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 xiPreface xiiiAcknowledgments xvii1. Challenges to the Design of Clinical Study 1Development of Clinical SOPs 3Selection of Study Patients, Investigators, and Study Sites 3Definition of Enrolled Subjects in a Clinical Study 7Definition of the Investigational Device System 7Research Contract Challenges 7Review of Literature 9Challenges to the Design of the Study Protocol, Statistical Analysis Plan (SAP), and Selection of Study Endpoints 11Masking or Blinding 12Primary and Secondary Outcomes 14Selection of Study Endpoints 14Differences between the Primary Endpoint in FDA and CE Mark Studies 15SAP and Study Endpoints 15Components of the SAP for Clinical Trials 17Roles and Responsibilities of the Clinical Personnel in Completing the Study Protocol 19Changing the Primary Outcome during the Conduct of the Study 20Definition of Primary and Secondary Endpoints 22Combined “Composite” Endpoints 22Surrogate Endpoints 23Reducing the Study’s Sample Size 25Statistical Terms to Define Endpoint Measurements 25Reporting Results of Clinical Trials 28Superiority and Equivalence Trials 30Subgroup Analysis 33Challenges to ICF 35Risk/Benefit Analysis 412. Challenges to Managing the Study 43Enhancing Patient Enrollment by Relaxation of Study Criteria 45Compliance with the Study Protocol 46Challenges Associated with Data Accuracy and Completeness 47Data Analysis 49Data Integrity 55Criteria for Using Meta-Analysis Studies 56Who Should have Access to Clinical Trial Records 57Managing Study Data and Quality Assurance 58Missing Data Analysis 59Examination of Data across Study Sites 60Challenges to Adverse Event Reporting 62Adverse Event Coding Systems 66Protocol Deviation Report 68Adverse Event Reporting in Final Study Clinical Report 68Difference between the US and EU Definitions and Reporting of Adverse Events 69Adverse Event Reporting Challenges 69Minimization of Bias in Clinical Trials 693. Selection of Historic Controls 71Types of Control Group in Medical Device Clinical Trials 73Purpose of Control Group 73Use of Placebo Control 74Advantages of Randomized Control Clinical Trials 74Disadvantages of Randomized Control Clinical Trials 74Commonly Used Pivotal Designs 75Definition of Historic Control 77Objective Performance Criteria (OPC) 78Examples of Clinical Studies with Historic Controls 80LACI Clinical Study 80Left Ventricular Assist Devices 86Summary of Clinical Studies 88Summary of Recommendations for Historic Control 964. Fraud and Misconduct in Clinical Trials 99Fraud and Misconduct in Clinical Trials 100Warning Signs of Fraud 101Tips for Detecting Serious Misconduct 102False Claims Act 102Fraud Prevention 103Policy on Handling Complaints of Misconduct 103Reporting Research Misconduct 104Bioresearch Monitoring Information System (BMIS) 1045. Challenges to the Regulation of Medical Device 107Determination of 510(K) Devices 108510(K) “Substantial Equivalence Decision Making Process” 111Determination of Nonsignificant Risk Devices (NSR) 111Similarities and Differences between Medical Device and Drug Regulations in Clinical Trials 112Definitions of Drugs and Devices 113Combination Products 126FDA–Sponsor Meetings 129BIMO Inspection 130Investigator-Initiated Clinical Trials 1326. Challenges of Global Clinical Studies and the CE Mark Process 137Global Trial Considerations 138Global Harmonization Task Force Challenges 142FDA Recommendations on Acceptance of Foreign Clinical Sites 143Operational Tips on Conductance of Global Clinical Trials 143CE Mark Process and Challenges 146International Standard ISO 14155 148Differences between FDA and CE Mark Clinical Trials 157Challenges to CE Mark Studies 1607. Challenging FDA PMA Cases 163PMA P970029 (TMR 2000 Holmium Laser System) 164PMA P040012 Carotid Stenting for Treating Carotid Disease 175Historic Control Assumptions 175Use of Angiographic Late Loss as Primary Endpoint in Drug-Eluting Stent PMA P070015 (Xience V DES) 1868. Bioethics in Clinical Research 199Bioethical Challenges in Clinical Studies 200Good Clinical Practice for the Investigator 201WHO Principles of GCP 202Guidelines and Ethical Principles 204IRB Review Process 206Glossary of Clinical, CE Mark, and Statistical Terms 211References 217Index 221