Clinical Trials Handbook

CURTIS L. MEINERT, PhD, is Professor in the Departments of Epidemiology and Biostatistics at the Johns Hopkins Bloomberg School of Public Health, where he served as founder of the Johns Hopkins Center for Clinical Trials. He is a Fellow of the American College of Epidemiology, the American Association for the Advancement of Science, the American Heart Association, and the Society for Clinical Trials. Dr. Meinert has focused his research on the methodological issues in clinical trials, including their design, conduct, policy, and practice. He is the author of Clinical Trials Dictionary: Terminology and Usage Recommendations, Second Edition (Wiley).

Acknowledgments xi

Preface xiii

On planning xv

Explanatory notes, focus, and conventions xvii

Abbreviations and designations xxi

I. General1

1. Terminology 3

2. Definitions 5

3. Measurement units 7

4. Trial type 9

5. Design and flow schematics 13

6. Design and operating principles 15

7. Counting and analysis rules 17

8. Multi-study umbrella name 19

9. Study name 21

II. Design Specifications25

10. Objective 27

11. Specific aims 29

12. Experimental variable 31

13. Treatment unit 33

14. Primary outcome 35

15. Outcome measures 39

16. Design synopsis 41

III. Funding45

17. Type of funding initiative 47

18. Funding: Specifications 49

19. Funding: Terminology 51

20. Funding: Type 59

21. Funding: Initiative 61

22. Funding: Period 63

23. Funding: Budget 65

24. Funding: Mode 67

IV. Treatment Groups/Treatment Administration69

25. Study groups 71

26. Comparison group 73

27. Study treatments 75

28. Test treatments 77

29. Control/comparison treatment 79

30. Placebo treatment 87

31. Sham treatment 91

32. Treatment modality 93

33. Treatment schedule 95

34. Treatment compliance measures 97

35. Protocol overrides 101

36. Protocol bailouts 103

V. Masking 105

37. Mask/masking: Definitions 107

38. Masking principles 111

39. Masking, censoring, and shielding specifications 113

40. Drug masking procedure 115

41. Drug packaging and labeling 117

42. Drug supply 121

43. Masking safeguards 123

44. Unmasking treatment assignment 125

45. Results blackouts 127

VI. Bias and Variance Control129

46. Bias control procedures 131

47. Stratification 135

48. Variance control procedures 139

49. Separations 141

VII. Treatment Assignment/Randomization 143

50. Assignment methods: Fixed vs. adaptive 145

51. Treatment assignment: Random vs. nonrandom 147

52. Randomization: Complete vs. restricted 151

53. Randomization unit 155

54. Randomization: Procedures 157

VIII. IRBs and Consents159

55. IRBs 161

56. IRBs: Models and procedures 163

57. Consent 169

58. Consent: Checklist 177

59. Consent: Disclaimers and notifications 181

60. Consent: Principles and purpose 183

61. Consent: Process 185

62. Consent: Types 189

63. Consent: Questions and answers 191

IX. Enrollment and Followup195

64. Notation 197

65. Timing conventions 199

66. Required approvals, permissions, accesses, and supplies 201

67. Start-up design 203

68. Start-up checklist 207

69. Recruitment design 209

70. Enrollment goals 211

71. Enrollment quotas 213

72. Followup: Terminology 217

73. Followup: Method 221

74. Followup: Length 223

75. Closeout design 225

76. Missed visit 229

77. Dropout 231

78. Loss to followup 235

79. Study timetable 239

80. Critical event path analysis 241

81. Eligibility criteria 243

82. Exclusions from enrollment 245

83. Eligibility and exclusions by reason 249

X. Sample Size251

84. Sample size: Design 253

85. Sample size: Specifications 257

86. Sample size: Calculation 259

87. Fixed vs. sequential sample size designs 261

88. Fixed vs. adaptive designs 263

89. Designed subgroup comparisons 265

XI. Data Collection and Processing267

90. Contact schedule 269

91. Examinations/visits 271

92. Examination/clinic visit schedule 275

93. Data collection 279

94. Data collection: Schedules and procedures 281

95. Data flow 283

96. Data processing procedures 285

97. Laboratory tests 287

98. Readings 289

99. Tissue repositories 293

100. Form design: Principles and procedures 295

101. Time window specifications 299

102. Data entry design 301

103. Data sharing: Internal 307

104. Data sharing: External 311

XII. Study Centers315

105. Center types 317

106. Centers 323

107. Center requirements 325

XIII. Investigators/Study Staff329

108. Investigator requirements 331

109. Clinic staffing requirements 333

110. Research group/Investigators 335

XIV. Committees337

111. Key Committees 339

112. Standing and working committees 341

113. Committee rules and procedures 343

114. Study officers 347

115. Study chair/vice-chair 349

116. Executive committee 353

117. Executive committee members 357

118. Steering committee 359

119. Steering committee members 361

120. Steering committee: Questions, answers, and observations 363

121. Steering committee representation models 367

XV. Treatment Effects Monitoring371

122. Treatment effects monitoring 373

123. Treatment effects monitoring: Purpose 375

124. Treatment effects monitoring: Approach 377

125. Treatment effects monitoring: Masking 379

126. Stopping rules and guidelines 381

127. Treatment effects monitoring: Questions and answers 383

128. Treatment effects monitoring committee 387

129. Treatment effects monitoring committee: Questions and answers 391

XVI. Quality Control and Assurance393

130. Quality control and assurance procedures 395

131. Performance monitoring 399

132. Training procedures 401

133. Assurances and certifications 403

134. Site visiting procedures 405

135. Audit procedures 409

XVII. Data Analysis413

136. Analysis datasets 415

137. Analysis questions regarding study results publications 417

138. Frequentist vs. Bayesian analysis 419

139. Final analysis 421

140. Subgroup analysis 423

XVIII. Publication/Presentation425

141. Publication 427

142. Publication policy 429

143. Authorship 431

144. Credits 435

145. Presentation policy 439

XIX. Policies441

146. Policies 443

147. Publicity policy 445

148. Policy on access to study documents 447

149. Policy on access to study data and results 449

150. Policy on advertising for patients 453

151. Policy on incentive payments 455

152. Policy on payment of patient-related travel expenses 457

153. Ancillary study policy 459

154. Policy on patient-care-related payments 461

155. Policy on conflicts of interest 463

156. Substudy policy 467

XX. Adverse Events469

157. Adverse events 471

158. Adverse event reporting procedures 475

XXI. Miscellaneous479

159. Key study documents 481

160. Design synopsis 483

161. Slide sets 485

162. Study CV 487

163. Study website 489

164. Study history log 491

165. Landmark events and dates 493

166. Registration 495

Appendices497

Appendix 1. Design summaries for selected finished trials 499

Appendix 2. Sample design slide sets 517

Appendix 3. Template summary worksheet 537

References 551

Index 557