TABLE OF CONTENTS Acknowledgments... xi Introduction... xiii 1 The Clinical Research Coordinator (CRC)... 1 Background and Training of the CRC...1 Personality and Skills... 2 Where Do CRCs Work?... 2 CRC Responsibilities... 4 Problems and Opportunities...7 2 Institutional Review Boards (IRBs) and Data Safety Monitoring Boards (DSMBs)...9 Introduction... 9 Types of IRBs...10 IRB Membership...10 IRB Operations...11 IRB Responsibilities...11 Vulnerable Subjects...12 State and Local Regulations...13 IRB Review of Proposed Research...13 Materials Submitted to the IRB by an Investigator...13 IRB Deliberations...15 Investigator Reporting Responsibilities...15 Continuing Review of a Research Study...16 Expedited Review...17
Conflict of Interest...17 IRB Registration...18 FDA Guidance Documents for IRBs...18 CRC Duties and Responsibilities...19 Data Safety Monitoring Boards (DSMBs)...19 Key Takeaways...21 Case Study: Conflict of Interest... 22 Discussion... 22 3 Informed Consent...23 Introduction... 23 Defining Informed Consent... 23 Preparing the Informed Consent Document... 24 Obtaining Informed Consent...28 The Consent Process...30 Exceptions from Consent...31 Conclusion...34 Key Takeaways... 35 4 Regulations and Good Clinical Practices (GCPs)... 37 Introduction...37 FDA Regulations for Clinical Trials...37 ICH Guideline for Good Clinical Practice...38 FDA Guidelines and Information Sheets...38 FDA Compliance Program Guidance Manuals...39 NIH-Regulated Research...39 FDA Bioresearch Monitoring Program (BIMO)...40 Good Clinical Practice (GCP)...40 Contacting the FDA...41 HIPAA...41 HIPAA Authorization...41 Protected Health Information (PHI)... 42 Recruitment of Study Subjects... 43 Obtaining Informed Consent under HIPAA... 45
The Declaration of Helsinki (1964)... 45 The Belmont Report (1979)...46 Key Takeaways...46 5 An Overview of Research...49 Introduction...49 Pre-Clinical Research...49 Clinical Trials... 52 Notes on Studies in Women and Children...56 Summary... 57 Key Takeaways...58 6 Devices and Biologics...59 Biologics and Vaccines...61 Key Takeaways...63 7 Standard Operating Procedures (SOPs)...65 Writing SOPs...66 Approval, Training and Implementation...71 SOPs for Investigative Sites...71 Key Takeaways... 75 Case Study: Why do we need SOPs?...77 8 Preparing for a Study...79 Introduction... 79 Site Assessments (Site Evaluations)... 79 How to Succeed in Getting Studies...81 Protocol Feasibility...82 Grants, Budgeting and Contracts...83 Investigative Site Study Files...86 Storage of Study Materials...90 Study Documents...91 Financial Disclosure...92 Investigator Meetings...94
Study Initiation Meetings...95 Working with CRAs...96 Other Sponsor Interactions... 97 Shipping of Biological Samples... 97 Key Takeaways...98 9 Protocols...101 Introduction...101 Protocols...101 Protocol Complexity... 109 Protocol Amendments...110 During the Study...111 Key Takeaways... 112 Case Study: Protocols... 114 10 Case Report Forms (CRFs) and Electronic Data Capture (EDC)...115 Case Report Forms (CRFs)... 115 Electronic Data Capture (EDC)... 120 Good, High-Quality Data... 121 Internal Quality Assurance...122 Key Takeaways...122 Case Study: The Cost of Errors...123 11 Investigational Product Accountability... 125 Responsibilities...125 During a Clinical Trial...127 Key Takeaways... 128 Case Study: Investigational Product Accountability... 128 12 Working with Study Subjects...131 Recruitment of Study Subjects... 131 New Strategies for Subject Recruitment... 138 Scheduling Subjects...143
Retention of Study Subjects...145 Subject Compliance... 150 Key Takeaways...155 13 Study Closure... 159 Introduction...159 Reasons for Study Closure...159 Closure Procedures... 160 Investigator s Final Report to the Sponsor and the IRB... 161 Administrative Issues... 161 Record Retention...162 Post-Study Critique...163 Key Takeaways... 164 14 Adverse Events (AEs) and Safety Monitoring... 165 Regulations... 165 Definitions...167 Adverse Events (AEs) on Marketed Products... 168 Adverse Events (AEs) in Clinical Trials... 169 Investigator Reporting Responsibilities...173 Sponsor Responsibilities...173 Differences Between Clinical Studies and Clinical Practice...174 Assessing the Relationship of an AE to the Study Drug...175 Common Reporting Problems...176 Key Takeaways...177 Case Study: Caught in the Middle with Adverse Events...178 15 Audits... 179 Sponsor Audits of Investigative Sites...179 IRB Audits of Investigative Sites...181 FDA Audits of Investigative Sites...181 Consequences... 189 Key Takeaways... 190 Case Study: Audit Attitude...191
Afterword...193 Appendix A Acronyms... 195 Appendix B Glossary... 197 Appendix C Appendix D Resources...203 Sample Forms, Checklists and Logs...207 Appendix E Title 21 Food and Drugs...245 Part 11 Electronic Records; Electronic Signatures...245 Part 50 Protection Of Human Subjects...249 Part 54 Financial Disclosure by Clinical Investigators...262 Part 56 Institutional Review Boards...266 Part 312 Investigational New Drug Applicaion... 276 Part 314 Applications for FDA Approval to market a new drug...321 Part 600 Biological Products: General...415 Part 601 Licensing...433 Part 610 General Biological Products Standards...463 Part 812 Investigational Device Exemptions... 489 Part 814 Premarket Approval of Medical Devices... 509 Appendix F Appendix G Harmonized Tripartite Guideline for Good Clinical Practice...539 Practice Examination...549 Index...563 About CenterWatch...567 About the Author... 573