Clinical Trials Audit Preparation: A Guide for Good Clinical Practice (GCP) Inspections / Edition 1

Clinical Trials Audit Preparation: A Guide for Good Clinical Practice (GCP) Inspections / Edition 1

by Vera Mihajlovic-Madzarevic

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ISBN-10: 0470248858

ISBN-13: 9780470248850

Pub. Date: 03/01/2010

Publisher: Wiley

A must-have guide for any professional in the drug manufacturing industry

The Good Clinical Practice (GCP) audit is a tedious but necessary exercise that assures that all parties do their job properly and in compliance with the applicable FDA code. Clinical Trials Audit Preparation demystifies the audit process for all parties involved, including


A must-have guide for any professional in the drug manufacturing industry

The Good Clinical Practice (GCP) audit is a tedious but necessary exercise that assures that all parties do their job properly and in compliance with the applicable FDA code. Clinical Trials Audit Preparation demystifies the audit process for all parties involved, including clinical research sponsors, clinical investigators, and institutional review boards.

This book provides a step-by-step explanation of the FDA audit procedures for clinical trials and of how pharmaceutical companies, clinical investigators, and institutional review boards should prepare for regulatory audits. The book emphasizes the processes and procedures that should be implemented before a clinical audit occurs, making this an imperative guide to any professional in the drug manufacturing industry, including drug manufacturing companies, regulatory affairs personnel, clinical investigators, and quality assurance professionals.

Among the topics discussed:

  • Good Clinical Practices and therapeutic product development in clinical research

  • The roles of the sponsor of a clinical investigation, the IRB, or independent ethics committee

  • The roles and responsibilities of the clinical trial investigator

  • The inspection preparation

  • The Audit Report and the Form 483

  • Warning letters issued to clinical investigators and clinical trial sponsors and their impact on product development

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Table of Contents

Preface xiii

Introduction xv

Background History on Clinical Research Standards xv

Glossary xvii

Chapter 1 Good Clinical Practice and Therapeutic Product Development 1

1.1 Good Clinical Practice in Clinical Research 2

1.1.1 Definition 2

1.1.2 GCP Compliance 2

1.1.3 GCP Objectives 2

1.1.4 Principles of ICH GCP 3

Clinical Trial Conduct 3

Risk Assessment 3

Subject's Rights and Safety 3

Background Information 3

Clinical Trial Protocol 3

Ethics Review and Approval 3

Medical Care of Trial Subject 4

Qualifications of Clinical Trial Personnel 4

Informed Consent Process 4

Data Management 4

Patient Confidentiality 4

Investigational Product Manufacturing, Handling, and Storage 4

Quality Assurance 4

1.1.5 GCP Applicability 5

1.2 Role of the Sponsor of a Clinical Investigation 6

1.2.1 GCP: Responsibilities of a Sponsor of a Clinical Trial 6

1.2.2 Essential Documents for the Clinical Trial 9

Retention of the Essential Documents for the Clinical Trial 9

Archiving of the Essential Documents for the Clinical Trial After Discontinuation of Development 9

Notification 10

Transfer of Data Ownership 10

Records Retention 10

1.2.3 Investigator Selection 10

Investigator's Qualifications 10

Resources at the Investigator's Site 11

Protocol and Investigator's Brochure 11

Agreement with the Investigator/Institution 11

1.2.4 Allocation of Responsibilities 11

1.2.5 Compensation to Subjects and Investigators 12

Compensation to Subjects for Trial-Related Injuries 12

Other types of Compensation to Trial Subjects 12

1.2.6 Financing 12

1.2.7 Notification/Submission to Regulatory Authorities 13

1.2.8 Confirmation of Review by IRB/IEC 13

1.2.9 Information on Investigational Products 14

1.2.10 Manufacturing, Packaging, Labelling, and Coding Investigational Products 14

Characterization, Manufacturing, and Labeling of the Investigational Product 14

Storage Conditions 14

Packaging of the Investigational Product 14

Coding and Decoding of the Investigational Product 14

Investigational Product Changes and Bioequivalence Studies 15

1.2.11 Supplying and Handling Investigational Products 15

Supply 15

Investigational Product Records 15

1.2.12 Record Access 16

Verification of Patient Consent to Record Access 16

1.2.13 Safety Information 16

Safety Issues 16

Communication of Safety Issues 16

1.2.14 Adverse Drug Reaction Reporting 17

Serious Unexpected Adverse Drug Reactions 17

SAE Reporting Compliance 17

Safety Updates and Periodic Reports 17

1.2.15 Monitoring 17

Purposes 18

Selection and Qualifications of Monitors 18

Monitoring Strategies 19

Monitor's Responsibilities 19

Monitoring Procedures 21

Monitoring Report 21

1.2.16 Audit 21

Purposes 22

Selection and Qualifications of Auditors 22

Auditing Procedures 22

Site Selection Criteria for Inspection 22

Reporting of Findings 23

Audit Certificate 23

1.2.17 Noncompliance 23

1.2.18 Premature Termination or Suspension of a Trial 24

1.2.19 Clinical Trial/Study Reports 24

1.2.20 Multicenter Trials 24

1.3 Role of the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 25

1.3.1 Responsibilities 25

Document Gathering 25

Review of Documentation 26

1.3.2 Considerations for Review 26

1.3.3 Additional Information to be Provided To Subjects 26

Nontherapeutic Trials 26

Emergency Situations 26

Payment to Study Subjects 27

Payment Information in the Consent Form 27

Composition, Functions, and Operations 27

IRB/IEC Standard Operating Procedures 28

Records 29

1.4 Roles and Responsibilities of the Clinical Trial Investigator 29

1.4.1 Investigator's Qualifications and Agreements 29

1.4.2 Adequate Resources 30

1.4.3 Medical Care of Trial Subjects 30

1.4.4 Communication with IRB/IEC 31

1.4.5 Compliance with Protocol 31

1.4.6 Investigational Product(s) 32

1.4.7 Randomization Procedures and Unblinding 33

1.4.8 Informed Consent of Trial Subjects 33

1.4.9 Records and Reports 37

1.4.10 Progress Reports 38

Safety Reporting 38

1.4.11 Premature Termination or Suspension of a Trial 38

1.5 Clinical Trial Protocol and Protocol Amendments 39

1.5.1 Contents of Trial Protocol 39

1.5.2 Investigator's Brochure 42

Introduction 42

General Considerations 43

Contents of the Investigator's Brochure 43

Chapter 2 Therapeutic Products Clinical Development in the United States 47

2.1 Drug Discovery 47

2.2 Preclinical Development 47

2.2.1 In Vitro Testing 47

2.2.2 In Vivo Testing (Animal Testing) 48

2.3 Clinical Development 48

2.4 FDA Considerations for Drug Development 50

2.4.1 Pre-IND Meeting 50

2.4.2 End of Phase II Meeting 50

2.4.3 Pre-NDA Meeting 51

2.5 Phase IV, Postmarketing Surveillance and GCP 51

2.6 Quality Assurance in Clinical Research 52

2.7 FDA Inspectional Background and Data 53

2.7.1 The FDA and GCP 53

2.7.2 FDA: Responsibilities of the Sponsor (Subpart D 21 CFR 312.50 to 21 CFR 312.58) 54

2.7.3 FDA: Responsibilities of the Investigator - (Subpart D 21 CFR 312.50 to 21 CFR 312.58) 56

Investigator Recordkeeping and Record Retention 56

Investigator Reports 57

Assurance of IRB Review 57

Inspection of Investigator's Records and Reports 57

Handling of Controlled Substances 58

Disqualification of a Clinical Investigator 58

2.7.4 FDA: Responsibilities of the Institutional Review Board (21 CFR Part 56) 59

Circumstances in Which IRB Review is Required 59

Exemptions from IRB Requirement 59

Waiver of IRB Requirement 60

IRB Membership 60

IRB Functions and Operations 61

IRB Review of Research 61

Expedited Review Procedures for Certain Kinds of Research Involving No More than Minimal Risk and for Minor Changes in Approved Research 62

Criteria for IRB Approval of Research 63

Review by Institution 64

Suspension or Termination of IRB Approval of Research 64

Cooperative Research 64

IRB Records 64

Lesser Administrative Actions for Noncompliance 65

Disqualification of an IRB or an Institution 65

Public Disclosure of Information Regarding Revocation 66

Reinstatement of an IRB or an Institution 66

Actions Alternative or Additional to Disqualification 66

2.8 FDA Bioresearch Monitoring Program 67

2.8.1 Clinical Trials Inspections! Background 67

2.8.2 Program Objectives 67

2.8.3 Types of Inspections Performed by the FDA 67

Routine Inspections 67

Directed (for Cause) Inspections 68

Classification of Inspections 68

2.8.4 Who Is Inspected? 68

2.8.5 Implementation of the FDA's Application Integrity Policy 68

2.8.6 BIMO Inspections for Clinical Trials 69

2.8.7 The FDA and International GCP Inspections 74

Criteria for International Sites Selection for Inspection 76

Chapter 3 The Inspection Preparation 77

3.1 Conduct of an Internal GCP Inspection: Quality Assurance Inspection 77

3.2 Steps to Prepare for the Internal QA Inspection 78

3.2.1 Inspection of the Trial Master File (TMF) 78

3.2.2 Inspection of an Investigator Site 79

3.2.3 Inspection of the Contract Research Organization (CRO) 79

3.2.4 Inspection of Clinical Laboratories 79

3.3 The GCP Quality Assurance Unit 80

3.3.1 Scope of an Internal GCP Inspection 80

3.3.2 Outcome of an Internal Inspection 81

3.4 Steps to Prepare for the Regulatory Inspection 82

3.5 Clinical Investigator Inspections Preparation 84

3.6 What to Do When an Investigator Site FDA Inspection is Announced 84

3.7 Sponsor's Inspection Preparation 86

3.8 What to Do When Sponsors FDA Inspector Arrive Unannounced 87

3.9 The Institutional Review Board Inspections Preparation 88

3.9.1 Central IRBs 90

3.10 What to Do When an IRB FDA Inspection is Announced 91

3.11 The Investigator Site Inspection 92

3.11.1 Objective of an FDA Investigator Site Inspection 92

3.11.2 Dynamics of a Clinical Investigator's Inspection (Scope) 93

3.12 Investigator's Responsibilities 93

3.13 Types of Clinical Investigator Site Inspections 101

3.14 Inspecdonal Procedures 102

3.14.1 The Investigator Site Documentation and Organization 102

3.14.2 The Sponsor's Role in the Investigator Site Audit 103

3.14.3 The Clinical Investigator Site Inspection Step by Step: The Day of the Inspection 103

3.15 FDA Audit Procedures for Investigative Sites 104

3.15.1 Authority and Administration 104

3.15.2 Inspecting the Protocol 106

3.15.3 Inspecting Subjects' Records 106

3.15.4 Inspecting Other Study Records 109

3.15.5 Inspecting the Consent of Human Subjects 109

3.15.6 Inspecting the Institutional Review Board Documentation 110

3.15.7 Inspecting the Sponsor's Documentation and Communications at the Investigator Site 111

3.15.8 Inspecting the Investigational Product (Test Article Accountability) 112

3.15.9 Inspecting the Records Retention Process 113

3.15.10 Inspecting Electronic Records and Signatures 113

3.15.11 Inspecting Device Studies 115

3.16 FDA Inspections of International Clinical Trial Sites 115

3.17 The Audit Report and Form 483 116

3.17.1 The Exit Interview 116

3.17.2 What Is Form 483? 117

3.17.3 Responding to a Form 483 119

3.17.4 The Follow-up 121

3.17.5 Warning Letter 121

3.17.6 Regulatory Actions Against Clinical Investigators 124

Notice of Initiation of Disqualification Proceeding and Opportunity to Explain (NIDPOE) (312.70) 124

What is a Disqualification of an Investigator? 125

What is the Consent Agreement? 125

3.17.7 The Clinical Hold 125

Issue of the Clinical Hold 126

Scope of the Clinical Hold 126

Meaning of the Clinical Hold 126

Extent of the Clinical Hold 126

Lift of the Clinical Hold 127

3.17.8 Reinstatement of Disqualified Investigators 127

3.17.9 Regulatory Action Against Companies or Persons (Not Investigators): Debarment 127

Chapter 4 Analysis of Warning Letters 129

4.1 Analysis of Warning Letters Issued to Clinical Investigators 129

4.1.1 Most Common Findings of Investigator Site Inspections 129

Findings Relating to Patient Information and Consent Form and Process 129

Findings Relating to Investigator's Supervision of the Clinical Trial 133

Findings Relating to Protocol Adherence 135

Findings Relating to Records in Clinical Trials 138

Findings Relating to the Investigational Product in Clinical Trials 142

Findings Relating to the Reporting of Adverse Events 143

Findings Relating to the Institutional Review Board's Approvals and Reporting 146

Findings Relating to the Investigator Acting in a Dual Role of Sponsor-Investigator 148

4.2 An Analysis of Warning Letters Issued to Clinical Trial Sponsors 149

4.2.1 Most Common Sponsors of Clinical Investigations Findings 149

Findings Relating to the Sponsor's Responsibilities to Ensure Proper Monitoring of a Clinical Trial 149

Findings Relating to the Sponsor's Responsibilities for the Investigational Product 152

Findings Relating to the Sponsor's Records of a Clinical Investigation 152

Findings Relating to the Sponsor Obtaining an IND to Conduct a Study 153

Findings Relating to the Sponsor's Responsibilities to Secure Agreements Within Parties 153

4.3 Analysis of Warning Letters Issued to Institutional Review Boards 154

4.3.1 Most Common Institutional Review Board Findings 155

Findings Relating to IRB Operational Procedures 155

Findings Relating to IRB Initial and Continuing Review Process 159

Findings Relating to IRB Recordkeeping and Retention 160

Findings Relating to IRB Composition and Membership 162

Findings Relating to IRB Review Process 163

Findings Relating to IRB Review Process of Special Populations in Clinical Trials 165

Administrative Actions to IRBs 165

Reinstatement of a Disqualified IRB 166

Conclusions on the Findings 167

Chapter 5 Fraud and Misconduct in Clinical Research 169

5.1 What Type of Data is Falsified? 170

5.2 How is Data Falsified? 171

5.3 Why is Data Falsified? 172

5.4 Who Falsified the Data? 172

5.5 What Can be Done to Detect Fraud? 173

5.6 How Do We Prevent Fraud? 173

Appendix A Some Answers to the Most Problematic Questions in Compliance 177

How Can an Investigator Site Demonstrate That the Proper Consent Process Was Followed? 177

How Does One Demonstrate that a Subject Understood the Consent Information? 177

How Does One Demonstrate that all the Clinical Trial Procedures were Followed? 178

How Does One Demonstrate Principal Investigator Personal Involvement in the Supervision of Clinical Trial Activities? 178

Why Follow Standard Operating Procedures in Clinical Trials? 178

Appendix B Guidance for Industry-E6 Good Clinical Practice: Consolidated Guidance 179

Introduction 181

Appendix C World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects 225

A Introduction 225

B Basic Principles for all Medical Research 226

C Additional Principles for Medical Research Combined with Medical Care 228

Appendix D Nuremberg Code 231

Appendix E The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research 233

Part A Boundaries Between Practice and Research 235

Part B Basic Ethical Principles 236

Part C Applications 238

Index 245

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