Data and Safety Monitoring Committees in Clinical Trials Book

Preface xv

1 Introduction 1

1.1 What Is a Data Monitoring Committee (DMC)? 1

1.2 Some Definitions 2

1.3 DMC in Federal Government-Sponsored Clinical Trials versus Pharmaceutical Industry Clinical Trials 3

1.4 Stewardship 4

1.5 Some Recent History 5

1.5.1 Development of DMCs in the Pharmaceutical Industry 5

1.5.2 Guidances-FDA, NIH, and ICH 5

1.5.3 Other Vehicles for Patient Protection 6

1.6 DMC's Place in the Drug Development Cycle 6

1.6.1 Phases of Drug Development 6

1.6.2 Limitations of a Clinical Program for Revealing Safety Issues 6

1.6.3 Postmarket Safety Actions 9

1.6.4 Role of DMCs in Exploratory and Confirmatory Trials 9

1.6.5 Investigator-Sponsored Trials 11

1.6.6 Open Label Extension Studies 11

1.7 Pharmaceutical Industry Demographics 12

1.7.1 Size of Companies 12

1.7.2 Public versus Private Companies 12

1.8 Conclusion 12

DMCounselor 14

2 Organization of a Safety Monitoring Program for a Confirmatory Trial 17

2.1 Members of the Safety Monitoring Team 17

2.1.1 The Sponsor 17

2.1.2 Data Monitoring Committee 18

2.1.3 Data Analysis Center 19

2.1.4 Institutional Review Board 20

2.1.5 Scope of DMC Authority 20

2.2 How Is a DMC Created? 20

2.3 Membership 22

2.3.1 Physicians 22

2.3.2 Biostatisticians 22

2.3.3 How Many Members Are Needed? 22

2.3.4 Ad Hoc Consultants 23

2.3.5 Ubiquitous DMC Members 23

2.3.6 Disclosure of DMC Membership 23

2.3.7 Multiple Sponsorship 25

2.3.8 From Where Are DMC Members Recruited? 25

2.4 Term 25

2.5 Conflicts of Interest 25

2.6 Compensation 26

2.7 Liability and Indemnification 26

2.8 Sponsor DMC Relationship 27

2.9 Interdisciplinary Training 27

2.10 Conclusion27

DMCounselor 28

3 Meetings 31

3.1 DMC Charter 31

3.2 Types of Meetings 31

3.2.1 Orientation or Organizational Meeting 32

3.2.2 Data Review 33

3.2.3 Ad Hoc 33

3.3 Orientation Meeting 33

3.3.1 Chair for Orientation Meeting 33

3.3.2 Introduction of the Safety Monitoring Team 33

3.3.3 Appointment of DMC Secretary 33

3.3.4 Presentation of DMC Charter 34

3.3.5 Masking Policy 34

3.3.6 Investigator Brochure 34

3.3.7 Protocol 35

3.3.8 Informed Consent 35

3.3.9 Data Flow 35

3.3.10 Useful Software 36

3.3.11 Review of Integrated Summary of Safety 36

3.3.12 Policy on Review of Publications and Package Insert 37

3.3.13 Formats for Tables, Listings, and Graphs 37

3.3.14 Schedule First Data Review Meeting 37

3.4 Data Review Meetings 38

3.4.1 Attendance 38

3.4.2 Open Session 39

3.4.2.1 Study Progress 39

3.4.2.2 Data Quality 39

3.4.2.3 Update on Pending Action Items 39

3.4.2.4 Questions for the DMC 39

3.4.2.5 Sample Agenda for Open Session 40

3.4.3 Closed Session 40

3.4.4 Scheduling of Next Meeting 40

3.4.5 Minutes 40

3.5 Ad Hoc Meetings 44

3.6 Conclusion 44

DMCounselor 44

4 Clinical Issues 47

4.1 Goals of Safety Analysis 47

4.2 Definitions 48

4.2.1 Adverse Event 48

4.2.2 Serious Adverse Event 48

4.2.3 Serious Adverse Event Reporting Requirements 48

4.3 Safety Data 49

4.3.1 Pharmacovigilence Group 49

4.3.2 Case Report Forms 49

4.3.3 Adverse Event Dictionary 49

4.3.4 Adverse Event Severity 50

4.3.5 SAE Narratives 51

4.3.6 Titration to Dose 51

4.4 Deaths 51

4.5 Impact of Multinational Trials 52

4.5.1 Cultural Issues 52

4.5.2 Political Issues 52

4.5.3 Medical/Surgical Practices Issues 53

4.6 Conclusion 54

DMCounselor 55

5 Statistical Issues 57

5.1 Goals of Statistical Analysis 57

5.2 Useful Data Displays 58

5.2.1 Enrollment by Center 59

5.2.2 Graph of Cumulative Patient Enrollment by Month 59

5.2.3 Graph of Cumulative Patient Exposure to Study Drug 59

5.2.4 Treatment Emergent Adverse Events 61

5.2.4.1 Classification 61

5.2.4.2 An Example 61

5.2.4.3 Incidence Calculation 62

5.2.4.4 Incidence and Exposure Time Calculation 62

5.2.4.5 Kaplan-Meier Time to First Occurrence 63

5.2.4.6 Incidence at a Time Point after Treatment Start-Landmark Estimate 63

5.2.4.7 Other Ways of Looking at Incidence 64

5.2.5 Laboratory Data 65

5.3 Analysis Methods-Frequentist 65

5.3.1 What Is Frequentist Analysis? 65

5.3.2 Hypothesis Tests 65

5.3.3 Confidence Intervals 68

5.3.3.1 Incidence 68

5.3.3.2 Rate per 100 Patient Years 68

5.3.3.3 Odds Ratio 69

5.3.3.4 Poisson Rate Ratio 70

5.3.3.5 Inference with Kaplan-Meier Landmark Estimates of Incidence 72

5.3.4 Data Analysis without Statistics 72

5.4 Power 72

5.5 Multiplicity 74

5.6 Analysis Methods-Likelihood 77

5.7 Analysis Methods-Bayesian 82

5.8 Conclusion 82

DMCounselor 86

6 Bias and Pitfalls 89

6.1 What Is Bias? 89

6.2 Sources of Bias 90

6.3 Knowledge of Treatment Assignment 90

6.3.1 By Sponsor Staff 90

6.3.2 By the DMC 91

6.4 Reporting Bias 92

6.4.1 Investigator Level 92

6.4.1.1 Knowledge of Treatment Assignment 92

6.4.1.2 Incomplete Follow-Up 93

6.4.1.3 Spontaneous versus Solicited Adverse Event Collection 93

6.4.2 Analysis Level 94

6.4.2.1 Early Termination Due to Efficacy 94

6.4.2.2 Granularity Bias 94

6.5 Competing Risks 96

6.6 Conclusion 98

DMCounselor 98

7 Data Monitoring Committee Decisions 101

7.1 Types of DMC Decisions 101

7.2 Decision-Making Environment 102

7.3 Risk versus Benefit Analyses 102

7.4 When a Safety Issue Arises 103

7.4.1 Unmasking 104

7.4.2 "Dear Investigator" Letter 105

7.4.3 Modification of Informed Consent 106

7.4.4 Protocol Modification 106

7.4.5 Trial Termination 106

7.4.6 Unmasking the Sponsor 108

7.5 Information beyond the Present Trial 108

7.6 Meta-Analysis 110

7.7 Final Meeting 112

7.8 Special Problems with Infant Pharma Companies 112

7.9 Conclusion 113

DMCounselor 113

8 Emerging Issues 119

8.1 Introduction 119

8.2 Issues in Technology 120

8.2.1 Adaptive Designs 120

8.2.1.1 Dropping a Dose or Treatment Group 120

8.2.1.2 Adaptive Assignment to Treatment Group 121

8.2.1.3 Changing Objectives: Superiority to Noninferiority 121

8.2.1.4 Seamless Transition: Phase II to Phase III 122

8.2.1.5 Change in Effect Size of Interest 122

8.2.1.6 Further Thoughts on Adaptive Designs 123

8.2.2 Real-Time SAE Reporting via the Internet 124

8.2.3 Causal Inference 125

8.2.4 Biomarkers 125

8.2.5 Exciting Times Ahead 126

8.3 Issues Due to Maturing of DMC Processes and Evolution of the Pharmaceutical Industry 126

8.3.1 Training of DMC Members 126

8.3.2 Cost Control 127

8.3.3 DMC Audit 128

8.3.4 Internal Safety Review Committee 128

8.3.5 Mergers and Licensing 129

8.3.6 Journal Policies Regarding Independent Review 129

8.4 Resignation from a DMC 130

8.5 Conclusion 130

DMCounselor 131

Appendix 135

Glossary 141

List of Abbreviations 153

References 155

Index 167