SAFE MEDICAL DEVICES FOR CHILDREN

Committee on Postmarket Surveillance of Pediatric Medical Devices

Board on Health Sciences Policy

Marilyn J. Field and Hugh Tilson, Editors

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, DC
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Safe Medical Devices for Children SAFE MEDICAL DEVICES FOR CHILDREN Committee on Postmarket Surveillance of Pediatric Medical Devices Board on Health Sciences Policy Marilyn J. Field and Hugh Tilson, Editors INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

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Safe Medical Devices for Children 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 Governing 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. 223-01-2460, Task Order No. 11 between the National Academy of Sciences and the U.S. Food and Drug Administration. 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 the project. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.). Committee on Postmarket Surveillance of Pediatric Medical Devices. Safe medical devices for children / Committee on Postmarket Surveillance of Pediatric Medical Devices, Board on Health Sciences Policy ; Marilyn J. Field and Hugh Tilson, editors ; Institute of Medicine of the National Academies.—1st ed. p. ; cm. “This study was supported by Contract No. 223-01-2460, Task Order No. 11 between the National Academy of Sciences and the U.S. Food and Drug Administration.” ISBN 0-309-09631-6 (hardcover) 1. Pediatrics—Equipment and supplies—Standards—United States. 2. Pediatrics—United States—Equipment and supplies—Evaluation. [DNLM: 1. Product Surveillance, Postmarketing—standards—Child—United States. 2. Equipment Safety—standards—Child—United States. 3. Equipment and Supplies—standards—Child—United States. WS 26 I61s 2005] I. Field, Marilyn J. (Marilyn Jane) II. Tilson, Hugh Hanna. III. Title. RJ34.I57 2005 362.198′92—dc22 2005024875 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 2006 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. Front Cover Photographs: Top row, second from left: CO2SMO® Capnograph/Pulse Oximeter (Used with permission of Respironics, Inc., Murrysville, PA). Top row, fourth from left: SJM Regent® Valve (Courtesy of St. Jude Medical, Inc.). Second row, second from left: Vertical Expandable Prosthetic Titanium Rib (VEPTR) (Courtesy of Robert M. Campbell, M.D., Thoracic Institute, CHRISTUS Santa Rosa Children’s Hospital). Second row, fourth from left: Auria BTE Processor (Courtesy of Advanced Bionics Corporation). Third row, first from left: Medtronic Paradigm® 515 insulin pump and Paradigm Link™ monitor (Reproduced with permission of Medtronic, Inc.). Third row, fourth from left: Courtesy of the National Center on Physical Activity and Disability.

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Safe Medical Devices for Children “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.

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Safe Medical Devices for Children THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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 engineers. 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president 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 Institute 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 Sciences 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. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Safe Medical Devices for Children COMMITTEE ON POSTMARKET SURVEILLANCE OF PEDIATRIC MEDICAL DEVICES HUGH TILSON (Chair), Clinical Professor, Public Health Leadership, and Adjunct Professor of Epidemiology and Health Policy, University of North Carolina at Chapel Hill School of Public Health JAMES M. ANDERSON, Professor of Pathology, Macromolecular Science and Biomedical Engineering, Institute of Pathology, Case Western Reserve University ERLE H. AUSTIN III, Professor of Surgery, University of Louisville School of Medicine, and Chief, Cardiovascular Surgery, Kosair Children’s Hospital MARK E. BRULEY, Vice President, Accident and Forensic Investigation, ECRI PAUL CITRON, Vice President (retired), Technology Policy and Academic Relations, Medtronic, Inc. WILLIAM H. DUMOUCHEL, Vice President of Research and Chief Statistical Scientist, Lincoln Technologies, Inc. ELLEN J. FLANNERY, Partner, Covington & Burling LINDA GOLODNER, President, National Consumers League STEPHEN J. HAINES, Lyle A. French Chair, Department of Neurosurgery, University of Minnesota Medical School PATRICIA HICKS, Associate Professor of Pediatrics, University of Texas Southwestern Medical School STEPHEN W. LAGAKOS, Chair, Harvard University School of Public Health, Department of Biostatistics GEORGE LISTER, Professor and Chair, Department of Pediatrics, University of Texas Southwestern Medical School JONATHAN J. ROSEN, Director, Office of Technology Implementation, Center for the Integration of Medicine and Innovative Technology Committee Consultants and Background Paper Authors JEFFREY P. BLOUNT, Assistant Professor of Surgery, Division of Pediatric Neurosurgery, University of Alabama at Birmingham MARTIN J. BURTON, Consultant Otolaryngologist, Radcliffe Infirmary, Oxford University DAVID FEIGAL, Research Professor, The Biodesign Institute at Arizona State University ANNETINE C. GELIJNS, Co-Director, International Center for Health Outcomes and Innovation Research, Columbia University

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Safe Medical Devices for Children BRIGID KILLELEA, Fellow, International Center for Health Outcomes and Innovation Research, Columbia University JANICE M. LEUNG, Medical Student, Johns Hopkins University VIPUL MANKAD, Professor of Medicine, University of Kentucky College of Medicine ERIC A. MANN, Acting Deputy Director, General Surgery Device Branch, Center for Devices and Radiological Health ALAN MOSKOWITZ, Co-Director, International Center for Health Outcomes and Innovation Research, Columbia University JOHN K. NIPARKO, Professor, Otolaryngology-Head and Neck Surgery, Johns Hopkins University DEBARA L. TUCCI, Associate Professor, Department of Surgery, Duke University MICHAEL VITALE, Director, Pediatric Outcomes, International Center for Health Outcomes and Innovation Research, Columbia University Study Staff MARILYN J. FIELD, Study Director MARGARET A. MCCOY, Research Associate PERRY LUKSIN, Senior Project Assistant (until August 2004) AYANNA N. VEST, Senior Project Assistant (from August 2004) Board on Health Sciences Policy Staff ANDREW POPE, Director, Board on Health Sciences Policy AMY HAAS, Administrative Assistant

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Safe Medical Devices for Children Preface We hope that this report will put a face on the children who benefit every day from medical devices, lend a voice to some of the challenges they face in realizing the benefits of the devices, and give heart to those who want to make things even better. In spirit, our report is for these children and their families. As written, this report responds to a request from Congress to investigate the questions described in the Summary and Chapter 1, and we have aimed much of our analysis and recommendations at legislative and administrative policymakers and those who advise them. At the same time, we have also tried to speak to the concerns of the broader community, including consumer and patient advocacy groups, concerned with the safe use of medical devices and the well-being of our nation’s children. Our committee profited greatly from face-to-face and other conversations with children; their parents and caregivers; the physicians, nurses, and other providers who take care of them and work diligently to assure safe use of devices; the scientists, engineers, and administrators who have attempted to understand and enhance the science of safety surveillance in the postmarket environment; the manufacturers who occupy such a vital place in the system of postmarket safety; and of course the regulators working to assure pre- and postmarket protections against problems with some medical devices. All provided valuable insights into the strengths and limitations of the enterprise and the opportunities to render it stronger. These, coupled with review of U.S. Food and Drug Administration (FDA) documents, clinical studies, and other secondary sources, sustained us in deep and far-reaching consideration and added reality and timeliness. We have drawn heavily on patient reports and clinical knowledge to illustrate child

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Safe Medical Devices for Children and family experiences with medical devices in a series of vignettes (particularly in Chapter 4) that we hope will portray the benefits and the harms—actual and potential—that real children and families face every day. As you read the results of our deliberations, we also hope that you will recognize—as we have—the following lessons. First, children are not just “little adults.” The biology and active lifestyles of children are unique and require particular attention during the development of medical products and procedures and also as part of continued monitoring and scientific assessment following their entry into clinical practice. And of course, the expected future life of the child undergoing therapy makes consideration of the multi-decade impact of medical interventions vital. Second, medical devices are not just “mechanical drugs.” Devices constitute a vital part of our therapeutic armamentarium, deserving no less attention than drugs and biologics and therapeutic nutritional products, but meriting recognition as a unique set of entities and challenges. The number and diversity of devices are remarkable, from the low-tech hospital bedrail and pervasive plastic tubing to the complex cardiac pacemaker and infant respirator. No simple approach to monitoring device safety in post-approval use will serve all situations. Third, regulation of medical devices has required more than just “another sentence” in the FDA statutes regulating pharmaceuticals. Much of the devices industry is extremely fast-moving; many products have short half-lives, and continuous device improvement may be the rule, with new and improved replacements introduced rapidly into the marketplace. These features require a tailored regulatory approach that encourages innovation while protecting patients. And yet, when devices are approved with the potential for causing important harms, short term or with longer latency, this balance must consider effective means for long-term, population-based monitoring. Fourth, monitoring the safety of devices cannot flourish as just a subfield of pharmacoepidemiology. Unique analytic approaches are needed for the unique characteristics of device use and outcomes. Many devices used in daily therapy are not identified by brand or batch number even to the institution, much less the end user. Furthermore, problems may arise far from the original place or time a device was used or implanted, for example, in the home or under the care of a physician not associated directly with the device, even in the case of implants. Added to the complexities of device research are the technical complexities of conducting pediatric studies, complexities that include small populations (which also may mean a small or nonexistent return on device development) and special research protection regulations. Still, the committee finds much in the world of pharmaceuticals, in the experience of adults, in the regulation of drugs and biologics, and in the field of pharmacoepidemiology that can contribute to identification of inad-

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Safe Medical Devices for Children equacies in protections related to pediatric medical devices and instruct in possible remedies. We can and must learn from these arenas. Our explorations made it clear that the effort to protect the public’s health in this area represents another example of the way public health systems in America function, as the collection of our society’s efforts to assure conditions in which people, particularly children, can be healthy. Such systems entail many participants—public and private—often working in parallel but still unaware that they are part of a larger system of protections. Such incomplete connections among the components of the system or failure to approach things in a systematic way can lead to inefficient, even ineffective approaches in public health, including this sector. Thus, in order to assure adequate protections for children who rely on medical devices, we present recommendations that recognize and address the essential roles and responsibilities of the whole spectrum of actors in the system, from the regulator and manufacturer to the clinician and researcher, from officials in Washington, D.C., to patients and their families in homes across the country. Some of our recommendations will be relatively easy to act on. Several of the professional societies we heard from, for example, are prepared to implement broader training on detection and reporting of device safety problems right now. Other recommendations will take more work. Better structured approaches to assure long-term monitoring of devices in children with potential for serious problems in the postmarket environment—without overburdening an often fragile industry—will take careful management, but we feel it must be done. Finding mechanisms to allow the evolving world of medical informatics to capture data about devices and link it automatically to other medical experience at the population level, for example, will take concerted efforts across multiple sectors of the health care system. We believe that all of our recommendations are feasible and necessary to assure adequate protections of our children in need of the benefits of medical devices. We would like to thank those who took the time and trouble to tell us their stories and communicate their experiences as well as the many who provided important scientific, clinical, and analytic perspectives and evidence. As chair, I had the privilege of convening a knowledgeable and thoughtful committee, the members of which were willing to listen, learn, and, despite their varied backgrounds and sometimes quite disparate views, come together around the findings and recommendations which we present. Finally, let me thank our outstanding Institute of Medicine staff, particularly Marilyn Field, the project director, for her steady hand, quick mind, and great good sense. Hugh Tilson, M.D., Dr.P.H. Committee Chair

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Safe Medical Devices for Children Acknowledgments The committee and staff are indebted to a number of individuals and groups for their assistance in the development of this report. The committee learned much through workshops and public meetings it organized to obtain information and perspectives from groups and individuals knowledgeable and concerned about research involving infants, children, and adolescents. Appendix A includes the meeting agendas and participant lists and cites the organizations that did not participate in the meeting but provided written statements to the committee. Special thanks go to the family members who talked with us by telephone and met with us to share their experiences of living day-to-day with complex, life-sustaining devices. They enriched our understanding of the varied benefits and stresses of child and family life with complex medical devices. We also appreciate the contributions of the outside authors of the background papers presented as appendixes to this report, particularly John Niparko and Janice Leung (Johns Hopkins University), Jeffrey Blount (University of Alabama at Birmingham), and Annetine Gelijns and Alan Moskowitz (Columbia University). A number of people at the Food and Drug Administration (FDA) provided important background and information for this study. Thomas Gross, the agency’s project officer for the study, was unfailingly helpful. He directly answered many questions about the agency’s postmarket surveillance program and related activities and also sought the expertise of his colleagues on other questions about aspects of the agency’s work. Susan Gardner, Roselie Bright, Donna-Bea Tillman, Joanne Less, Lori Brown, Deborah Yoder, and

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Safe Medical Devices for Children Gregory Campbell are among those who provided additional understanding of FDA’s policies and programs. We appreciate the opportunity provided by the American Academy of Pediatrics, the National Organization for Rare Disorders, and the Elizabeth Glazer Pediatric AIDS Foundation to participate in meetings on barriers to the development of devices for pediatric use. The discussions provided insights that are relevant throughout the medical device development cycle. Elaine Vining (American Academy of Pediatricians) and Jeanne Ireland (Elizabeth Glazer Pediatric AIDS Foundation) also offered additional ideas and information. Jon Abramson (Wake Forest University), who led these meetings, described his discussions with the FDA some years ago to discuss surveillance of pediatric medical devices, among other topics. Among many who helped the committee clarify issues, find important information, or otherwise complete its work are Robert Campbell (University of Texas Health Sciences Center, San Antonio); Jennita Reefhuis (Centers for Disease Control and Prevention); Sonja McKinley and Lynn Sleeper (New England Research Institute); Robert Bartlett (University of Michigan); Anthony Slonim, Billie Short, and K. Rais-Bahrami (Children’s National Medical Center); Richard Platt (Harvard University); Andrew Mahar (Childen’s Hospital San Diego); Frank Johnson (St. Louis University); Tara Federici (AdvaMed); Susan Alpert and Laura Visser (Medtronic); Hope Treviso (Thoracic Institute); Kit Song and Kristie Bjornson (University of Washington); Cliff Megerian (Case Western University); Barry Rumack; James Donahue (Marshfield Clinic Research Foundation); Alexander Walker (Ingenix); Adam Feuerstein (TheStreet.com); Sue Tolleson-Rinehart, Alan Stiles, Ali S. Calikoglu, and colleagues at the University of North Carolina; Richard Platt (Harvard Medical School); James Donahue (Marshfield Clinic Research Foundation); Richard Chinook (Loma Linda University); Alex Walker (Ingenix); Steven Webber (University of Pittsburgh). As usual, many within the Institute of Medicine were helpful to the study staff. The committee would especially like to thank William McLeod, Sally Stanfield, Michele de la Menardiere, James Hinchman, Julie Wiltshire, Janice Mehler, Alex Ommaya, Marie Michnich, Clyde Behney, and Jennifer Bitticks.

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Safe Medical Devices for Children Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures 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 reports 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 individuals for their review of this report: Edward M. Basile, J.D., King & Spalding, L.L.P. Bruce Boissonnault, Niagara Health Quality Coalition Francis Sessions Cole, III, M.D., Washington University in St. Louis Neal E. Fearnot, Ph.D., MED Institute, Inc., Cook Group Incorporated Harry A. Guess, M.D., Ph.D., University of North Carolina at Chapel Hill Jonathan S. Kahan, J.D., Hogan & Hartson, L.L.P. Elizabeth Magill, J.D., University of Virginia Law School Cliff A. Megerian, M.D., Case Western Reserve University Michael R. Neuman, Ph.D., M.D., Michigan Technological University Robert J. Panzer, M.D., University of Rochester Medical Center Frederick J. Schoen, M.D., Ph.D., Harvard Medical School Deborah Shatin, Ph.D., Center for Health Care Policy and Evaluation Anthony D. Slonim, M.D., M.P.H., Children’s National Medical Center Michael G. Vitale, M.D., M.P.H., International Center for Health Outcomes and Innovation Research John Thomas Watson, Ph.D., Jacobs School of Engineering Von Liebig Center

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Safe Medical Devices for Children 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 this report was overseen by RICHARD B. JOHNSTON, JR., M.D., University of Colorado School of Medicine and EDWARD B. PERRIN, Ph.D., University of Washington. Appointed by the National Research Council and the Institute of Medicine, these individuals were responsible for making certain that an independent examination of this report was carried out in accordance with the institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Safe Medical Devices for Children Contents     PREFACE   vii     ACKNOWLEDGMENTS   xi     REVIEWERS   xiii     SUMMARY (with List of Recommendations)   1 1   INTRODUCTION   17      Origin of Study Tasks and Overview of Report,   25      Selected Concepts and Definitions,   27      Evolution of Medical Device Regulation,   36      Medical Device Regulation in Context,   41 2   MEDICAL DEVICES FOR INFANTS, CHILDREN, AND ADOLESCENTS   46      Definitions,   48      FDA Guidance on Assessment of Pediatric Medical Devices,   54      Device Design, Device Use, and Developmental Differences,   55      Identifying Problems or Concerns with Medical Devices Used with Children,   69 3   REGULATORY FRAMEWORK FOR POSTMARKET SURVEILLANCE OF MEDICAL DEVICES   73      Organization of FDA for Medical Device Regulation,   74      Basics of Premarket Regulation of Medical Devices,   76      Basics of Postmarket Surveillance,   85

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Safe Medical Devices for Children      Responses to Potential Safety Problems,   97      Confidentiality of Information Obtained by FDA,   102      FDA Programs That Cross the Premarket/Postmarket Boundary,   107 4   IDENTIFYING AND UNDERSTANDING ADVERSE MEDICAL DEVICE EVENTS   112      Adverse Device Event Reporting and FDA,   114      Anatomy of Adverse Device Events: Illustrative Vignettes,   126      Sources of Adverse Device Events,   148      Limitations of Adverse Event Reporting Programs,   152      FDA Initiatives to Improve Adverse Event Reporting and Related Activities,   164      Other Reporting and Analysis of Adverse Events,   170      Conclusions and Recommendations,   173 5   MONITORING OF POSTMARKET STUDY COMMITMENTS INVOLVING MEDICAL DEVICES   183      Background,   185      Monitoring of Postmarket Study Commitments for Medical Devices,   190      Conclusions and Recommendations,   195 6   ADEQUACY OF PEDIATRIC POSTMARKET SURVEILLANCE STUDIES   199      FDA-Required Studies and Other Information,   201      Dimensions and Complexities of Medical Device Research,   207      Special Challenges of Research Involving Children,   220      Conclusions and Recommendations,   222 7   CHILDREN AND MEDICAL DEVICE SAFETY: A SHARED RESPONSIBILITY   229      FDA Performance of Postmarket Surveillance of Medical Devices,   232      Resources to Support Postmarket Device Surveillance,   238      Tensions in Public Policy and Device Innovation,   240      Shared Responsibilities for Medical Device Safety,   241     REFERENCES   250     APPENDIXES         A  Study Origins and Activities   281     B  Medical Devices for Pediatric Care   288     C  The Dynamics of Pediatric Device Innovation: Putting Evidence In Context   302

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Safe Medical Devices for Children     D  Questions and Methods in Surveillance Programs   327     E  The Regulatory History of Cerebrospinal Fluid Shunts for Hydrocephalus   347     F  Cochlear Implants in Children: A Review of Reported Complications, Patterns of Device Failure, and Assessment of Current Approaches to Surveillance   382     G  Glossary and Acronyms   422     H  Committee Biographical Statements,   433     INDEX   439

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Safe Medical Devices for Children Boxes, Figures, and Tables BOXES S.1   Design or Adaptation of Medical Devices for Use with Children,   2 S.2   Identifying Concerns or Adaptations with Pediatric Use of Medical Devices (with Examples),   3 1.1   Examples of Life-Saving and Life-Sustaining Medical Devices for Children,   20 1.2   Categories of Medical Devices for Purposes of FDA Scientific Review,   31 2.1   Examples of Developmental Considerations or Potential Complications for Drugs and Devices,   57 2.2   Design or Adaptation of Medical Devices for Use with Children,   58 2.3   Identifying Concerns or Adaptations with Pediatric Use of a Medical Device (with Examples),   70 3.1   Selected Definitions Related to Medical Device Reporting Requirements,   88 3.2   Medical Device Reporting Requirements for Device Manufacturers,   90 3.3   Medical Device Reporting Requirements for User Facilities,   91 3.4   Topics in Medical Device Quality Systems Manual: A Small Entity Compliance Guide,   108

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Safe Medical Devices for Children 4.1   Excerpts from Examples of Reports Involving Children in FDA Adverse Event Database,   122 4.2   Possible Sources of Adverse Device Events with Examples,   149 6.1   Example of Medical Device Testing: Atrial Septal Occluder,   209 7.1   Key Points in FDA Report to Congress on Barriers to the Availability of Medical Devices Intended for the Treatment or Diagnosis of Diseases and Conditions That Affect Children,   231 FIGURES 1.1   Child in iron lung, World Health Organization, c. 1938,   18 1.2   Zoe and Dad on a hike,   19 1.3   Time lines of key dates in development of the Synchromed® drug pump and the Vertical Expandable Prosthetic Titanium Rib (VEPTR),   43 1.4   Total product life cycle for medical devices,   44 2.1   Child with early external pacemaker, c. 1957,   62 2.2   A modern implantable pacemaker,   63 4.1   Identifying and investigating an adverse device event in a health care facility,   158 6.1   Evolution of the Vertical Expandable Prosthetic Titanium Rib (VEPTR) showing versions from 1987, 1989, 1991, and 1996,   205 C.1   Medical device R&D spending as a percent of sales,   307 E.1   Ventricles of the human brain,   348 E.2   The cerebrospinal fluid system,   349 E.3   CT scans of a child with hydrocephalus and a child with transependymal flow at the tips of the lateral ventricles,   353 E.4   MRIs of a child with hydrocephalus,   354 E.5   Endoscopic view of a ventricular catheter partially covered in fibrinous debris,   357 E.6   Shunt infection publications by year,   361 E.7   Literature reports of shunt complications,   363 F.1   Ear-level processor,   384 F.2   Body-worn processor,   384 F.3   An implanted receiver and electronics package,   385 F.4   An electrode array,   385

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Safe Medical Devices for Children F.5   An implanted electronics and receiver package connected to an electrode ray, which is inserted through the cochlea,   386 F.6   The cochlear implant system comprised of its internal and external components,   386 TABLES 1.1   Selective Time Line of Key Dates in Development of the Food and Drug Administration’s Regulatory Authority over Medical Products, Especially Devices,   37 3.1   Budget Authority and Total Program Level Funding History for Center for Devices and Radiological Health FY 1994–2005 (in millions),   75 3.2   Examples of FDA Class I, II, and III Devices,   77 4.1   Adverse Event Reports Submitted to FDA, Late 1984 Through December 2004,   116 4.2   FDA Adverse Event Reports Involving Individuals Under Age 21 (1999–2004),   121 4.3   Medical Device Class I Recalls and Safety Alerts, Public Health Advisories, and Notices, 1998–2004,   162 4.4   Cumulative Number of Facilities Recruited into MedSun,   165 C.1   Some Recently Approved Devices Tested for Use in Children,   311 D.1   List of 12 Shunt Complication Event Types and the Text Strings That Were Used to Classify the Reports in Searching the Descriptive Narrative in MAUDE Reports,   343 D.2   Counts (N) for a Classification of 784 Reports of Shunt Complication by Type of Event and Manufacturer,   343 D.3   The 15 Largest Reporting Ratios (RR = N/E) for Manufacturer–Event Type Combinations Listed in Table D.1,   344 E.1   Articles on Shunt Complications by Type of Complication,   363 E.2   Codes for Determination of Substantial Equivalence by FDA for 510(k) Notifications,   366 E.3   Search Strategy (MDR Reports) for Adverse Events for CSF Shunts,   370 E.4   CSF Shunt Reports in the MAUDE Database Misclassified as a Non-Shunt Device,   371 E.5   Outcome as Reported for CSF Shunt Events in MDR and MAUDE Databases,   372

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Safe Medical Devices for Children E.6   Classification of Complications in the MDR and MAUDE Databases and Published Literature,   373 E.7   Disproportionality Analysis of CSF Shunt Events in MAUDE Database,   374 F.1   Malformations Based on Embryogenesis as Described by Jackler and Colleagues,   396

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