The Design and Management of Medical Device Clinical Trials

SALAH M. ABDEL-ALEEM, PhD, is Senior Manager of Clinical Operations at Proteus Biomedical, Inc., a medical device and pharmaceutical company that develops therapies for cardiovascular and diabetic diseases.¿He has over twenty years of experience in academic and corporate settings and has performed clinical research tasks and activities, such as the development of clinical standard operating procedures, clinical protocols, case report forms, clinical study forms, and investigator brochures for various academic and corporate settings. Dr. Abdel-aleem is the author of Design, Execution, and Management of Medical Device Clinical Trials, also published by Wiley.

List of Abbreviations xi

Preface xiii

Acknowledgments xvii

1. Challenges to the Design of Clinical Study 1

Development of Clinical SOPs 3

Selection of Study Patients, Investigators, and Study Sites 3

Definition of Enrolled Subjects in a Clinical Study 7

Definition of the Investigational Device System 7

Research Contract Challenges 7

Review of Literature 9

Challenges to the Design of the Study Protocol, Statistical Analysis Plan (SAP), and Selection of Study Endpoints 11

Masking or Blinding 12

Primary and Secondary Outcomes 14

Selection of Study Endpoints 14

Differences between the Primary Endpoint in FDA and CE Mark Studies 15

SAP and Study Endpoints 15

Components of the SAP for Clinical Trials 17

Roles and Responsibilities of the Clinical Personnel in Completing the Study Protocol 19

Changing the Primary Outcome during the Conduct of the Study 20

Definition of Primary and Secondary Endpoints 22

Combined “Composite” Endpoints 22

Surrogate Endpoints 23

Reducing the Study’s Sample Size 25

Statistical Terms to Define Endpoint Measurements 25

Reporting Results of Clinical Trials 28

Superiority and Equivalence Trials 30

Subgroup Analysis 33

Challenges to ICF 35

Risk/Benefit Analysis 41

2. Challenges to Managing the Study 43

Enhancing Patient Enrollment by Relaxation of Study Criteria 45

Compliance with the Study Protocol 46

Challenges Associated with Data Accuracy and Completeness 47

Data Analysis 49

Data Integrity 55

Criteria for Using Meta-Analysis Studies 56

Who Should have Access to Clinical Trial Records 57

Managing Study Data and Quality Assurance 58

Missing Data Analysis 59

Examination of Data across Study Sites 60

Challenges to Adverse Event Reporting 62

Adverse Event Coding Systems 66

Protocol Deviation Report 68

Adverse Event Reporting in Final Study Clinical Report 68

Difference between the US and EU Definitions and Reporting of Adverse Events 69

Adverse Event Reporting Challenges 69

Minimization of Bias in Clinical Trials 69

3. Selection of Historic Controls 71

Types of Control Group in Medical Device Clinical Trials 73

Purpose of Control Group 73

Use of Placebo Control 74

Advantages of Randomized Control Clinical Trials 74

Disadvantages of Randomized Control Clinical Trials 74

Commonly Used Pivotal Designs 75

Definition of Historic Control 77

Objective Performance Criteria (OPC) 78

Examples of Clinical Studies with Historic Controls 80

LACI Clinical Study 80

Left Ventricular Assist Devices 86

Summary of Clinical Studies 88

Summary of Recommendations for Historic Control 96

4. Fraud and Misconduct in Clinical Trials 99

Fraud and Misconduct in Clinical Trials 100

Warning Signs of Fraud 101

Tips for Detecting Serious Misconduct 102

False Claims Act 102

Fraud Prevention 103

Policy on Handling Complaints of Misconduct 103

Reporting Research Misconduct 104

Bioresearch Monitoring Information System (BMIS) 104

5. Challenges to the Regulation of Medical Device 107

Determination of 510(K) Devices 108

510(K) “Substantial Equivalence Decision Making Process” 111

Determination of Nonsignificant Risk Devices (NSR) 111

Similarities and Differences between Medical Device and Drug Regulations in Clinical Trials 112

Definitions of Drugs and Devices 113

Combination Products 126

FDA–Sponsor Meetings 129

BIMO Inspection 130

Investigator-Initiated Clinical Trials 132

6. Challenges of Global Clinical Studies and the CE Mark Process 137

Global Trial Considerations 138

Global Harmonization Task Force Challenges 142

FDA Recommendations on Acceptance of Foreign Clinical Sites 143

Operational Tips on Conductance of Global Clinical Trials 143

CE Mark Process and Challenges 146

International Standard ISO 14155 148

Differences between FDA and CE Mark Clinical Trials 157

Challenges to CE Mark Studies 160

7. Challenging FDA PMA Cases 163

PMA P970029 (TMR 2000 Holmium Laser System) 164

PMA P040012 Carotid Stenting for Treating Carotid Disease 175

Historic Control Assumptions 175

Use of Angiographic Late Loss as Primary Endpoint in Drug-Eluting Stent PMA P070015 (Xience V DES) 186

8. Bioethics in Clinical Research 199

Bioethical Challenges in Clinical Studies 200

Good Clinical Practice for the Investigator 201

WHO Principles of GCP 202

Guidelines and Ethical Principles 204

IRB Review Process 206

Glossary of Clinical, CE Mark, and Statistical Terms 211

References 217

Index 221