Design, Execution, and Management of Medical Device Clinical Trials

List of Abbreviations xi

Preface xv

Acknowledgments xxi

1 An Overview of Clinical Study Tasks and Activities 1

Key Clinical Study Tasks and Activities 2

Discussion of Key Tasks and Activities 3

Management of Key Clinical Tasks and Activities 9

Example of the Spread Sheet for Managing Clinical Study Activities 10

The Clinical Research Team 10

2 Development of Clinical Protocols, Case Report Forms, Clinical Standard Operating Procedures, Informed Consent Form, Study Regulatory Binder, Study Research Agreement, and Other Clinical Materials 15

Clinical Protocol 17

Case Report Forms (CRFs) 28

Example of the Case Report Form Template 32

Informed Consent Form (ICF) 35

Instructions for Use of Device 38

Study Regulatory Binder 39

Study Research Agreement 40

Research Agreement Template 43

Research Contract Challenges 50

Clinical Forms and Certificates 51

Clinical Standard Operating Procedures (SOPs) 54

3 Qualification/Selection of Study Investigators and Study Monitoring Visits 63

Qualification and Selection of Investigators 64

Monitoring Visits 67

Monitoring Reports 73

Interim Monitoring Visit Report Template 75

4 Adverse Events Definitions and Reporting Procedures 81

Adverse Event Definitions 83

Policies, Regulations, and Guidelines Regarding Adverse Event Reporting 84

Adverse Event Reporting Pathway 84

Terms for Causality Assessment 85

GAPS/Challenges in Adverse Event Reporting 86

Adverse Event Reporting Time Periods (21 CFR 803) 88

Differences between the United States and Europe in Reporting Adverse Events 88

Serious Adverse Event Narratives 89

Classification of Adverse Events 90

Special Requirement for Reporting Certain Adverse Events 92

Case Example 92

Mandatory Device Reporting for FDA-Approved Devices 92

5 Statistical Analysis Plan (SAP) and Biostatistics in Clinical Research 93

Statistical Analysis Plan (SAP) 94

Selection of Study Endpoints 97

Biostatistics in Clinical Research 101

6 Final Clinical Study Report 113

Final Clinical Report’s Outline 114

Discussion of Sections in the Final Clinical Report 116

7 Medical Device Regulations Combination Product, Study Committees, and FDA-Sponsor Meetings 127

Medical Device Regulations 129

Combination Products 164

Study Committees 168

FDA-Sponsor Meetings 170

Registration of Clinical Trials 174

Implementation of the HIPAA Privacy Rule in Clinical Research 175

Institutional Review Boards (IRB) 180

FDA’s Oversight of Clinical Trials (Bioresearch Monitoring) 191

Code of Federal Regulations of Medical Devices 194

8 Design Issues in Medical Devices Studies 195

Design of the Clinical Trial 196

Assumptions and Parameters of Clinical Trial Design 196

Clinical Trials’ Design Issues and Data Analysis Issues 202

Use of Historic Controls as the Control Group in IDE Studies 206

Summary of Recommendations When Using Historic Controls 218

9 Investigator-Initiated Clinical Research 221

Definition and Examples of Investigator-Initiated Clinical Research 222

Development, Conduct, and Management of Investigator-Initiated Clinical Research 224

Regulation of Investigator-Initiated Clinical Research 225

Required Infrastructure for Investigator-Initiated Clinical Research 226

Clinical Research Sponsored by NIH 227

10 Ethical Conduct for Human Research 229

The Nuremberg Code (1947) 230

World Medical Association—Declaration of Helsinki (1964–Present) 231

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1974) 231

The Belmont Report (1978) 232

Special Ethical Concerns in Clinical Research on Use of Placebo 232

Glossary of Clinical Trial and Statistical Terms 235

References 249

Index 255