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MEDICAL DEVICES AND THE PUBLIC’S HEALTH THE FDA 510(k) CLEARANCE PROCESS AT 35 YEARS Committee on the Public Health Effectiveness of the FDA 510(k) Clearance Process Board on Population Health and Public Health Practice

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. HHSF223200810020I, Task Order #13 between the National Academy of Sciences and the Department of Health and Hu- man Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-21242-7 International Standard Book Number-10: 0-309-21242-1 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap. edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2011. Medical Devices and the Public’s Health: The FDA 510(k) Clearance Process at 35 Years. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding en- gineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON THE PUBLIC HEALTH EFFECTIVENESS OF THE FDA 510(k) CLEARANCE PROCESS DAVID R. CHALLONER (Chair), Vice President for Health Affairs, Emeritus, University of Florida, Gainesville, FL GARY S. DORFMAN, Professor and Vice Chair for Research, Department of Diagnostic Radiology, Weill Cornell Medical College, New York, NY BARBARA EVANS, Associate Professor; Codirector, Health Law & Policy Institute; Director, Center on Biotechnology and Law, University of Houston Law Center, Houston, TX LAZAR J. GREENFIELD, Professor of Surgery and Chair Emeritus, University of Michigan, Ann Arbor, MI STEVEN GUTMAN, Associate Director, Technology Evaluation Center, BlueCross BlueShield Association, Alexandria, VA YUSUF M. KHAN, Assistant Professor, University of Connecticut Health Center, Farmington, CT DAVID KORN, Vice Provost for Research, Harvard University, Boston, MA ELIZABETH W. PAXTON, Director of Surgical Outcomes and Analysis, Kaiser Permanente, San Diego, CA SHARI LAWRENCE PFLEEGER, Director of Research, Institute for Information Infrastructure Protection, Washington, DC WILLIAM W. VODRA, Senior Counsel (Retired), Arnold & Porter, LLP, Washington, DC BRIAN WOLFMAN, Visiting Professor of Law, Georgetown University Law Center, Washington, DC KATHRYN C. ZOON, Scientific Director and Director, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Consultant to the Committee SUSANNE LUDGATE, Clinical Director, Medicines and Healthcare Products Regulatory Agency, UK Study Staff ABIGAIL E. MITCHELL, Study Director HEATHER M. COLVIN, Program Officer MELISSA G. FRENCH, Associate Program Officer KATHLEEN M. SHEPHERD, Senior Program Assistant NORMAN GROSSBLATT, Senior Editor ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice v

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Reviewers T his report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise, in accordance with pro- cedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individual’s for their review of this report: Halyna Breslawec, Cosmetic Ingredient Review Paul Citron, Medtronic, Inc. (retired) Khaled El Emam, University of Ottawa Ellen Flannery, Covington & Burling, LLP Thomas Fogarty, Fogarty Engineering Gordon Gillerman, National Institute of Standards and Technology George Isham, HealthPartners, Inc. Alan Kent, Global Harmonization Task Force Arthur Levin, Center for Medical Consumers Mark B. McClellan, The Brookings Institution Richard Merrill, University of Virginia Richard Platt, Harvard Medical School Miriam Provost, Biologics Consulting Group, Inc. Fran Visco, National Breast Cancer Coalition vii

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viii REVIEWERS Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Edwin P. Przybylowicz, Eastman Kodak (retired) and Brian L. Strom, University of Pennsylvania School of Medicine. Appointed by the National Research Council and In- stitute of Medicine, respectively, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the author committee and the institution.

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Acknowledgments T he committee thanks everyone who presented and participated in panel discussions during the public workshops, informing our task and assisting in developing our approach and thought process on the statement task. The following individuals presented information at the workshops: David Feigal, Arizona State University School of Law; Robert Fischell, Neuralieve, Inc.; Kevin Fu, Department of Computer Sci- ence, University of Massachusetts, Amherst; Susan Gardner, Center for Devices and Radiological Health (CDRH), US Food and Drug Adminis- tration (FDA); Ralph Hall, University of Minnesota Law School; Peter Barton Hutt, Covington and Burling, LLP; David Jeffrys, Eisai Europe Ltd.; William Maisel, formerly with the Medical Device Safety Institute (now with the FDA); Josh Makower, ExploraMed Development, LLC; Frederick Masoudi, Denver Health Medical Center; Eric Peterson, Divi- sion of Cardiology, Duke University Medical Center; Philip Phillips, PCS, LLC; Rita Redberg, Division of Cardiology, University of California, San Francisco; Frederic Resnic, Brigham and Women’s Hospital; Janet Trunzo, AdvaMed; Timothy Ulatowski, CDRH; and Paul Varosy, Department of Veterans Affairs (VA) Eastern Colorado Health Care System. Doug Mowen, of PricewaterhouseCoopers, was unexpectedly unable to present at the June 2010 workshop but provided materials for the committee’s review. Many of the presenters also participated in the panel discussions. Other panel discussants whom the committee thanks are Amy Allina, National Women’s Health whom; Susan Alpert, Medtronic, Inc.; D. Bruce Burlington, indepen- dent consultant; Larry Kessler, University of Washington School of Public Health; and William Vaughan, consultant to Consumer’s Union. ix

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x ACKNOWLEDGMENTS The committee thanks the representatives of the FDA who provided helpful information on CDRH, medical-device regulation, and various as- pects of the 510(k) clearance process: Philip Desjardins, Maggie Dietrich, Ann Ferriter, Christy Foreman, Heather Rosecrans, Donna-Bea Tillman, and Jeffrey Shuren. The committee thanks the authors of the commissioned papers: David Feigal, Arizona State University School of Law; Kevin Fu, Department of Computer Science, University of Massachusetts, Amherst; Larry Kessler, University of Washington School of Public Health; William Maisel, Medical Device Safety Institute; and Philip Phillips, PCS, LLC. The papers were an excellent resource of information and proved to be very helpful. All affilia- tions were contemporaneous. The committee thanks members of the public who provided oral com- ments during the public meetings and persons and organizations that sub- mitted written materials and comments. There was a wide variety of points of view in the commentary, and those viewpoints afforded valuable insight into the complexity of the process and its outcomes. The time and effort made in traveling to the public meetings and in preparing written materials and statements were greatly appreciated. The committee also thanks Katharine Larson and Lindsay S. Narvaez, students at the University of Houston Law Center, for their assistance in researching and formatting legal citations. The committee thanks those who provided a critical perspective of the European system of device regulation: Susanne Ludgate, of the Medicines and Healthcare Products Regulatory Agency (UK), served as a consultant to the committee, and Christopher Hodges, of the University of Oxford, also provided extremely valuable insight into the European Union’s medical- device regulatory system.

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Preface T he vast majority of the medical devices used in health care in the United States that are reviewed by the US Food and Drug Admin- istration (FDA) before entering the marketplace are cleared (not approved) for human use in a process called premarket notification, or the 510(k) clearance process, named after Section 510(k) of the authorizing legislation passed by Congress in 1976. Stimulated by reports of problems with several 510(k)-cleared devices, the public, legislators, the Government Accountability Office, the Department of Health and Human Services Of- fice of the Inspector General, and the courts, including the Supreme Court, have all questioned the logic and value of the 510(k) clearance process be- ing used by a federal agency charged with responsibility for protecting and promoting the public’s health. After 35 years, at a time of rapidly changing science and technology, questions persist about whether the 510(k) process is protecting and promoting the public’s health. Thus, the FDA asked the Institute of Medicine (IOM) to evaluate the 510(k) clearance process and to make recommendations aimed at protecting the health of the public while preserving the legitimate interests of industry and patients by making avail- able a mechanism to achieve timely access of medical devices to the market. The committee determined that it could not evaluate the 510(k) clear- ance process for bringing devices to market in isolation; it was necessary to understand the full spectrum of devices reviewed by the FDA—from the sim- plest tongue depressor to the most complex implantable devices. The 510(k) clearance process, the mechanism used for premarket review of most Class II devices, is embedded in the vast middle. In reviewing the legislative and regulatory history of the 510(k) program, the committee found that it was designed in 1976 to provide only a determination of the substantial equiva- xi

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xii PREFACE lence of a new device to an already marketed (predicate) device; it was not designed to determine whether a new device provides a reasonable assurance of safety and effectiveness or whether it promotes innovation. That finding complicated the committee’s work in that the FDA, in the charge to the com- mittee, stated that the goals of the 510(k) clearance process are to “make available to consumers devices that are safe and effective” and to “promote innovation in the medical device industry.” The committee struggled with how to address the conflict between the legislative framework of the program and the FDA’s stated goals. The report lays out the committee’s rationale and approach for address- ing this conflict and provides recommendations to the FDA that it believes will result in an improved regulatory system for bringing Class II medical devices to market. The recommendations are focused on strengthening the science base needed to make better-informed regulatory decisions and on giving the FDA the tools that it needs to identify and remove problematic de- vices from the market. The committee believes that taking the recommended steps will generate the information needed to design a robust regulatory framework for Class II devices. The new framework would increase the public’s confidence that safe and effective medical devices are being made available in a timely manner. Because of the high visibility of concerns about the 510(k) clearance process, the FDA has undertaken its own internal study in parallel with the IOM study to determine how the process might be improved within the FDA’s existing legislative authorities. Although IOM was not specifically charged with weighing in on or critiquing the FDA’s recommendations, the committee did use the FDA’s data and analyses in reaching its own conclu- sions and recommendations. I would like to thank the members of the committee for their incred- ibly hard work over the past 16 months. They came from very different backgrounds and perspectives on the development and use of devices for human health care. The time that the committee members invested in this study was considerable. Although their discussions and deliberations often were spirited, they collaborated effectively and reached consensus on the findings, conclusions, and recommendations. Finally, the committee thanks the IOM staff, including the study direc- tor, Abigail Mitchell; the program officer, Heather Colvin; the associate program officer, Melissa French; and the senior program assistant, Kathleen Shepherd. The staff’s efforts were essential in the information-gathering and writing process, and in providing the committee with necessary assistance and support. David R. Challoner, Chair Committee on the Public Health Effectiveness of the FDA 510(k) Clearance Process

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Contents ACRONYMS AND ABBREVIATIONS xix SUMMARY 1 The Committee’s Task, 4 Conclusions, 4 Recommendations, 7 1 INTRODUCTION 15 What Is a Medical Device?, 16 The Challenge of Regulating Medical Devices, 17 The Committee’s Approach to Its Task, 19 Attributes of an Ideal Medical-Device Regulatory System, 21 Center for Devices and Radiological Health Activities Related to the 510(k) Process, 22 Organization of the Report, 26 References, 26 2 KEY MEDICAL-DEVICE LEGISLATIVE AND REGULATORY ACTIONS 29 The 1938 Act, 30 The 1976 Act, 30 The 1990 Act, 34 The 1997 Act, 37 The 2002 and 2007 Acts, 38 Summary of Findings, 39 References, 40 xiii

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xiv CONTENTS 3 COMPONENTS OF US MEDICAL-DEVICE REGULATION 41 Tools and Authorities for Regulating Marketed Devices, 41 Food and Drug Administration Enforcement and Other Powers, 54 Comparison of the Food and Drug Administration’s Authorities Over Marketed Drugs and Marketed Devices, 62 Device Classification and Premarket Review, 68 Infrastructure of the Center for Devices and Radiological Health, 73 Summary of Findings, 82 References, 82 4 THE 510(k) CLEARANCE PROCESS 85 Implementation of the 510(k) Process, 86 Evidence Supporting 510(k) Submissions, 104 De Novo Premarket Review, 115 Summary of Findings, 118 References, 119 5 POSTMARKETING SURVEILLANCE, COMPLIANCE, AND ENFORCEMENT 123 The Food and Drug Administration’s Current Postmarketing Surveillance Activities, 124 Non–Food and Drug Administration Postmarket Data-Collection Efforts, 137 Communicating with Consumers, 142 Summary of Findings, 143 References, 144 6 EXTERNAL FACTORS THAT AFFECT THE MEDICAL-DEVICE REGULATORY SYSTEM 149 The Growing Number and Complexity of Medical Devices, 149 Innovation and the 510(k) Clearance Process, 164 The Medical-Device Ecosystem, 169 Globalization of the Medical-Device Industry, 173 Summary of Findings, 184 References, 185 7 CONCLUSIONS AND RECOMMENDATIONS 189 Protecting the Public’s Health by Ensuring the Safety and Effectiveness of Medical Devices, 190 Facilitating Innovation in Support of Public Health, 193 Recommendations, 196 References, 204

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xv CONTENTS APPENDIXES A HISTORY OF MEDICAL-DEVICE LEGISLATION AND REGULATION IN THE UNITED STATES 207 Device Regulation Under the 1938 Federal Food, Drug, and Cosmetic Act, 211 Development and Enactment of the Medical Device Amendments of 1976, 213 Basic Structure of the Medical Device Amendments, 214 Implementation of the Medical Device Amendments: Long-Term Trends, 224 The Safe Medical Devices Act of 1990, 249 Developments in 1990–1997, 259 The Food and Drug Administration Modernization Act of 1997, 265 1997–2009 Developments, 272 Closing Observations, 275 References, 276 B COMMITTEE BIOGRAPHIES 279 INDEX 287

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Boxes, Figures, and Tables BOXES S-1 The Three Device Classes, 2 S-2 Definition of Substantial Equivalence in the 1990 Safe Medical Devices Act, 3 1-1 Attributes of an Ideal Medical-Device Regulatory System, 21 1-2 CDRH’s Preliminary Finding and Recommendations from Its Review of the 510(k) Clearance Process, 24 4-1 Case Study: Biliary Stents in Peripheral Vasculature, 99 5-1 Case Study: Cardiovascular Intravascular Filters, 136 6-1 Example Recall Announcement, 158 FIGURES 3-1 Federal government, Department of Health and Human Services, and FDA funding, FY 2008, 74 3-2 Third-party 510(k) submissions as percentage of total 510(k) submissions received, FY 1999–2009, 77 4-1 The FDA substantial-equivalence decision tree, 93 4-2 Percentage of 510(k) decisions within 90 FDA days, FY 2002–2008, 111 xvii

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xviii BOXES, FIGURES, AND TABLES 4-3 Number of 510(k) review cycles, FY 2002–2008, 112 4-4 Number of de novo requests received, CY 1998–2009, 117 4-5 Average total time from 510(k) receipt to de novo approval, CY 2005–2009, 118 6-1 Original 510(k) submissions to CDRH, FY 1976–2009, 150 6-2 Number of 510(k) product codes, 1990–2009, 151 6-3 Pages per 510(k) submission and total page volume received, 1983– 2008, 152 6-4 Example of a medical-device software malfunction, 157 6-5 Transmission of medical data, 161 6-6 Vision of future data transmission, 162 TABLES 3-1 Comparison of FDA Authorities to Obtain Postmarket Information on Risks Posed by Drugs and Medical Devices, 64 3-2 Comparison of FDA Authorities to Take Remedial Actions in Light of New Safety Findings, 66 3-3 Summary of Key Differences Between PMA Applications and 510(k) Submissions, 72 3-4 Frequency of Problems with Third-Party Reviews of 510(k) Submissions, 78 4-1 FDA Review Time by Availability of Guidance, 106 5-1 Medical-Device Adverse-Event Reports, 2003–2007, 125 6-1 European Commission Risk Classification Scheme, 179 6-2 Conformity Assessment Procedure by Class, 181 A-1 510(k) Submissions and Those Found Not Substantially Equivalent, 1976–1982, 231 A-2 510(k) Submissions and Those Found Not Substantially Equivalent, FY 1989–1996, 232

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Acronyms and Abbreviations AIMDD active implantable medical devices ALJ administrative law judge CA competent authority CART Clinical Assessment, Reporting, and Tracking program CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CEN European Committee for Standardization CFR Code of Federal Regulations CMS Centers for Medicare and Medicaid Services DEN Device Experience Network DELTA Data Extraction and Longitudinal Time Analysis DHR device history record EHR electronic health record EU European Union FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act FDAMA Food and Drug Administration Modernization Act FFDCA Federal Food, Drug, and Cosmetic Act FTC Federal Trade Commission FTE full-time equivalent xix

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xx ABBREVIATIONS FY fiscal year GAO Government Accountability Office (formerly General Accounting Office) GHTF Global Harmonization Task Force GMP good manufacturing practices HHS Department of Health and Human Services (formerly Department of Health, Education, and Welfare) HIMA Health Industry Manufacturers Association IG inspector general IOM Institute of Medicine IVDD in vitro diagnostic medical devices MAUDE Manufacturer and User Device Experience database MD EPINET Medical Device Epidemiology Network MDA Medical Device Amendments MDR medical-device report MedSun Medical Product Surveillance Network NB notified body NCDR ICD National Cardiovascular Data Registry for implantable cardioverter defibrillators NDA new drug application NSE not substantially equivalent OC Office of Compliance OCP Office of Combination Products ODE Office of Device Evaluation OMB White House Office of Management and Budget ORA Office of Regulatory Affairs OTS off-the-shelf PMA premarket approval QSR quality-system regulations SE substantially equivalent SMDA Safe Medical Devices Act STED summary technical document UDI unique device identification