of the Samuel Oschin Cancer Institute, and Professor of Medicine at Cedars-Sinai Medical Center in Los Angeles, California. Dr. Piantadosi is one of the world’s leading experts in the design and analysis of clinical trials for cancer research. He has taught clinical trials methods extensively in formal courses and short venues. He has advised numerous academic programs and collaborations nationally regarding clinical trial design and conduct, and has served on external advisory boards for the National Institutes of Health and other prominent cancer programs and centers. The author of more than 260 peer-reviewed scientific articles, Dr. Piantadosi has published extensively on research results, clinical applications, and trial methodology. While his papers have contributed to many areas of oncology, he has also collaborated on diverse studies outside oncology including lung disease and degenerative neurological disease.

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

11.6 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

AppendixB Abbreviations 764

AppendixC Notation and Terminology 769

C.1 Introduction 769

C.2 Notation 769

C.2.1 Greek Letters 770

C.2.2 Roman Letters 771

C.2.3 Other Symbols 772

C.3 Terminology and Concepts 772

Appendix D Nuremberg Code 788

D.1 Permissible Medical Experiments 788

References 790

Index 871 

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