Clinical Trials Audit Preparation (eBook)

A Guide for Good Clinical Practice (GCP) Inspections

Vera Mihajlovic-Madzarevic (Autor)

eBook Download: PDF

2011
John Wiley & Sons (Verlag)
978-0-470-57274-0 (ISBN)

Infos

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

VERA MIHAJLOVIC-MADZAREVIC has more than twenty years of experience in scientific and clinical research in the academia and industry. She is the Director of Global Research Pharma Canada. She conducts Good Clinical Practice (GCP) audits for the pharmaceutical, biotech, and medical device industries worldwide in compliance with FDA, Health Canada, and other regulations. She also trains clinical and scientific personnel in GCP and clinical research, leading the Training and Professional Development Programs at the Clinical Research Institute of America (criamerica.com) and the Academy of Applied Pharmaceutical Sciences.

Inhalt

CLINICAL TRIALSAUDIT PREPARATION 3
CONTENTS 7
PREFACE 15
INTRODUCTION 17
Background History on Clinical Research Standards 17
GLOSSARY 19
CHAPTER 1 GOOD CLINICAL PRACTICE AND THERAPEUTIC PRODUCT DEVELOPMENT 25
1.1 Good Clinical Practice in Clinical Research 26
1.1.1 Definition 26
1.1.2 GCP Compliance 26
1.1.3 GCP Objectives 26
1.1.4 Principles of ICH GCP 27
Clinical Trial Conduct 27
Risk Assessment 27
Subject’s Rights and Safety 27
Background Information 27
Clinical Trial Protocol 27
Ethics Review and Approval 27
Medical Care of Trial Subject 28
Qualifications of Clinical Trial Personnel 28
Informed Consent Process 28
Data Management 28
Patient Confidentiality 28
Investigational Product Manufacturing, Handling, and Storage 28
Quality Assurance 28
1.1.5 GCP Applicability 29
1.2 Role of the Sponsor of a Clinical Investigation 30
1.2.1 GCP: Responsibilities of a Sponsor of a Clinical Trial 30
1.2.2 Essential Documents for the Clinical Trial 33
Retention of the Essential Documents for the Clinical Trial 33
Archiving of the Essential Documents for the Clinical Trial After Discontinuation of Development 33
Notification 34
Transfer of Data Ownership 34
Records Retention 34
1.2.3 Investigator Selection 34
Investigator’s Qualifications 34
Resources at the Investigator’s Site 35
Protocol and Investigator’s Brochure 35
Agreement with the Investigator/Institution 35
1.2.4 Allocation of Responsibilities 35
1.2.5 Compensation to Subjects and Investigators 36
Compensation to Subjects for Trial-Related Injuries 36
Other types of Compensation to Trial Subjects 36
1.2.6 Financing 36
1.2.7 Notification/Submission to Regulatory Authorities 37
1.2.8 Confirmation of Review by IRB/IEC 37
1.2.9 Information on Investigational Products 38
1.2.10 Manufacturing, Packaging, Labelling, and Coding Investigational Products 38
Characterization, Manufacturing, and Labeling of the Investigational Product 38
Storage Conditions 38
Packaging of the Investigational Product 38
Coding and Decoding of the Investigational Product 38
Investigational Product Changes and Bioequivalence Studies 39
1.2.11 Supplying and Handling Investigational Products 39
Supply 39
Investigational Product Records 39
1.2.12 Record Access 40
Verification of Patient Consent to Record Access 40
1.2.13 Safety Information 40
Safety Issues 40
Communication of Safety Issues 40
1.2.14 Adverse Drug Reaction Reporting 41
Serious Unexpected Adverse Drug Reactions 41
SAE Reporting Compliance 41
Safety Updates and Periodic Reports 41
1.2.15 Monitoring 41
Purposes 42
Selection and Qualifications of Monitors 42
Monitoring Strategies 43
Monitor’s Responsibilities 43
Monitoring Procedures 45
Monitoring Report 45
1.2.16 Audit 45
Selection and Qualifications of Auditors 46
Auditing Procedures 46
Site Selection Criteria for Inspection 46
Reporting of Findings 47
Audit Certificate 47
1.2.17 Noncompliance 47
1.2.18 Premature Termination or Suspension of a Trial 48
1.2.19 Clinical Trial/Study Reports 48
1.2.20 Multicenter Trials 48
1.3 Role of the Institutional Review Board/Independent Ethics Committee (IRB/IEC) 49
1.3.1 Responsibilities 49
Document Gathering 49
Review of Documentation 50
1.3.2 Considerations for Review 50
1.3.3 Additional Information to be Provided To Subjects 50
Nontherapeutic Trials 50
Emergency Situations 50
Payment to Study Subjects 51
Payment Information in the Consent Form 51
Composition, Functions, and Operations 51
IRB/IEC Standard Operating Procedures 52
Records 53
1.4 Roles and Responsibilities of the Clinical Trial Investigator 53
1.4.1 Investigator’s Qualifications and Agreements 53
1.4.2 Adequate Resources 54
1.4.3 Medical Care of Trial Subjects 54
1.4.4 Communication with IRB/IEC 55
1.4.5 Compliance with Protocol 55
1.4.6 Investigational Product(s) 56
1.4.7 Randomization Procedures and Unblinding 57
1.4.8 Informed Consent of Trial Subjects 57
1.4.9 Records and Reports 61
1.4.10 Progress Reports 62
Safety Reporting 62
1.4.11 Premature Termination or Suspension of a Trial 62
1.5 Clinical Trial Protocol and Protocol Amendments 63
1.5.1 Contents of Trial Protocol 63
1.5.2 Investigator’s Brochure 66
Introduction 66
General Considerations 67
Contents of the Investigator’s Brochure 67
CHAPTER 2 THERAPEUTIC PRODUCTS CLINICAL DEVELOPMENT IN THE UNITED STATES 71
2.1 Drug Discovery 71
2.2 Preclinical Development 71
2.2.1 In Vitro Testing 71
2.2.2 In Vivo Testing (Animal Testing) 72
2.3 Clinical Development 72
2.4 FDA Considerations for Drug Development 74
2.4.1 Pre-IND Meeting 74
2.4.2 End of Phase II Meeting 74
2.4.3 Pre-NDA Meeting 75
2.5 Phase IV, Postmarketing Surveillance and GCP 75
2.6 Quality Assurance in Clinical Research 76
2.7 FDA Inspectional Background and Data 77
2.7.1 The FDA and GCP 77
2.7.2 FDA: Responsibilities of the Sponsor (Subpart D 21 CFR 312.50 to 21 CFR 312.58) 78
2.7.3 FDA: Responsibilities of the Investigator – (Subpart D 21 CFR 312.50 to 21 CFR 312.58) 80
Investigator Recordkeeping and Record Retention 80
Investigator Reports 81
Assurance of IRB Review 81
Inspection of Investigator’s Records and Reports 81
Handling of Controlled Substances 82
Disqualification of a Clinical Investigator 82
2.7.4 FDA: Responsibilities of the Institutional Review Board (21 CFR Part 56) 83
Circumstances in Which IRB Review is Required 83
Exemptions from IRB Requirement 83
Waiver of IRB Requirement 84
IRB Membership 84
IRB Functions and Operations 85
IRB Review of Research 85
Expedited Review Procedures for Certain Kinds of Research Involving No More than Minimal Risk and for Minor Changes in Approved Research 86
Criteria for IRB Approval of Research 87
Review by Institution 88
Suspension or Termination of IRB Approval of Research 88
Cooperative Research 88
IRB Records 88
Lesser Administrative Actions for Noncompliance 89
Disqualification of an IRB or an Institution 89
Public Disclosure of Information Regarding Revocation 90
Reinstatement of an IRB or an Institution 90
Actions Alternative or Additional to Disqualification 90
2.8 FDA Bioresearch Monitoring Program 91
2.8.1 Clinical Trials Inspectional Background 91
2.8.2 Program Objectives 91
2.8.3 Types of Inspections Performed by the FDA 91
Routine Inspections 91
Directed (for Cause) Inspections 92
Classification of Inspections 92
2.8.4 Who Is Inspected? 92
2.8.5 Implementation of the FDA’s Application Integrity Policy 92
2.8.6 BIMO Inspections for Clinical Trials 93
2.8.7 The FDA and International GCP Inspections 98
Criteria for International Sites Selection for Inspection 100
CHAPTER 3 THE INSPECTION PREPARATION 101
3.1 Conduct of an Internal GCP Inspection: Quality Assurance Inspection 101
3.2 Steps to Prepare for the Internal QA Inspection 102
3.2.1 Inspection of the Trial Master File (TMF) 102
3.2.2 Inspection of an Investigator Site 103
3.2.3 Inspection of the Contract Research Organization (CRO) 103
3.2.4 Inspection of Clinical Laboratories 103
3.3 The GCP Quality Assurance Unit 104
3.3.1 Scope of an Internal GCP Inspection 104
3.3.2 Outcome of an Internal Inspection 105
3.4 Steps to Prepare for the Regulatory Inspection 106
3.5 Clinical Investigator Inspections Preparation 108
3.6 What to Do When an Investigator Site FDA Inspection is Announced 108
3.7 Sponsor’s Inspection Preparation 110
3.8 What to Do When Sponsors FDA Inspector Arrive Unannounced 111
3.9 The Institutional Review Board Inspections Preparation 112
3.9.1 Central IRBs 114
3.10 What to Do When an IRB FDA Inspection is Announced 115
3.11 The Investigator Site Inspection 116
3.11.1 Objective of an FDA Investigator Site Inspection 116
3.11.2 Dynamics of a Clinical Investigator’s Inspection (Scope) 117
3.12 Investigator’s Responsibilities 117
3.13 Types of Clinical Investigator Site Inspections 125
3.14 Inspectional Procedures 126
3.14.1 The Investigator Site Documentation and Organization 126
3.14.2 The Sponsor’s Role in the Investigator Site Audit 127
3.14.3 The Clinical Investigator Site Inspection Step by Step: The Day of the Inspection 127
3.15 FDA Audit Procedures for Investigative Sites 128
3.15.1 Authority and Administration 128
3.15.2 Inspecting the Protocol 130
3.15.3 Inspecting Subjects’ Records 130
3.15.4 Inspecting Other Study Records 133
3.15.5 Inspecting the Consent of Human Subjects 133
3.15.6 Inspecting the Institutional Review Board Documentation 134
3.15.7 Inspecting the Sponsor’s Documentation and Communications at the Investigator Site 135
3.15.8 Inspecting the Investigational Product (Test Article Accountability) 136
3.15.9 Inspecting the Records Retention Process 137
3.15.10 Inspecting Electronic Records and Signatures 137
3.15.11 Inspecting Device Studies 139
3.16 FDA Inspections of International Clinical Trial Sites 139
3.17 The Audit Report and Form 483 140
3.17.1 The Exit Interview 140
3.17.2 What Is Form 483? 141
3.17.3 Responding to a Form 483 143
3.17.4 The Follow-up 145
3.17.5 Warning Letter 145
3.17.6 Regulatory Actions Against Clinical Investigators 148
Notice of Initiation of Disqualification Proceeding and Opportunity to Explain (NIDPOE) (312.70) 148
What is a Disqualification of an Investigator? 149
What is the Consent Agreement? 149
3.17.7 The Clinical Hold 149
Issue of the Clinical Hold 150
Scope of the Clinical Hold 150
Meaning of the Clinical Hold 150
Extent of the Clinical Hold 150
Lift of the Clinical Hold 151
3.17.8 Reinstatement of Disqualified Investigators 151
3.17.9 Regulatory Action Against Companies or Persons (Not Investigators): Debarment 151
CHAPTER 4 ANALYSIS OF WARNING LETTERS 153
4.1 Analysis of Warning Letters Issued to Clinical Investigators 153
4.1.1 Most Common Findings of Investigator Site Inspections 153
Findings Relating to Patient Information and Consent Form and Process 153
Findings Relating to Investigator’s Supervision of the Clinical Trial 157
Findings Relating to Protocol Adherence 159
Findings Relating to Records in Clinical Trials 162
Findings Relating to the Investigational Product in Clinical Trials 166
Findings Relating to the Reporting of Adverse Events 167
Findings Relating to the Institutional Review Board’s Approvals and Reporting 170
Findings Relating to the Investigator Acting in a Dual Role of Sponsor–Investigator 172
4.2 An Analysis of Warning Letters Issued to Clinical Trial Sponsors 173
4.2.1 Most Common Sponsors of Clinical Investigations Findings 173
Findings Relating to the Sponsor’s Responsibilities to Ensure Proper Monitoring of a Clinical Trial 173
Findings Relating to the Sponsor’s Responsibilities for the Investigational Product 176
Findings Relating to the Sponsor’s Records of a Clinical Investigation 176
Findings Relating to the Sponsor Obtaining an IND to Conduct a Study 177
Findings Relating to the Sponsor’s Responsibilities to Secure Agreements Within Parties 177
4.3 Analysis of Warning Letters Issued to Institutional Review Boards 178
4.3.1 Most Common Institutional Review Board Findings 179
Findings Relating to IRB Operational Procedures 179
Findings Relating to IRB Initial and Continuing Review Process 183
Findings Relating to IRB Recordkeeping and Retention 184
Findings Relating to IRB Composition and Membership 186
Findings Relating to IRB Review Process 187
Findings Relating to IRB Review Process of Special Populations in Clinical Trials 189
Administrative Actions to IRBs 189
Reinstatement of a Disqualified IRB 190
Conclusions on the Findings 191
CHAPTER 5 FRAUD AND MISCONDUCT IN CLINICAL RESEARCH 193
5.1 What Type of Data is Falsified? 194
5.2 How is Data Falsified? 195
5.3 Why is Data Falsified? 196
5.4 Who Falsified the Data? 196
5.5 What Can be Done to Detect Fraud? 197
5.6 How Do We Prevent Fraud? 197
APPENDIX A SOME ANSWERS TO THE MOST PROBLEMATIC QUESTIONS IN COMPLIANCE 201
How Can an Investigator Site Demonstrate That the Proper Consent Process Was Followed? 201
How Does One Demonstrate that a Subject Understood the Consent Information? 201
How Does One Demonstrate that all the Clinical Trial Procedures were Followed? 202
How Does One Demonstrate Principal Investigator Personal Involvement in the Supervision of Clinical Trial Activities? 202
Why Follow Standard Operating Procedures in Clinical Trials? 202
APPENDIX B GUIDANCE FOR INDUSTRY—E6 GOOD CLINICAL PRACTICE: CONSOLIDATED GUIDANCE 203
Introduction 203
APPENDIX C WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ETHICAL PRINCIPLES FOR MEDICAL RESEARCH INVOLVING HUMAN SUBJECTS 249
A. Introduction 249
B. Basic Principles for all Medical Research 250
C. Additional Principles for Medical Research Combined with Medical Care 252
APPENDIX D NUREMBERG CODE 255
APPENDIX E THE BELMONT REPORT: ETHICAL PRINCIPLES AND GUIDELINES FOR THE PROTECTION OF HUMAN SUBJECTS OF RESEARCH 257
Part A: Boundaries Between Practice and Research 259
Part B: Basic Ethical Principles 260
Part C: Applications 262
INDEX 269

Rezensionen

"To help the reader, in addition to the detailed and meticulous discussions in the book's five chapters, appendices provide ready access to fundamental literature . . .Clinical Trials Audit Preparation is recommended to readers, and receives the JCS Library Award." (Journal for Clinical Studies, 1 November 2010)

"Clinical Trials Audit Preparation: A Guide for Good Clinical Practice (GCP) Inspections" is a comprehensive manual for avoiding inspections, preparing for inspections, and being inspected. It is also a useful guide for inspectors." (Journal of Clinical Research Best Practices, 6 June 2011)

Produkt-Details

• Erscheint lt. Verlag: 1.3.2011
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie
• Themenwelt: Naturwissenschaften ► Chemie
• Schlagworte: Audit • Boards • Book • Chemie • Chemistry • Clinical • Drug • Drug Discovery & Development • Explanation • FDA • GCP • good clinical • Guide • institutional • Klinische Studien • Manufacturing • musthave • Parties • Pharmaceutical companies • Pharmaceutical Statistics • Pharmazeutische Statistik • Practice • Preparation • Prepare • Process • Professional • Qualitätssicherung • Qualitätssicherung in der Chemie • Qualitätssicherung • Qualitätssicherung in der Chemie • Quality assurance • Research • Statistics • Statistik • stepbystep • tedious • Wirkstoffforschung u. -entwicklung
• ISBN-10: 0-470-57274-4 / 0470572744
• ISBN-13: 978-0-470-57274-0 / 9780470572740