SUSAN S. ELLENBERG, PHD, is Professor of Biostatistics, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, USA.

THOMAS R. FLEMING, PHD, is Professor of Biostatistics and Statistics, Department of Biostatistics, School of Public Health, University of Washington, USA.

DAVID L. DEMETS, PHD, is Professor Emeritus and Founding Chair of the Department of Biostatistics and Medical Informatics, University of Wisconsin?Madison, USA.

Preface to the Second Edition xiii

Preface to the First Edition xv

1 Introduction 1

1.1 Motivation 1

1.2 History of data monitoring committees in government-sponsored trials 8

1.3 Data monitoring committees in trials sponsored by the pharmaceutical industry 15

1.4 Statistical methods for interim monitoring 18

1.5 When are data monitoring committees needed? 21

1.6 Models for data monitoring committees 22

1.7 Where we are today 24

1.8 Fundamental principles of data monitoring 25

References 27

2 Responsibilities of the Data Monitoring Committee and Motivating Illustrations 35

2.1 Fundamental charges 36

2.2 Specific tasks of the data monitoring committee 39

2.2.1 Initial review 40

2.2.1.1 Review of the study protocol 40

2.2.1.2 Review of procedures to ensure quality of study conduct 45

2.2.2 Evaluating the quality of ongoing study conduct 47

2.2.3 Assessing safety and efficacy data 56

2.2.3.1 Termination due to favorable benefit-to-risk 58

2.2.3.2 Termination due to unfavorable benefit-to-risk 63

2.2.3.3 Termination due to inability to answer trial questions 65

2.2.3.4 Continuation of ongoing clinical trials 68

2.2.3.5 Consideration of the overall picture: primary and secondary analyses 72

2.2.3.6 Modifying sample sizes based on ongoing assessment of event rates 76

2.2.4 Reviewing the final results 80

2.3 The data monitoring committee charter 83

References 84

3 Composition of a Data Monitoring Committee 89

3.1 Introduction 89

3.2 Required areas of expertise 90

3.3 Other relevant characteristics of committee members 96

3.4 Committee size 98

3.5 Selecting the committee chair 102

3.6 Responsibility for appointing committee members 102

3.7 Representation of other study components on the committee 104

3.8 Preparation for service on a committee 106

References 109

4 Independence of the Data Monitoring Committee: Avoiding Conflicts of Interest 113

4.1 Introduction 113

4.2 Rationale for independence 114

4.3 Financial independence 116

4.3.1 Commercial sponsors 117

4.3.2 Government sponsors 118

4.3.3 Academic investigators 118

4.4 Intellectual independence 125

4.5 Emotional conflicts 131

4.6 Best practices to address challenges to the DMC's independence 132

4.6.1 Adequate training/experience in the DMC process 133

4.6.2 Indemnification of DMC members 135

4.6.3 Maintaining confidentiality of interim data 136

4.6.4 Flexibility of procedures 138

4.6.5 DMC meeting format 139

4.6.6 Creating independent relationships and reducing conflicts of interest 141

4.6.7 Adequately informative DMC reports 142

4.7 Summary 143

References 144

5 Confidentiality Issues Relating to the Data Monitoring Committee 147

5.1 Rationale 147

5.2 Limits of confidentiality 159

5.2.1 Interim analysis reports 159

5.2.2 Access to aggregate data on efficacy and safety outcomes 161

5.2.3 Providing access to interim data on a "need-to-know" basis 164

5.2.4 Settings and procedures allowing broader unblinding of safety data 166

5.2.5 Consequences of unblinding interim data for regulatory review in ongoing trials 168

5.2.6 Some illustrations of broader unblinding 175

5.2.7 The steering committee and maintaining confidentiality 187

5.2.8 Indirect challenges to confidentiality 189

5.3 The need for the DMC to review unblended data 190

5.4 Conclusions: consensus regarding confidentiality 195

References 198

6 Data Monitoring Committee Meetings 203

6.1 Introduction 203

6.2 Specific objectives and timing of meetings 204

6.2.1 Organizational meeting 205

6.2.2 Early safety/trial integrity reviews 208

6.2.3 Formal interim efficacy analyses 212

6.2.4 End-of-trial debriefing 213

6.3 Preparation of meeting reports 214

6.3.1 Currentness of data in the report 217

6.3.2 Inclusion of unadjudicated data 220

6.4 Format for meetings 221

6.4.1 The initial closed session 223

6.4.2 The open session 224

6.4.3 The final closed session 227

6.4.4 Various formats for holding the open and closed sessions 227

6.4.5 Meeting duration and venue 229

6.5 DMC meeting minutes and the DMC recommendations 230

6.5.1 The DMC recommendations, the open minutes, and the closed minutes 230

6.5.2 The level of detail 232

6.5.3 The authorship of the minutes and the sign-off by committee members 233

References 235

7 Data Monitoring Committee Interactions with Other Trial Components or Related Groups 237

7.1 Introduction 238

7.2 Study sponsors 238

7.2.1 Industry sponsors 239

7.2.2 Government sponsors 241

7.3 Study steering committee/principal investigator 243

7.4 Study investigators 247

7.5 Trial statisticians and statistical centers 247

7.5.1 The independent statistical center 248

7.5.2 Ensuring optimal data presentations 253

7.6 Institutional review boards 253

7.7 Regulatory agencies 256

7.8 Study participants and/or advocacy groups 257

7.9 Other data monitoring committees 259

References 262

8 Statistical, Philosophical, and Ethical Issues in Data Monitoring 265

8.1 The need for statistical approaches to monitoring accumulating data 266

8.2 Overview of statistical methods 270

8.2.1 Group sequential methods 271

8.2.1.1 Some group sequential boundaries for establishing benefit 273

8.2.1.2 Group sequential alpha spending functions 277

8.2.1.3 Some group sequential boundaries when early results are unfavorable 280

8.2.2 Triangular boundaries 284

8.2.3 Stochastic curtailment/conditional power 286

8.2.4 Bayesian monitoring 290

8.2.5 The general approach to sequential stopping boundaries 293

8.2.6 Software packages for sequential clinical trial designs 294

8.2.7 Adaptive clinical trial designs 294

8.3 Protocol specification of the monitoring plan 299

8.4 Other statistical considerations in monitoring trial data 300

8.4.1 Primary versus secondary endpoints 300

8.4.2 Short-term versus long-term treatment effects 302

8.4.3 Results in subgroups 303

8.4.4 Taking external information into account 307

8.4.5 Evaluating safety in the context of evidence about efficacy: role of boundaries 309

8.4.6 Ensuring proper robustness when defining boundaries for establishing benefit 311

8.5 Ethical considerations 313

8.5.1 Early termination philosophies 313

8.5.1.1 Responding to early beneficial trends 314

8.5.1.2 Responding to early unfavorable trends 318

8.5.1.3 Responding to unexpected safety concerns 324

8.5.2 Other ethical considerations 325

References 326

9 Determining When a Data Monitoring Committee is Needed 335

9.1 Introduction 336

9.2 Typical settings for an independent data monitoring committee 336

9.3 Other settings in which an independent data monitoring committee may be valuable 339

9.3.1 Early trials of high-risk treatments 339

9.3.2 Trials in vulnerable populations 340

9.3.3 Trials with potentially large public health impact 341

9.4 An alternative monitoring approach: the internal monitoring committee 342

9.5 A decision model assessing need for an independent DMC or an internal monitoring committee 346

9.6 Settings with little need for an independent or internal monitoring committee 351

9.7 Summary 352

References 353

10 Regulatory Considerations for the Operation of Data Monitoring Committees 355

10.1 Introduction 356

10.2 Data monitoring committees in government regulations 356

10.3 Regulatory guidance 357

10.3.1 US Food and Drug Administration 357

10.3.2 International regulatory guidance 360

[...]opean Union 360

10.3.2.2 International Conference on Harmonization 361

10.3.2.3 The World Health Organization 363

10.4 Regulatory approaches relevant to data monitoring committee operation: the US FDA 364

10.5 Policies of funding agencies regarding DMC operations 367

10.5.1 National Institutes of Health 367

10.5.2 Other federal agencies 369

10.5.3 Funding agencies outside the US 369

10.6 Involvement of FDA staff in data monitoring committee deliberations 370

10.7 Examples of regulatory authority interaction with data monitoring committees 372

References 379

11 Legal Considerations for DMCs 383

11.1 DMC indemnification 383

11.1.1 Motivating examples 385

11.1.2 Emergence of DMCs and heightened awareness of their existence 388

11.1.3 Further motivation for indemnification to protect the DMC 390

11.1.4 Some specific concerns from current experiences with indemnification 392

11.1.5 Potential solutions to indemnification issues 394

11.1.6 Confidential disclosure agreement (CDA) 397

11.1.7 Summary of indemnification, liability, and contracting issues 399

11.2 Balancing legal and ethical responsibilities: a need for a mediator? 400

11.2.1 A case study: the setting of Actimmune in patients with idiopathic pulmonary fibrosis 402

11.2.2 IMMUNE response AIDS clinical trial 405

References 406

Appendix A The Data Monitoring Committee Charter 411

Appendix B Performance Standards Document 431

Statistics in Practice 451