Margaret Liu is a clinical trials consultant based in Singapore and former manager of the Monitoring Group at the Duke Clinical Research Institute (DCRI). Kate Davis is Business Development Specialist for DCRI Communications Group, Durham, NC, US.

"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)

• Foreword by Robert A. Harrington xiiiPreface xvList of Abbreviations xviii1 Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research 12 The Process: Developing New Drugs, Biologics, and Devices 13The Drug Development Process 14Background Information 14Pre-Clinical Studies 15The Investigational New Drug Application 16Clinical Trial Phases 17Application to Market New Drugs and Biologics 20FDA Review Groups 21Early or Expanded Access to Unapproved Drugs and Biologics 24Orphan Drugs 25Developing New Devices 26Background Information 27What is a Medical Device? 28Medical Device Classification 29Requirements for Marketing New Devices 33Humanitarian Use Devices 36Early or Expanded Access to Unapproved Medical Devices 36FDA Device Review 38Combination Products 38Postmarketing Surveillance of Drugs, Biologics, and Devices 39Phase 4 Postmarketing Drug and Biologics Studies 40Phase 4 Postmarketing Device Studies 40Direct Reporting Based on Observations 413 Good Clinical Practice and the Regulations 49Good Clinical Practice 50Regulations 50Guidelines 59Local Laws 60Responsibilities in the Code of Federal Regulations 62Principal Investigator Responsibilities 62Institutional Review Board Responsibilities 67Sponsor Responsibilities 68Sponsor-Investigators 70Where to Obtain Information and Guidance for the Regulations and GCP 70The Federal Register 70FDA Guidance Documents 71Online Resources 714 Informed Consent and the Regulations 73What Is Informed Consent? 74Ethical Codes Regarding Informed Consent 75The Belmont Report: Application of Respect for Persons 75The Declaration of Helsinki 76The Nuremberg Code 77Regulatory Requirements for Informed Consent 77General Requirements for Informed Consent (21 CFR 50.20) 78Exceptions from the General Requirements (21 CFR 50.23) 79Exceptions from Informed Consent Requirements for Emergency Research (21 CFR 50.24) 79Elements of Informed Consent (21 CFR 50.25) 80Documentation of Informed Consent (21 CFR 50.27) 82Consent from Vulnerable Subjects 85HIPAA/Privacy Rule Requirements 90The Informed Consent Process 92Writing the Consent Form 92Obtaining Informed Consent 95Documenting Informed Consent 96Continuing Informed Consent 975 Institutional Review Boards 101What is an Institutional Review Board? 102Types of IRBs 103IRB Membership 104IRB Activities 107Reviewing Research 107Reporting Unanticipated Problems Involving Risks to Subjects or Others 109 Establishing Written Procedures 110Types of IRB Review 111Full Committee Review 111Expedited Review 112Items That Must be Submitted for IRB Review 113Exemptions: When IRB Approval Is Not Required 113Continuing Review after Initial Study Approval 114Review of Adverse Events and Unanticipated Problems 115Communication between IRBs and Investigators 116Investigator Notification of the Outcome of IRB Review 116Communication During Study 116IRB Notification at Study Completion 117Communication between IRBs and Study Sponsors 117IRB Records and Reports 118Accreditation of IRBs 119Registration 1206 Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others 123Why Collect Adverse Event Data? 124Safety Profile 125Benefits and Risks Evaluation 125Package Insert 125Adverse Events 125Internal and External Adverse Events 126Serious Adverse Events 126Unanticipated Problems Involving Risks to Subjects or Others 127Investigator Responsibilities 129Collecting Adverse Event Data 129Reporting Adverse Event Data 130Expedited Reporting of Adverse Events 131Reporting Unanticipated Problems Involving Risks to Subjects or Others 133Reporting Unanticipated Adverse Device Effects 135IRB Responsibilities 135Review and Reporting of Serious Adverse Events 135Review and Reporting of Unanticipated Problems 136Sponsor Responsibilities 136Expedited Reporting in Drug Trials 137Expedited Reporting in Device Trials 138Routine Reporting by Sponsors 1397 Monitoring, Audits, and Inspections 141Monitoring Plan 143On-Site Monitoring 144Types of On-Site Monitoring Visits 145Documenting Monitoring Visits 151In-House Monitoring 152Computerized Checks 153Source Document Verification Done at the Sponsor or Data Center 153Protected Health Information 154Audits and Inspections 154Audits and Inspections in the Regulations and Guidelines 155Sponsor Quality Assurance Audits 156FDA Inspections 1578 The Principal Investigator, the Clinical Research Coordinator, and the Study Site 163The Principal Investigator 164Characteristics of an Effective Principal Investigator 165Conflict of Interest 167Investigator Delegation of Study Activities 169Staffing to Support Clinical Trials 169Clinical Research Coordinator 169Subinvestigators 172Support Personnel 173Space and Resource Needs 173Workspace for the Clinical Research Coordinator 173Equipment 174Storage Space 174Additional Space 175The Local Institutional Review Board 1759 The Protocol 177Common Components of a Protocol 180Background and Rationale 180Study Organization 180Objectives/Endpoints 181Quality of Life Parameters 181Economic Factors 182Surrogate Endpoints 182Study Design 183Use of Control Groups 184Randomization 185Blinding 187Observational Studies 188Study Population 190Study Treatment Plan 191Safety Assessment, Management, and Reporting 192Replacement of Withdrawn, Dropped Out, and Lost to Follow-up Subjects 193Statistical Aspects 193Power 193Sample Size 193Intention-to-treat Principle 194Interim Analysis 195Data and Safety Monitoring Board 196Subject Data and Record Retention 197Monitoring 19710 Study Feasibility: Reviewing a Specific Protocol 199Reviewing a Specific Protocol 200Study Design 200Research Subject Population 201Investigator Time Requirements 202Clinical Research Coordinator and Other Study Personnel 202Laboratory Tests and Procedures 204Additional Space and Equipment 205Budget Considerations 206Preparing a Budget 207Budget Planning 209Negotiating a Budget 211Should We Do this Study at Our Site? 21111 Study Activities 213Study Start-up Phase 215Review the Protocol, Develop a Budget, Prepare Documents for IRB Submission 215Establish the Site Study Team 216Participate in Investigator Meetings 219Develop a Recruitment and Enrollment Plan 219Conduct Education and Training Sessions for Site Personnel 228Begin Randomization and Enrollment of Subjects 230Study Maintenance Phase 230Complete Data Forms 231Report Serious Adverse Events (SAE) and Unanticipated Problems 231Conduct Subject Follow-up Visits 231Ensure Subject Retention and Compliance 233Unblind Study Treatment Only When Required 238Maintain Study Drug/Device Accountability 239Manage Specimens, Samples, and Other Study-related Materials 239Obtain Answers to Urgent Clinical Questions 239Continue Communication 239Maintain Study File 240Study Completion and Close-Out Phase 240Completion of All Subject Data Forms and Resolution of Data Queries 241Destruction or Return of Study Materials 241Review of Site Study File 241Submission of the Final Report 241Long-term Storage of Study Records 24212 Study Documents/Essential Documents 245Documents at Study Start-Up 246Confidentiality Agreement 247Signed Protocol and Applicable Amendments 247Letter of Agreement 247Investigator’s Brochure 248Curriculum Vitae (CV)/Statement of Investigator Qualifications 248Medical Licensure Form 248Form FDA 1572 248Financial Disclosure Information 250IRB Approval 250IRB-Approved Consent Form 252RB-Approved Advertisements and Subject Materials 253Laboratory Certification and Normal Ranges Form 253Site Demographics Form 255Study Personnel CVs/Résumés and Training Records 255Contractual Agreement/Financial Contract 255Documents While the Study is in Progress 256Protocol Amendments and IRB Approval 256Revised Consent Forms and IRB Approval 257Updated Form FDA 1572 257CVs for New PIs and Subinvestigators 257 Updated Laboratory Certification and Normal Ranges Form 258IRB Correspondence 258Subject Recruitment Advertisements and Educational Materials 258Screening Log 258Confidential Master Subject Log 259Signed Consent Forms for All Enrolled Subjects 259Test Article Accountability Forms 259Serious and Reportable Adverse Event Forms 259Subject Data Forms and Query Forms 261Source Documents 261Signature and Delegation Log 263Site Visit Log 263Written Communication and Correspondence 263Documents at Study Close-out 263Outstanding Data Forms and Query Forms 264Complete Sets of All Subject Data Forms 264Final Reports 264Test Article Accountability Records 264Maintaining Your Site Study File 266Record Retention 266Principal Investigator Status Change 267Final Financial Disclosure Report 267Sample Study File Organization 26713 Management of Study Drugs, Biologics, and Devices 271Study Drugs and Biologics 272Study Drug Accountability 272Study Drug Packaging 273Study Drug Receipt 274Study Drug Storage 274Dispensing Study Drug 274Study Drug Unblinding 277Final Disposition of Study Drug 278Study Devices 278Device Labeling 278Device Accountability 279Device Tracking 27914 Managing Clinical Trial Data 281HIPAA, the Privacy Rule, and Clinical Trial Data 282Use of Protected Health Information With Individual Authorization 283Use of Protected Health Information Without Individual Authorization 283Subject Identifiers 284Guidelines and Regulations Regarding Clinical Trial Data 284ICH E6 Section 2: The Principles of ICH GCP 284ICH E6 Section 4: Records and Reports 28521 CFR 312 and §812 285Electronic Data 285Study Site Responsibilities Regarding Clinical Trial Data 287Record the Data in Source Documents 287Complete Data Forms 290Correct the Data 302Submit the Data 307Store/Archive the Data 308Source Document Verification of Clinical Trial Data 308Release of Protected Medical Information 309Confidentiality of Clinical Trial Data 310Endpoint Adjudication 31015 Global Health and International Trials 313International Clinical Trials 314Ethnic and Racial Differences 315Ethical Issues and Cultural Sensitivities 316Why International Trials Are Important 317HIV/AIDS 318Malaria 318Tuberculosis 318Polio 319International Regulations 320Concerns 321Future Efforts 322Appendices 325Appendix A 327Appendix B 342Appendix C 355Appendix D 362Appendix E 370Epilogue by Lisa G. Berdan 379Glossary 382Index 395

Margaret Liu is a clinical trials consultant based in Singapore and former manager of the Monitoring Group at the Duke Clinical Research Institute (DCRI). Kate Davis is Business Development Specialist for DCRI Communications Group, Durham, NC, US.

"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)

• Foreword by Robert A. Harrington xiiiPreface xvList of Abbreviations xviii1 Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research 12 The Process: Developing New Drugs, Biologics, and Devices 13The Drug Development Process 14Background Information 14Pre-Clinical Studies 15The Investigational New Drug Application 16Clinical Trial Phases 17Application to Market New Drugs and Biologics 20FDA Review Groups 21Early or Expanded Access to Unapproved Drugs and Biologics 24Orphan Drugs 25Developing New Devices 26Background Information 27What is a Medical Device? 28Medical Device Classification 29Requirements for Marketing New Devices 33Humanitarian Use Devices 36Early or Expanded Access to Unapproved Medical Devices 36FDA Device Review 38Combination Products 38Postmarketing Surveillance of Drugs, Biologics, and Devices 39Phase 4 Postmarketing Drug and Biologics Studies 40Phase 4 Postmarketing Device Studies 40Direct Reporting Based on Observations 413 Good Clinical Practice and the Regulations 49Good Clinical Practice 50Regulations 50Guidelines 59Local Laws 60Responsibilities in the Code of Federal Regulations 62Principal Investigator Responsibilities 62Institutional Review Board Responsibilities 67Sponsor Responsibilities 68Sponsor-Investigators 70Where to Obtain Information and Guidance for the Regulations and GCP 70The Federal Register 70FDA Guidance Documents 71Online Resources 714 Informed Consent and the Regulations 73What Is Informed Consent? 74Ethical Codes Regarding Informed Consent 75The Belmont Report: Application of Respect for Persons 75The Declaration of Helsinki 76The Nuremberg Code 77Regulatory Requirements for Informed Consent 77General Requirements for Informed Consent (21 CFR 50.20) 78Exceptions from the General Requirements (21 CFR 50.23) 79Exceptions from Informed Consent Requirements for Emergency Research (21 CFR 50.24) 79Elements of Informed Consent (21 CFR 50.25) 80Documentation of Informed Consent (21 CFR 50.27) 82Consent from Vulnerable Subjects 85HIPAA/Privacy Rule Requirements 90The Informed Consent Process 92Writing the Consent Form 92Obtaining Informed Consent 95Documenting Informed Consent 96Continuing Informed Consent 975 Institutional Review Boards 101What is an Institutional Review Board? 102Types of IRBs 103IRB Membership 104IRB Activities 107Reviewing Research 107Reporting Unanticipated Problems Involving Risks to Subjects or Others 109 Establishing Written Procedures 110Types of IRB Review 111Full Committee Review 111Expedited Review 112Items That Must be Submitted for IRB Review 113Exemptions: When IRB Approval Is Not Required 113Continuing Review after Initial Study Approval 114Review of Adverse Events and Unanticipated Problems 115Communication between IRBs and Investigators 116Investigator Notification of the Outcome of IRB Review 116Communication During Study 116IRB Notification at Study Completion 117Communication between IRBs and Study Sponsors 117IRB Records and Reports 118Accreditation of IRBs 119Registration 1206 Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others 123Why Collect Adverse Event Data? 124Safety Profile 125Benefits and Risks Evaluation 125Package Insert 125Adverse Events 125Internal and External Adverse Events 126Serious Adverse Events 126Unanticipated Problems Involving Risks to Subjects or Others 127Investigator Responsibilities 129Collecting Adverse Event Data 129Reporting Adverse Event Data 130Expedited Reporting of Adverse Events 131Reporting Unanticipated Problems Involving Risks to Subjects or Others 133Reporting Unanticipated Adverse Device Effects 135IRB Responsibilities 135Review and Reporting of Serious Adverse Events 135Review and Reporting of Unanticipated Problems 136Sponsor Responsibilities 136Expedited Reporting in Drug Trials 137Expedited Reporting in Device Trials 138Routine Reporting by Sponsors 1397 Monitoring, Audits, and Inspections 141Monitoring Plan 143On-Site Monitoring 144Types of On-Site Monitoring Visits 145Documenting Monitoring Visits 151In-House Monitoring 152Computerized Checks 153Source Document Verification Done at the Sponsor or Data Center 153Protected Health Information 154Audits and Inspections 154Audits and Inspections in the Regulations and Guidelines 155Sponsor Quality Assurance Audits 156FDA Inspections 1578 The Principal Investigator, the Clinical Research Coordinator, and the Study Site 163The Principal Investigator 164Characteristics of an Effective Principal Investigator 165Conflict of Interest 167Investigator Delegation of Study Activities 169Staffing to Support Clinical Trials 169Clinical Research Coordinator 169Subinvestigators 172Support Personnel 173Space and Resource Needs 173Workspace for the Clinical Research Coordinator 173Equipment 174Storage Space 174Additional Space 175The Local Institutional Review Board 1759 The Protocol 177Common Components of a Protocol 180Background and Rationale 180Study Organization 180Objectives/Endpoints 181Quality of Life Parameters 181Economic Factors 182Surrogate Endpoints 182Study Design 183Use of Control Groups 184Randomization 185Blinding 187Observational Studies 188Study Population 190Study Treatment Plan 191Safety Assessment, Management, and Reporting 192Replacement of Withdrawn, Dropped Out, and Lost to Follow-up Subjects 193Statistical Aspects 193Power 193Sample Size 193Intention-to-treat Principle 194Interim Analysis 195Data and Safety Monitoring Board 196Subject Data and Record Retention 197Monitoring 19710 Study Feasibility: Reviewing a Specific Protocol 199Reviewing a Specific Protocol 200Study Design 200Research Subject Population 201Investigator Time Requirements 202Clinical Research Coordinator and Other Study Personnel 202Laboratory Tests and Procedures 204Additional Space and Equipment 205Budget Considerations 206Preparing a Budget 207Budget Planning 209Negotiating a Budget 211Should We Do this Study at Our Site? 21111 Study Activities 213Study Start-up Phase 215Review the Protocol, Develop a Budget, Prepare Documents for IRB Submission 215Establish the Site Study Team 216Participate in Investigator Meetings 219Develop a Recruitment and Enrollment Plan 219Conduct Education and Training Sessions for Site Personnel 228Begin Randomization and Enrollment of Subjects 230Study Maintenance Phase 230Complete Data Forms 231Report Serious Adverse Events (SAE) and Unanticipated Problems 231Conduct Subject Follow-up Visits 231Ensure Subject Retention and Compliance 233Unblind Study Treatment Only When Required 238Maintain Study Drug/Device Accountability 239Manage Specimens, Samples, and Other Study-related Materials 239Obtain Answers to Urgent Clinical Questions 239Continue Communication 239Maintain Study File 240Study Completion and Close-Out Phase 240Completion of All Subject Data Forms and Resolution of Data Queries 241Destruction or Return of Study Materials 241Review of Site Study File 241Submission of the Final Report 241Long-term Storage of Study Records 24212 Study Documents/Essential Documents 245Documents at Study Start-Up 246Confidentiality Agreement 247Signed Protocol and Applicable Amendments 247Letter of Agreement 247Investigator’s Brochure 248Curriculum Vitae (CV)/Statement of Investigator Qualifications 248Medical Licensure Form 248Form FDA 1572 248Financial Disclosure Information 250IRB Approval 250IRB-Approved Consent Form 252RB-Approved Advertisements and Subject Materials 253Laboratory Certification and Normal Ranges Form 253Site Demographics Form 255Study Personnel CVs/Résumés and Training Records 255Contractual Agreement/Financial Contract 255Documents While the Study is in Progress 256Protocol Amendments and IRB Approval 256Revised Consent Forms and IRB Approval 257Updated Form FDA 1572 257CVs for New PIs and Subinvestigators 257 Updated Laboratory Certification and Normal Ranges Form 258IRB Correspondence 258Subject Recruitment Advertisements and Educational Materials 258Screening Log 258Confidential Master Subject Log 259Signed Consent Forms for All Enrolled Subjects 259Test Article Accountability Forms 259Serious and Reportable Adverse Event Forms 259Subject Data Forms and Query Forms 261Source Documents 261Signature and Delegation Log 263Site Visit Log 263Written Communication and Correspondence 263Documents at Study Close-out 263Outstanding Data Forms and Query Forms 264Complete Sets of All Subject Data Forms 264Final Reports 264Test Article Accountability Records 264Maintaining Your Site Study File 266Record Retention 266Principal Investigator Status Change 267Final Financial Disclosure Report 267Sample Study File Organization 26713 Management of Study Drugs, Biologics, and Devices 271Study Drugs and Biologics 272Study Drug Accountability 272Study Drug Packaging 273Study Drug Receipt 274Study Drug Storage 274Dispensing Study Drug 274Study Drug Unblinding 277Final Disposition of Study Drug 278Study Devices 278Device Labeling 278Device Accountability 279Device Tracking 27914 Managing Clinical Trial Data 281HIPAA, the Privacy Rule, and Clinical Trial Data 282Use of Protected Health Information With Individual Authorization 283Use of Protected Health Information Without Individual Authorization 283Subject Identifiers 284Guidelines and Regulations Regarding Clinical Trial Data 284ICH E6 Section 2: The Principles of ICH GCP 284ICH E6 Section 4: Records and Reports 28521 CFR 312 and §812 285Electronic Data 285Study Site Responsibilities Regarding Clinical Trial Data 287Record the Data in Source Documents 287Complete Data Forms 290Correct the Data 302Submit the Data 307Store/Archive the Data 308Source Document Verification of Clinical Trial Data 308Release of Protected Medical Information 309Confidentiality of Clinical Trial Data 310Endpoint Adjudication 31015 Global Health and International Trials 313International Clinical Trials 314Ethnic and Racial Differences 315Ethical Issues and Cultural Sensitivities 316Why International Trials Are Important 317HIV/AIDS 318Malaria 318Tuberculosis 318Polio 319International Regulations 320Concerns 321Future Efforts 322Appendices 325Appendix A 327Appendix B 342Appendix C 355Appendix D 362Appendix E 370Epilogue by Lisa G. Berdan 379Glossary 382Index 395