Description
Book SynopsisThe publication of the second edition of this manual comes at an important juncture in the history of clinical research. As advances in information technology make it possible to link individuals and groups in diverse locations in jointly seeking the answers to pressing global health problems, it is critically important to remain vigilant about moral and ethical safeguards for every patient enrolled in a trial. Those who study this manual will be well aware of how to ensure patient safety along with fiscal responsibility, trial efficiency, and research integrity.
Robert Harrington, Professor of Medicine, Director, Duke Clinical Research Institute, Durham, North Carolina, USA
The Duke Clinical Research Institute (DCRI) is one of the world''s leading academic clinical research organizations; its mission is to develop and share knowledge that improves the care of patients around the world through innovative clinical research. This concise handbook provides a practical nut
Trade Review
"This is an excellent guide to how to conduct clinical trials of medical devices and biologics in the light of recent regulatory and clinical developments. The roles and responsibilities of institutional review boards and recent developments regarding subject privacy concerns and regulations are well covered. This manual also provides sample forms and worksheets for data management." (Doody's, 5 August 2011)
"A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons from a Horse Named Jim, 2nd Edition" is a good introduction to clinical research, primarily from the site perspective. The book gives readers a solid foundation of principles and knowledge." (Journal of Clinical Research Best Practices, 8 August 2011)
Table of ContentsForeword by Robert A. Harrington xiii
Preface xv
List of Abbreviations xviii
1 Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research 1
2 The Process: Developing New Drugs, Biologics, and Devices 13
The Drug Development Process 14
Background Information 14
Pre-Clinical Studies 15
The Investigational New Drug Application 16
Clinical Trial Phases 17
Application to Market New Drugs and Biologics 20
FDA Review Groups 21
Early or Expanded Access to Unapproved Drugs and Biologics 24
Orphan Drugs 25
Developing New Devices 26
Background Information 27
What is a Medical Device? 28
Medical Device Classification 29
Requirements for Marketing New Devices 33
Humanitarian Use Devices 36
Early or Expanded Access to Unapproved Medical Devices 36
FDA Device Review 38
Combination Products 38
Postmarketing Surveillance of Drugs, Biologics, and Devices 39
Phase 4 Postmarketing Drug and Biologics Studies 40
Phase 4 Postmarketing Device Studies 40
Direct Reporting Based on Observations 41
3 Good Clinical Practice and the Regulations 49
Good Clinical Practice 50
Regulations 50
Guidelines 59
Local Laws 60
Responsibilities in the Code of Federal Regulations 62
Principal Investigator Responsibilities 62
Institutional Review Board Responsibilities 67
Sponsor Responsibilities 68
Sponsor-Investigators 70
Where to Obtain Information and Guidance for the Regulations and GCP 70
The Federal Register 70
FDA Guidance Documents 71
Online Resources 71
4 Informed Consent and the Regulations 73
What Is Informed Consent? 74
Ethical Codes Regarding Informed Consent 75
The Belmont Report: Application of Respect for Persons 75
The Declaration of Helsinki 76
The Nuremberg Code 77
Regulatory Requirements for Informed Consent 77
General Requirements for Informed Consent (21 CFR 50.20) 78
Exceptions from the General Requirements (21 CFR 50.23) 79
Exceptions from Informed Consent Requirements for Emergency Research (21 CFR 50.24) 79
Elements of Informed Consent (21 CFR 50.25) 80
Documentation of Informed Consent (21 CFR 50.27) 82
Consent from Vulnerable Subjects 85
HIPAA/Privacy Rule Requirements 90
The Informed Consent Process 92
Writing the Consent Form 92
Obtaining Informed Consent 95
Documenting Informed Consent 96
Continuing Informed Consent 97
5 Institutional Review Boards 101
What is an Institutional Review Board? 102
Types of IRBs 103
IRB Membership 104
IRB Activities 107
Reviewing Research 107
Reporting Unanticipated Problems Involving Risks to Subjects or Others 109
Establishing Written Procedures 110
Types of IRB Review 111
Full Committee Review 111
Expedited Review 112
Items That Must be Submitted for IRB Review 113
Exemptions: When IRB Approval Is Not Required 113
Continuing Review after Initial Study Approval 114
Review of Adverse Events and Unanticipated Problems 115
Communication between IRBs and Investigators 116
Investigator Notification of the Outcome of IRB Review 116
Communication During Study 116
IRB Notification at Study Completion 117
Communication between IRBs and Study Sponsors 117
IRB Records and Reports 118
Accreditation of IRBs 119
Registration 120
6 Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others 123
Why Collect Adverse Event Data? 124
Safety Profile 125
Benefits and Risks Evaluation 125
Package Insert 125
Adverse Events 125
Internal and External Adverse Events 126
Serious Adverse Events 126
Unanticipated Problems Involving Risks to Subjects or Others 127
Investigator Responsibilities 129
Collecting Adverse Event Data 129
Reporting Adverse Event Data 130
Expedited Reporting of Adverse Events 131
Reporting Unanticipated Problems Involving Risks to Subjects or Others 133
Reporting Unanticipated Adverse Device Effects 135
IRB Responsibilities 135
Review and Reporting of Serious Adverse Events 135
Review and Reporting of Unanticipated Problems 136
Sponsor Responsibilities 136
Expedited Reporting in Drug Trials 137
Expedited Reporting in Device Trials 138
Routine Reporting by Sponsors 139
7 Monitoring, Audits, and Inspections 141
Monitoring Plan 143
On-Site Monitoring 144
Types of On-Site Monitoring Visits 145
Documenting Monitoring Visits 151
In-House Monitoring 152
Computerized Checks 153
Source Document Verification Done at the Sponsor or Data Center 153
Protected Health Information 154
Audits and Inspections 154
Audits and Inspections in the Regulations and Guidelines 155
Sponsor Quality Assurance Audits 156
FDA Inspections 157
8 The Principal Investigator, the Clinical Research Coordinator, and the Study Site 163
The Principal Investigator 164
Characteristics of an Effective Principal Investigator 165
Conflict of Interest 167
Investigator Delegation of Study Activities 169
Staffing to Support Clinical Trials 169
Clinical Research Coordinator 169
Subinvestigators 172
Support Personnel 173
Space and Resource Needs 173
Workspace for the Clinical Research Coordinator 173
Equipment 174
Storage Space 174
Additional Space 175
The Local Institutional Review Board 175
9 The Protocol 177
Common Components of a Protocol 180
Background and Rationale 180
Study Organization 180
Objectives/Endpoints 181
Quality of Life Parameters 181
Economic Factors 182
Surrogate Endpoints 182
Study Design 183
Use of Control Groups 184
Randomization 185
Blinding 187
Observational Studies 188
Study Population 190
Study Treatment Plan 191
Safety Assessment, Management, and Reporting 192
Replacement of Withdrawn, Dropped Out, and Lost to Follow-up Subjects 193
Statistical Aspects 193
Power 193
Sample Size 193
Intention-to-treat Principle 194
Interim Analysis 195
Data and Safety Monitoring Board 196
Subject Data and Record Retention 197
Monitoring 197
10 Study Feasibility: Reviewing a Specific Protocol 199
Reviewing a Specific Protocol 200
Study Design 200
Research Subject Population 201
Investigator Time Requirements 202
Clinical Research Coordinator and Other Study Personnel 202
Laboratory Tests and Procedures 204
Additional Space and Equipment 205
Budget Considerations 206
Preparing a Budget 207
Budget Planning 209
Negotiating a Budget 211
Should We Do this Study at Our Site? 211
11 Study Activities 213
Study Start-up Phase 215
Review the Protocol, Develop a Budget, Prepare Documents for IRB Submission 215
Establish the Site Study Team 216
Participate in Investigator Meetings 219
Develop a Recruitment and Enrollment Plan 219
Conduct Education and Training Sessions for Site Personnel 228
Begin Randomization and Enrollment of Subjects 230
Study Maintenance Phase 230
Complete Data Forms 231
Report Serious Adverse Events (SAE) and Unanticipated Problems 231
Conduct Subject Follow-up Visits 231
Ensure Subject Retention and Compliance 233
Unblind Study Treatment Only When Required 238
Maintain Study Drug/Device Accountability 239
Manage Specimens, Samples, and Other Study-related Materials 239
Obtain Answers to Urgent Clinical Questions 239
Continue Communication 239
Maintain Study File 240
Study Completion and Close-Out Phase 240
Completion of All Subject Data Forms and Resolution of Data Queries 241
Destruction or Return of Study Materials 241
Review of Site Study File 241
Submission of the Final Report 241
Long-term Storage of Study Records 242
12 Study Documents/Essential Documents 245
Documents at Study Start-Up 246
Confidentiality Agreement 247
Signed Protocol and Applicable Amendments 247
Letter of Agreement 247
Investigator’s Brochure 248
Curriculum Vitae (CV)/Statement of Investigator Qualifications 248
Medical Licensure Form 248
Form FDA 1572 248
Financial Disclosure Information 250
IRB Approval 250
IRB-Approved Consent Form 252
RB-Approved Advertisements and Subject Materials 253
Laboratory Certification and Normal Ranges Form 253
Site Demographics Form 255
Study Personnel CVs/Résumés and Training Records 255
Contractual Agreement/Financial Contract 255
Documents While the Study is in Progress 256
Protocol Amendments and IRB Approval 256
Revised Consent Forms and IRB Approval 257
Updated Form FDA 1572 257
CVs for New PIs and Subinvestigators 257
Updated Laboratory Certification and Normal Ranges Form 258
IRB Correspondence 258
Subject Recruitment Advertisements and Educational Materials 258
Screening Log 258
Confidential Master Subject Log 259
Signed Consent Forms for All Enrolled Subjects 259
Test Article Accountability Forms 259
Serious and Reportable Adverse Event Forms 259
Subject Data Forms and Query Forms 261
Source Documents 261
Signature and Delegation Log 263
Site Visit Log 263
Written Communication and Correspondence 263
Documents at Study Close-out 263
Outstanding Data Forms and Query Forms 264
Complete Sets of All Subject Data Forms 264
Final Reports 264
Test Article Accountability Records 264
Maintaining Your Site Study File 266
Record Retention 266
Principal Investigator Status Change 267
Final Financial Disclosure Report 267
Sample Study File Organization 267
13 Management of Study Drugs, Biologics, and Devices 271
Study Drugs and Biologics 272
Study Drug Accountability 272
Study Drug Packaging 273
Study Drug Receipt 274
Study Drug Storage 274
Dispensing Study Drug 274
Study Drug Unblinding 277
Final Disposition of Study Drug 278
Study Devices 278
Device Labeling 278
Device Accountability 279
Device Tracking 279
14 Managing Clinical Trial Data 281
HIPAA, the Privacy Rule, and Clinical Trial Data 282
Use of Protected Health Information With Individual Authorization 283
Use of Protected Health Information Without Individual Authorization 283
Subject Identifiers 284
Guidelines and Regulations Regarding Clinical Trial Data 284
ICH E6 Section 2: The Principles of ICH GCP 284
ICH E6 Section 4: Records and Reports 285
21 CFR 312 and §812 285
Electronic Data 285
Study Site Responsibilities Regarding Clinical Trial Data 287
Record the Data in Source Documents 287
Complete Data Forms 290
Correct the Data 302
Submit the Data 307
Store/Archive the Data 308
Source Document Verification of Clinical Trial Data 308
Release of Protected Medical Information 309
Confidentiality of Clinical Trial Data 310
Endpoint Adjudication 310
15 Global Health and International Trials 313
International Clinical Trials 314
Ethnic and Racial Differences 315
Ethical Issues and Cultural Sensitivities 316
Why International Trials Are Important 317
HIV/AIDS 318
Malaria 318
Tuberculosis 318
Polio 319
International Regulations 320
Concerns 321
Future Efforts 322
Appendices 325
Appendix A 327
Appendix B 342
Appendix C 355
Appendix D 362
Appendix E 370
Epilogue by Lisa G. Berdan 379
Glossary 382
Index 395
