P. Michael Dubinsky - The Fundamentals of Clinical Research

1 Cover

2 Title Page The Fundamentals of Clinical Research A Universal Guide for Implementing Good Clinical Practice P. Michael Dubinsky Spartansburg, PA, USA Karen A. Henry University of California, Berkeley Richmond, CA, USA A Universal Guide for Implementing Good Clinical Practice

3 Copyright Page

4 PrefaceGoal Scope of this Book How to Use this Book Opinion of the Authors

5 About the Authors

6 About the Authors

7 Part I: Good Clinical Practice History 1 History 1.1 Introduction 1.2 Objectives 1.3 Chronology 1.4 The Emergence of the ICH and Its Guidelines 1.5 Summary References

8 Part II: Drug Development in the Regulatory Environment 2 Regulatory Environment 2.1 Introduction 2.2 Objective 2.3 Regulatory Matrix 2.4 Laws, Regulations, and Policies 2.5 Guidelines and Guidance Materials 2.6 Regulatory/Competent Authority Organizations 2.7 Academic Medical Centers (AMCs) 2.8 Professional Organizations 2.9 Summary References 3 GCP in Context 3.1 Introduction 3.2 Objectives 3.3 Summary Reference 4 The Intersection of GCP and Regulation 4.1 Introduction 4.2 Objectives 4.3 The Principles of ICH E6(R2) 4.4 The Definition of GCP Embodies the Full Spectrum of Trial Activity – The Definition of GCP Reads 4.5 Glossary 4.6 Combining Key Elements 4.7 Being Linked to an Organization That Is Respected and Authoritative 4.8 Standard Operating Procedures 4.9 Efficiency of Developing and Updating Materials 4.10 Value Added Practices and Principles are Adopted 4.11 Summary Reference 5 Regulatory Affairs 5.1 Introduction 5.2 Objectives of the Chapter 5.3 Regulatory Affairs 5.4 Interacting with Regulatory/Competent Authorities 5.5 Communicating with Regulatory/Competent Authorities and Others 5.6 Meetings – When and How They fit‐GCP 5.7 Applications 5.8 Summary References

9 Part III: Good Clinical Practice 6 GCP Definition and Principles 6.1 Introduction 6.2 Objectives 6.3 The Definition of Good Clinical Practice 6.4 Good Clinical Practice Principles 6.5 Summary Reference 7 Players Roles and Responsibilities Overview 7.1 Introduction 7.2 Objectives 7.3 Summary Reference 8 IRB/IEC Roles and Responsibilities 8.1 Introduction 8.2 Objectives 8.3 Responsibilities of the IRB/IEC 8.4 Composition, Functions, and Operations 8.5 Procedures 8.6 Records 8.7 Noncompliance by IRB/IECs – Areas of Risk 8.8 Summary References 9 Investigator and Sponsor Roles and Responsibilities 9.1 Introduction 9.2 Objectives 9.3 Summary References 10 The Research Volunteer 10.1 Introduction 10.2 Objectives 10.3 Summary Reference 11 Regulatory Authority – Roles and Responsibilities 11.1 Introduction 11.2 Objectives 11.3 Definition and Overview 11.4 Trial Approval – Submission of Applications 11.5 Communication, Reporting, and Oversight 11.6 Inspections and Oversight 11.7 Summary

10 Part IV: Individual Clinical Trial 12 Individual Clinical Trial Overview 12.1 Introduction 12.2 Objectives 12.3 Summary Reference 13 Risk Assessment and Quality Management 13.1 Introduction 13.2 Objectives 13.3 Risk Assessment 13.4 Summary Reference 14 Trial Management; Start‐up, On‐Study, and Close‐Out 14.1 Introduction 14.2 Objectives 14.3 Summary Reference 15 Trial Resourcing and Outsourcing 15.1 Introduction 15.2 Objectives 15.3 Summary Reference 16 The Investigator's Brochure 16.1 Introduction 16.2 Objectives 16.3 Summary Reference 17 The Investigational Product (Clinical Supplies) 17.1 Introduction 17.2 Objectives 17.3 Manufacturing and Labeling Requirements 17.4 IP Accountability and Management 17.5 Factors to Consider in the Overall Trial Risk‐Assessment 17.6 Summary References 18 The Clinical Trial Protocol and Amendments 18.1 Introduction 18.2 Objectives 18.3 Summary References 19 Informed Consent and Other Human Subject Protection 19.1 Introduction 19.2 Objectives 19.2.10 Summary of Study Records Related to Human Subject Protection 19.3 Summary Reference 20 Data Collection and Data Management 20.1 Introduction 20.2 Objectives 20.3 GCP Responsibilities for Data Quality 20.4 Data Flow in a Clinical Trial 20.5 Source Data and Source Documents 20.6 Development and Implementation of the Case Report Form (CRF) 20.7 Database Development 20.8 Data Management Processes 20.9 Database Lock 20.10 The Data Management Plan 20.11 Quality‐by‐Design Considerations Regarding Clinical Trial Data Collection and Management 20.12 Summary Reference 21 Safety Monitoring and Reporting 21.1 Introduction 21.2 Objectives 21.3 Summary References 22 Monitoring Overview 22.1 Introduction 22.2 Objectives 22.3 Summary Reference 23 Investigator/Institution Selection 23.1 Introduction 23.2 Objectives 23.3 Summary Reference 24 Investigator/Institution Initiation 24.1 Introduction 24.2 Objectives 24.2.4 The Investigator/Institution Initiation Visit 24.2.5 Consequences of Inadequate Investigator(s)/Institution(s) Initiation 24.3 Summary Reference 25 Investigator/Institution Interim Monitoring 25.1 Introduction 25.2 Objectives 25.3 Summary Reference 26 Investigator/Institution Close‐out 26.1 Introduction 26.2 Objectives 26.3 Summary Reference 27 Study Design and Data Analysis 27.1 Introduction 27.2 Objectives 27.3 Clinical Trial Phases and Study Designs in Drug Development 27.4 GCP Considerations for Study Design and Analysis 27.5 Statistical Analysis Plan 27.6 Preparation of Study Data for Analysis 27.7 Analyzing and Reporting Study Data 27.8 Summary References 28 The Clinical Study Report 28.1 Introduction 28.2 Objectives 28.3 Context for a Clinical Study/Trial Report in a Clinical Trial and in Clinical Development 28.4 Summary References 29 Essential Documents 29.1 Introduction 29.2 Objectives 29.3 Summary Reference

11 Part V: Quality in Clinical Trials 30 Quality Systems in Clinical Research 30.1 Introduction References 31 Quality Responsibilities 31.1 Introduction Reference 32 Standard Operating Procedures 32.1 Introduction 33 Quality Assurance Components 33.1 Introduction 33.2 Objectives 33.3 Audit Plans 33.4 Audit Implementation 33.5 Corrective and Preventive Action – CAPA 33.6 Summary 34 Regulatory Authority Inspections 34.1 Introduction 34.2 Objectives 34.3 Scheduling and Conducting GCP Inspections 34.4 Inspection Readiness – Preparation, Hosting, and Follow‐up 34.5 Summary

12 References for all Chapters

13 Index

14 End User License Agreement

1 Chapter 13Table 13.1 Documentation of information gathered during risk identification.

2 Chapter 14Table 14.1 Functions of the sponsor.Table 14.2 Functions of the investigator.

3 Chapter 18Table 18.1 Example of phase 2 study objectives, endpoints, and study assessm...

4 Chapter 19Table 19.1 Descriptions of minimum elements for adequate informed consent of...Table 19.2 Essential documents pertaining to the protection of the rights, s...

5 Chapter 22Table 22.1 GCP principle and associated trial monitoring application.

6 Chapter 23Table 23.1 Investigator/institution selection checklist.

7 Chapter 24Table 24.1 Investigator/institution iniiation checklist.

8 Chapter 25Table 25.1 Investigator/institution interim monitoring checklist.

9 Chapter 26Table 26.1 Investigator/institution closeout checklist.

10 Chapter 31Table 31.1 Overview of expectations which fall to the sponsor.

11 Chapter 32Table 32.1 Expectations for written procedures (constructed from ICH E6(R2)...Table 32.2 The most common issues arising from SOPs.

1 Chapter 2 Figure 2.1 The clinical trial regulatory matrix.

2 Chapter 7 Figure 7.1 Players interaction.

3 Chapter 11 Figure 11.1 Regulatory Authority’s interaction with other players.

4 Chapter 12 Figure 12.1 Milestones for a clinical trial.

5 Chapter 14Figure 14.1 Example of items tracked in a clinical trial management system f...Figure 14.2 Examples of other operational items tracked for a specific trial...Figure 14.3 Example of table of contents for trial operations plan.Figure 14.4 Milestones for a clinical trial.