A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons from a Horse Named Jim, 2nd Edition

Foreword 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