Clinical Evaluation of Medical Devices

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1 Clinical Evaluation of Medical Devices

2 Clinical Evaluation of Medical Devices Principles and Case Studies Edited by Karen Becker Witkin THE WEINBERG GROUP, INC. Washington, DC Springer Science+ Business Media, LLC

3 1998 Springer Science+Business Media New York Originally published by Humana Press Inc. in 1998 Softcover reprint of the hardcover 1 st edition 1998 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All authored papers, comments, opinions, conclusions, or recommendations are those of the author( s), and do not necessarily reflect the views of the publisher. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: ; Fax: ; humana@mindspring.com, or visit our Website: This publication is printed on acid-free paper. Gii) ANSI Z (American Standards Institute) Permanence of Paper for Printed Library Materials. Cover design by Patricia F. Cleary. Cover illustrations (clockwise/rom top left): Fig. I in Chapter 12, "Polyurethane Pacemaker Leads: The Contribution o/clinical Experience to the Elucidation 0/ Failure Modes and Biodegradation Mechanisms, "by Ken Stokes; Fig. 2 in Chapter 6, "Prospective Multicenter Clinical Trials in Orthopedics: Special Concerns and Challenges," by John D. Van Vleet; Fig. 3 in Chapter II, "Role of Device Retrieval and Analysis in the Evaluation of Substitute Heart Valves," by Frederick 1. Schoen; Fig. 5 in Chapter 12; Fig. IB in Chapter II; and Fig. 4 in Chapter 12. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Springer Science+Business Media, LLC, provided that the base fee of US $8.00 per copy, plus, US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Springer Science+Business Media,LLC. Thefee code for users of the Transactional Reporting Service is: [ /98 $ $00.25] I Library of Congress Cataloging in Publication Data Main entry under title: Clinical evaluation of medical devices/edited by Karen Becker Witkin. p. cm. Includes index. ISBN ISBN (ebook) DOI / I. Medical instruments and apparatus-evaluation. 2. Clinical trials. I. Witkin, Karen Becker [DNLM: 1. Equipment and Supplies-standards. 2. Device Approval--standards. 3. Clinical Trials-standards. 4. Evaluation Studies. W 26 C R856.C '.28-dc21 DNLMIDLC for Library of Congress CIP

4 Foreword The world is changing rapidly, and nowhere is this more apparent than in medicine. The standards are rapidly rising in the field of medical device trials. A few years ago, device developers would look askance if one told them that medical device trials and drug trials should have the same standards. Today, such a statement does not seem as outrageous, although there is still a large gap in the design of trials and number oftrials conducted for medical device and drug development programs. More than 20 years after the enactment of the US Medical Device Amendments, we can see that they served as an impetus to raise clinical trial standards for devices. Whether the data to establish the safety and efficacy of a device come from one, two, or even more clinical trials is less important in evaluating the device than whether the data are medically and scientifically supportive of its safety and efficacy. Having at least two separate studies, and at least two sites confirm results, adds a great deal of scientific credibility and support to a conclusion of safety and efficacy, even though a confirmatory trial is not yet a regulatory requirement in most countries. It used to be easy to identify a device and a drug, but distinctions between the two are becoming blurred. There are devices that are pure chemicals and others that are taken internally. Several drug-device combinations are already available or are currently in development. Applying the clinical standards for devices to such combination trials raises several questions that must be addressed before such clinical trials are initiated (for example, determining whether a drug-device combination should adhere to either the drug or the device standards). Many people claim that device trials need not be held to high clinical standards because it is sometimes unethical to conduct such controlled trials. Although this is occasionally true (trials may also be unethical for some drugs), it is important not to use this as an excuse to avoid designing controlled trials whenever possible. Unfortunately, it is often the regulators who serve as enforcers, ensuring that this approach is followed. Clinical Evaluation o/medical Devices: Principles and Case Studies presents clear discussions of appropriate trial designs that may be used when the most rigorous designs are not possible. The readers of this book are indeed fortunate to have so many talented authors writing about this topic. Given the enormous heterogeneity of medical devices, the case studies in Part II presenting valuable real-life experiences should provide great v

5 vi Foreword benefit to readers. Although the reader working in one particular area may focus on the closest parallel chapter in Part II, there are numerous reasons why all chapters should be skimmed, if not read closely, for useful information. A careful reader will benefit immeasurably from the many experiences and lessons shared in these pages. I believe that the dedication of two-thirds of the chapters to case studies is a noteworthy strength ofthis book. Karen Becker Witkin has assembled an outstanding group of authors and has organized Clinical Evaluation of Medical Devices: Principles and Case Studies in a manner that will make sense to both experts and tyros in the device industry. Many device companies are struggling with issues of developing their products as rapidly as possible, as well as the regularly escalating standards for clinical trials. This book provides a state-of-the-art overview that will enable companies to develop their products more efficiently. Adhering to the highest possible standards in pivotal clinical studies makes good business sense because it will generate reliable data and will enable regulatory authorities to review and approve a dossier more rapidly. This enables the corporate marketing group to provide convincing data to physicians, who are the ultimate customers for the devices, because claims and performance statements can then be made for their devices that are better than those of their competitors. Another benefit of adhering to high standards is that third party payors and formulary groups can also be given convincing data. Moreover, if the product does not meet the minimally acceptable criteria established in advance of the trial, it then allows the company to terminate the project with the least psychic and monetary expense. This can be an important factor in helping a company move on to its next project, avoiding wasted time and energy on a project oflittle or no value. Bert Spilker, MD, PhD President, Orphan Medical, Inc. Minnetonka, MN

6 Preface The medical device industry is renowned for its innovative products. The successful conception, development, and continuous improvement of thousands of novel medical devices and health care technologies over the last 50 years is a testament to the productive collaboration between engineers and physicians fostered by this industry. Today, the continuing evolution in the design of new medical devices coincides with the evolution of techniques for testing these products--both during development and postmarketing. In a health care environment that demands evidence-based medicine, clinical evaluation of medical devices is increasingly a focal point of systematic research, particularly for implanted devices and technologies that significantly impact on patient health. Clinical Evaluation of Medical Devices: Principles and Case Studies is an attempt to capture the foundations and best experience of this clinical research area, now maturing into a specialty science with distinct methodologies and objectives. In recent years, the singular research approaches required for clinical studies of device performance have been enhanced by concerted efforts to adapt and incorporate the principles of rigorous clinical research developed for pharmaceutical products. Part I of this work provides an overview of the role of clinical research in the development and marketing of medical devices, the basic principles used in the design of such studies, and international regulatory requirements for research and registration of medical devices. Part II is a series of case studies selected to illustrate the broad array of study designs that have been successfully applied to many different research problems and a variety of therapeutic or diagnostic products. Clinical Evaluation of Medical Devices.' Principles and Case Studies evolved from a course I organized in collaboration with the US Food and Drug Administration, generously sponsored by the Society for Biomaterials. I am grateful to those colleagues who graciously contributed their time and expertise in the form of chapters and ideas contributing to the final concept. Additionally, without the expert and enthusiastic assistance of my associates at THE WEINBERG GROUP INC., particularly Diane Mandell and Diane Wallerson, this book would not have been possible. Finally, I am indebted to Thomas O. Henteleff and Daniel R. Dwyer (Kleinfeld, Kaplan, and Becker) for introducing me to the complex and fascinating world of vii

7 viii Preface medical device regulation, and to Myron S. Weinberg and Matthew R. Weinberg for their substantial and unquestioning support to the pursuit of my interest in this field. Karen Becker Witkin THE WEINBERG GROUP, INC. Washington, DC

8 Contents Foreword Bert Spilker... v Preface... vii Contributors... xi PART I. FUNDAMENTALS OF CLINICAL STUDY DESIGN AND EVALUATION Clinical Trials in Development and Marketing of Medical Devices Karen Becker Witkin Observational Research: The Nonexperimental Approach Rosanne B. McTyre and Linda M. Pottern Choosing and Evaluating Outcome Measures for Clinical Studies of Medical Devices Selma A. Kunitz, Michele Gargano, and Rene KozloJJ Regulatory Requirements for Clinical Trials of Medical Devices and Diagnostics Sharon A. Segal PART II. INTRODUCTION TO CASE STUDIES KAREN BECKER WITKIN Clinical Studies of Prosthetic Heart Valves Using Historical Controls Gary L. Grunkemeier Prospective Multicenter Clinical Trials in Orthopedics: Special Concerns and Challenges John D. Van Vleet Long-Term Evaluation of Total Hip Arthroplasty Frederick J. Dorey Injectable Collagen and a Rare Adverse Event-True Association or Artifact?: Results of Postmarket Surveillance Research Diane E. Mandell, Rosanne B. McTyre, Frank DeLustro, and Ross Erickson In Vitro Diagnostics: Design of Clinical Studies to Validate Effectiveness Wayne R. Patterson ix

9 x Contents 10 A Controlled Study of Intra-Articular Hyalgan in the Treatment of Osteoarthritis of the Knee Roberto Fiorentini, Frank C. Dorsey, Sharon A. Segal, and Roland Moskowitz Role of Device Retrieval and Analysis in the Evaluation of Substitute Heart Valves Frederick J. Schoen Polyurethane Pacemaker Leads: The Contribution of Clinical Experience to the Elucidation of Failure Modes and Biodegradation Mechanisms Ken Stokes Glossary Index

10 Contributors FRANK DELuSTRO, PHD Cohesion Inc., Palo Alto, CA FREDERICK J. DOREY, PHD Department of Orthopaedic Surgery and Statistics, UCLA School of Medicine, Los Angeles, CA FRANK C. DORSEY, PHD Biometric Research Institute, Inc., Arlington, VA Ross ERICKSON, PHD Collagen Corporation, Palo Alto, CA ROBERTO FIORENTINI, MD FIDIA Pharmaceutical Corp., Washington, DC MICHELE GARGANO, PHD Kunitz and Associates, Inc., Rockville, MD GARY L. GRUNKEMEIER, PHD St. Vincent Heart Institute, Portland, OR RENE KOZLOFF, PHD Kunitz and Associates, Inc., Rockville, MD SELMA A. KUNITZ, PHD Kunitz and Associates, Inc., Rockville, MD DIANE E. MANDELL, PHD THE WEINBERG GROUP, INC., Washington, DC ROSANNE B. McTYRE, PHD THE WEINBERG GROUP, INC., Washington, DC ROLAND MOSKOWITZ, MD Division of Rheumatic Diseases, Department of Medicine, University Hospitals of Cleveland, OH WAYNE R. PATTERSON, PHD Department of Pathology, The University of Texas Medical Branch, Galveston, TX LINDA M. POTTERN, PHD Office of Disease Prevention, National Institutes of Health, Bethesda, MD FREDERICK J. SCHOEN, MD, PHD Department of Pathology, Brigham and Women's Hospital, Boston, MA SHARON A. SEGAL, PHD THE WEINBERG GROUP, INC., Washington, DC BERT SPILKER, MD, PHD Orphan Medical, Minnetonka, MN KEN STOKES, PHD Medtronic, Inc., Minneapolis, MN JOHN D. VAN VLEET, PHD DePuy, Inc., Warsaw, IN KAREN BECKER WITKIN, PHD THE WEINBERG GROUP, INC., Washington, DC xi

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