Fundamentals of Clinical Trials / Edition 4

Fundamentals of Clinical Trials / Edition 4

by Lawrence M. Friedman, Curt D. Furberg, David DeMets

ISBN-10: 1441915850

ISBN-13: 9781441915856

Pub. Date: 09/21/2010

Publisher: Springer New York

This is the fourth edition of a very successful textbook on clinical trials methodology, written by three recognized experts who have long and extensive experience in all areas of clinical trials. Most chapters have been revised considerably from the third edition. A chapter on ethics has been added and topics such as noninferiority and adaptive designs now receive

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This is the fourth edition of a very successful textbook on clinical trials methodology, written by three recognized experts who have long and extensive experience in all areas of clinical trials. Most chapters have been revised considerably from the third edition. A chapter on ethics has been added and topics such as noninferiority and adaptive designs now receive considerable discussion. There is much new material on adverse events, adherence, data monitoring, and issues in analysis.
This book is intended for the clinical researcher who is interested in designing a clinical trial and developing a protocol. It is also of value to researchers and practitioners who must critically evaluate the literature of published clinical trials and assess the merits of each trial and the implications for the care and treatment of patients. The authors use numerous examples of published clinical trials from a variety of medical disciplines to illustrate the fundamentals.
The text is organized sequentially from defining the question to trial closeout. One chapter is devoted to each of the critical areas to aid the clinical trial researcher. These areas include pre-specifying the scientific questions to be tested and appropriate outcome measures, determining the organizational structure, estimating an adequate sample size, specifying the randomization procedure, implementing the intervention and visit schedules for participant evaluation, establishing an interim data and safety monitoring plan, detailing the final analysis plan, and reporting the trial results according to the pre-specified objectives.
Although a basic introductory statistics course is helpful in maximizing the benefit of this book, a researcher or practitioner with limited statistical background would still find most if not all the chapters understandable and helpful. While the technical material has been kept to a minimum, the statistician may still find the principles and fundamentals presented in this text useful. This book has been successfully used for teaching courses in clinical trial methodology.

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Springer New York
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4th ed. 2010
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Table of Contents

1 Introduction to Clinical Trials 1

Fundamental Point 2

What Is a Clinical Trial? 2

Clinical Trial Phases 3

Phase I Studies 4

Phase II Studies 6

Phase III/IV Trials 7

Why Are Clinical Trials Needed? 8

Problems in the Timing of a Trial 11

Study Protocol 12

References 14

2 Ethical Issues 19

Fundamental Point 20

Planning and Design 20

Does the Question Require a Clinical Trial? 20

Randomization 21

Control Group 22

Protection from Conflict of Interest 23

Informed Consent 24

Conduct 27

Trials in Developing Countries 27

Recruitment 28

Safety and Efficacy Monitoring 29

Early Termination for Other than Scientific or Safety Reasons 29

Privacy and Confidentiality 30

Data Falsification 31

Reporting 31

Publication Bias, Suppression, and Delays 31

Conflicts of Interest and Publication 32

References 32

3 What is the Question? 37

Fundamental Point 37

Selection of the Questions 38

Primary Question 38

Secondary Questions 38

Adverse Events 39

Ancillary Questions, Substudies 40

Natural History 40

Large, Simple Clinical Trials 41

Superiority vs. Noninferiority Trials 41

Intervention 42

Response Variables 43

Specifying the Question 45

Biomarkers and Surrogate Response Variables 47

General Comments 50

References 51

4 Study Population 55

Fundamental Point 55

Definition of Study Population 55

Rationale 55

Considerations in Defining the Study Population 57

Generalization 62

Recruitment 64

References 65

5 Basic Study Design 67

Fundamental Point 68

Randomized Control Trials 69

Nonrandomized Concurrent Control Studies 72

Historical Controls and Databases 73

Strengths of Historical Control Studies 73

Limitations of Historical Control Studies 74

Role of Historical Controls 78

Cross-Over Designs 79

Withdrawal Studies 81

Factorial Design 82

Group Allocation Designs 83

Hybrid Designs 84

Large, Simple and Pragmatic Clinical Trials 84

Studies of Equivalency and Noninferiority 86

Adaptive Designs 90

References 91

6 The Randomization Process 97

Fundamental Point 97

Fixed Allocation Randomization 98

Simple Randomization 99

Blocked Randomization 100

Stratified Randomization 102

Adaptive Randomization Procedures 105

Baseline Adaptive Randomization Procedures 105

Response Adaptive Randomization 108

Mechanics of Randomization 109

Recommendations 111

Appendix 111

Adaptive Randomization Algorithm 111

References 113

7 Blindness 119

Fundamental Point 119

Types of Trials 119

Unblinded 119

Single-Blind 120

Double-Blind 122

Triple-Blind 123

Protecting the Double-Blind Design 124

Matching of Drugs 125

Coding of Drugs 127

Official Unblinding 127

Inadvertent Unblinding 128

Assessment and Reporting of Blindness 129

References 131

8 Sample Size 133

Fundamental Point 133

Statistical Concepts 134

Dichotomous Response Variables 139

Two Independent Samples 139

Paired Dichotomous Response 144

Adjusting Sample Size to Compensate for Nonadherence 145

Sample Size Calculations for Continuous Response Variables 147

Two Independent Samples 147

Paired Data 148

Sample Size for Repeated Measures 150

Sample Size Calculations for "Time to Failure" 152

Sample Size for Testing "Equivalency" or Noninferiority of Interventions 155

Sample Size for Cluster Randomization 157

Estimating Sample Size Parameters 159

Multiple Response variables 161

References 162

9 Baseline Assessment 169

Fundamental Point 169

Uses of Baseline Data 169

Baseline Comparability 170

Stratification 171

Subgrouping 171

Pharmacogenetics 172

Changes of Baseline Measurement 173

Natural History Analyses 173

What Constitutes a True Baseline Measurement? 174

Screening for Participants 174

Regression Toward the Mean 175

Interim Events 176

Uncertainty About Qualifying Diagnosis 177

Contamination of the Intervention 178

Assessment of Baseline Comparability 179

Testing for Baseline Imbalance 180

References 181

10 Recruitment of Study Participants 183

Fundamental Point 183

Considerations Before Participant Enrollment 184

Selection of Study Sample 184

Common Recruitment Problems 184

Planning 186

Recruitment Sources 188

Conduct 190

Monitoring 192

Approaches to Lagging Recruitment 194

References 197

11 Data Collection and Quality Controls 199

Fundamental Point 200

Problems in Data Collection 201

Major Types 201

Minimizing Poor Quality Data 203

Design of Protocol and Manual 203

Development of Forms 203

Training and Certification 204

Pretesting 205

Techniques to Reduce Variability 206

Data Entry 206

Quality Monitoring 207

Monitoring of Forms 208

Monitoring of Procedures 208

Monitoring of Drug Handling 209

Audits Leader 210

References 212

12 Assessing and Reporting Adverse Events 215

Fundamental Point 216

Clinical Trials in the Assessment of Adverse Events 216

Strengths 216

Limitations in Identification of SAEs 217

Determinants of Adverse Events 218

Definitions 218

Classification of Adverse Events 219

Ascertainment 220

Dimensions 221

Length of Follow-Up 221

Analyzing Adverse Events 223

Types of Analysis 223

Analysis of Data from Nonadherent Participants 224

Reporting of Adverse Events 224

Scientific 224

Published Reports 225

Regulatory 226

Identification of SAEs 227

Potential Solutions 228

References 229

13 Assessment of Health-Related Quality of Life 233

Fundamental Point 234

Defining Health-Related Quality of Life 234

Primary HRQL Dimensions 235

Additional HRQL Dimensions 236

Uses of Health-Related Quality of Life 237

Methodological Issues 239

Trial Design 239

Study Population 240

Intervention 240

Selection of HRQL Instruments 241

Modes of Administration 242

Frequency of Assessment (Acute Vs. Chronic) 243

Symptom Expression (Episodic Vs. Constant) 244

Functional Impact (Present Vs. Absent) 244

Interpretation 244

Scoring of HRQL Measures 245

Determining the Significance of HRQL Measures 245

Utility Measures/Preference Scaling 246

References 247

14 Participant Adherence 251

Fundamental Point 252

Considerations Before Participant Enrollment 253

Design Factors 253

Participant Factors 255

Maintaining Good Participant Adherence 258

Adherence Monitoring 262

Dealing with Low Adherence 265

Special Populations 266

References 267

15 Survival Analysis 269

Fundamental Point 269

Estimation of the Survival Curve 270

Kaplan-Meier Estimate 274

Cutler-Ederer Estimate 278

Comparison of Two Survival Curves 279

Point-by-Point Comparison 279

Comparison of Median Survival Times 279

Total Curve Comparison 280

Generalizations 285

Covariate Adjusted Analysis 287

References 290

16 Monitoring Response Variables 293

Fundamental Point 295

Monitoring Committee 295

Repeated Testing for Significance 299

Decision for Early Termination 301

Decision to Extend a Trial 310

Statistical Methods Used in Monitoring 313

Classical Sequential Methods 314

Group Sequential Methods 315

Flexible Group Sequential Procedures: Alpha Spending Functions 318

Applications of Group Sequential Boundaries 321

Asymmetric Boundaries 324

Curtailed Sampling and Conditional Power Procedures 325

Other Approaches 330

Trend Adaptive Designs and Sample Size Adjustments 332

References 334

17 Issues in Data Analysis 345

Fundamental Point 345

Which Participants Should be Analyzed? 346

Ineligibility 347

Nonadherence 350

Missing or Poor Quality Data 355

Competing Events 362

Composite Outcomes 363

Covariate Adjustment 364

Surrogates as Covariates 365

Baseline Variables as Covariates 368

Subgroup Analyses 371

Not Counting Some Events 376

Comparison of Multiple Variables 377

Use of Cutpoints 378

Noninferiority Trial Analysis 379

Meta-Analysis of Multiple Studies 382

Rationale and Issues 382

Statistical Methods 386

Analysis Following Trend Adaptive Designs 389

Appendix 389

Mantel-Haenszel Statistic 389

References 390

18 Closeout 399

Fundamental Point 399

Termination Procedures 399

Planning 399

Scheduling of Closeout Visits 400

Final Response Ascertainment 401

Transfer of Posttrial Care 402

Data and Other Study Material 403

Cleanup and Verification 403

Storage 404

Dissemination of Results 405

Poststudy Follow-up 407

References 409

19 Reporting and Interpreting of Results 411

Fundamental Point 412

Guidelines for Reporting 413

Authorship 413

Disclosure of Conflict of Interest 414

Presentation of Data 414

Interpretation 415

Publication Bias 416

Did the Trial Work as Planned? 417

Baseline Comparability 417

Blindness 417

Adherence and Concomitant Treatment 418

Limitations 418

Analysis 419

How do the Findings Compare with Results from Other Studies? 420

What are the Clinical Implications of the Findings? 421

References 422

20 Multicenter Trials 427

Fundamental Point 427

Reasons for Multicenter Trials 428

Conduct of Multicenter Trials 429

Globalization of Trials 436

General Comments 437

References 438

Index 443

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