PROCEEDINGS FROM THE WORKSHOP ON SCIENCE-BASED ASSESSMENT

ACCELERATING PRODUCT DEVELOPMENT OF COMBINATION MEDICAL DEVICES

Bonnie A. Scarborough, Editor

Roundtable on Biomedical Engineering Materials and Applications

National Materials Advisory Board

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices PROCEEDINGS FROM THE WORKSHOP ON SCIENCE-BASED ASSESSMENT ACCELERATING PRODUCT DEVELOPMENT OF COMBINATION MEDICAL DEVICES Bonnie A. Scarborough, Editor Roundtable on Biomedical Engineering Materials and Applications National Materials Advisory Board NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices 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. Support for this project was provided by Alfred University, Boston Scientific Corporation, California State University Program for Education and Research in Biotechnology, Center for Integration of Medicine and Innovative Technology, Dow Chemical Company, Edwards Lifesciences Corporation, Johnson & Johnson, Medtronic, Inc., National Institute of Standards and Technology, National Institutes of Health, National Science Foundation, New Jersey Associated Institutions for Materials Science, Office of Naval Research, University of Florida, U.S. Army, U.S. Department of Veterans Affairs, and 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 views of the organizations or agencies that provided support for the project. Available in limited quantities from the National Materials Advisory Board, 500 Fifth Street, N.W., Washington, DC 20001; Internet, http://www.nationalacademies.org/nmab Additional copies 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 Copyright 2004 by the National Academy of Sciences. All rights reserved. Case cover images (left to right): Absorbable collagen sponge carrier and LT-CAGETM lumbar tapered fusion device; images courtesy of W. McKay, Medtronic Sofamor Danek. TransluteTM carrier; courtesy of R. Sahatjian, Boston Scientific Corporation. Cartilage-bone construct grown in vitro; courtesy of A. Ratcliffe, Synthasome, Inc. Printed in the United States of America

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices 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. Bruce M. Alberts 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 technol-ogy 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 operat-ing 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 adminis-tered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices ROUNDTABLE ON BIOMEDICAL ENGINEERING MATERIALS AND APPLICATIONS ROBERT M. NEREM, Chair, Georgia Institute of Technology, Atlanta MINDY AISEN, U.S. Department of Veterans Affairs, Washington, D.C. PAUL CITRON, Medtronic, Inc., Minneapolis, Minnesota CRYSTAL CUNANAN, Edwards Lifesciences Corporation, Irvine, California A. STEPHEN DAHMS, California State University Program for Education and Research in Biotechnology, San Diego ALAN GOLDSTEIN, Alfred University, Alfred, New York SUZANNE JANICKI, The Dow Chemical Company, Midland, Michigan CAROL LUCAS, National Science Foundation, Arlington, Virginia WINFRED PHILLIPS, University of Florida, Gainesville THOMAS REID, Walter Reed Army Institute of Research, Silver Spring, Maryland DIANNE REKOW, New York University, New York JONATHAN JAY ROSEN, Center for Integration of Medicine and Innovative Technology, Boston, Massachusetts RONALD SAHATJIAN, Boston Scientific Corporation, Natick, Massachusetts JOEL M. SCHNUR, Naval Research Laboratory, Washington, D.C. ANGELO SCOPELIANOS, Johnson & Johnson, Somerville, New Jersey RICHARD E. SWAJA, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland JOHN A. TESK, National Institute of Standards and Technology, Gaithersburg, Maryland TERRY O. WOODS, U.S. Food and Drug Administration, Rockville, Maryland NRC Staff BONNIE A. SCARBOROUGH, Program Officer TERI THOROWGOOD, Research Associate EMILY ANN MEYER, Research Associate MARTA VORNBROCK, Research Assistant LAURA TOTH, Project Assistant PABLO WHALEY, Intern

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices NATIONAL MATERIALS ADVISORY BOARD JULIA M. PHILLIPS, Chair, Sandia National Laboratories, Albuquerque, New Mexico JOHN ALLISON, Ford Motor Company, Dearborn, Michigan PAUL BECHER, Oak Ridge National Laboratory, Oak Ridge, Tennessee BARBARA D. BOYAN, Georgia Institute of Technology, Atlanta ROBERT J. CAVA, Princeton University, Princeton, New Jersey DIANNE CHONG, The Boeing Company, St. Louis, Missouri FIONA DOYLE, University of California, Berkeley GARY FISCHMAN, Consultant, Palatine, Illinois KATHERINE G. FRASE, IBM, Hopewell Junction, New York HAMISH L. FRASER, Ohio State University, Columbus JOHN J. GASSNER, U.S. Army Natick Soldier Center, Natick, Massachusetts THOMAS S. HARTWICK, TRW, Redmond, Washington ARTHUR H. HEUER, Case Western Reserve University, Cleveland, Ohio ELIZABETH HOLM, Sandia National Laboratories, Albuquerque, New Mexico FRANK E. KARASZ, University of Massachusetts, Amherst SHEILA F. KIA, General Motors Research and Development Center, Warren, Michigan CONILEE G. KIRKPATRICK, HRL Laboratories, Malibu, California ENRIQUE J. LAVERNIA, University of California, Davis TERRY LOWE, Los Alamos National Laboratories, Los Alamos, New Mexico HENRY J. RACK, Clemson University, Clemson, South Carolina LINDA SCHADLER, Rensselaer Polytechnic Institute, Troy, New York JAMES C. SEFERIS, University of Washington, Seattle T.S. SUDARSHAN, Materials Modification, Inc., Fairfax, Virginia JULIA WEERTMAN, Northwestern University, Evanston, Illinois NRC Staff TONI MARECHAUX, Director

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices Preface INTRODUCTION The Food, Drug, and Cosmetics Act of 1938 and the Safe Medical Devices Act of 1990 have driven the development of much of the current science for assessing materials, devices, drugs, and biologics. The U.S. Food and Drug Administration (FDA) has established testing centers that specialize in the assessment of products belonging to one of three categories: Device: an apparatus or implant, including any component or accessory, intended for the diagnosis, mitigation, treatment, or prevention of disease or intended to affect the structure or function of the body, that does not achieve its primary intended purposes through chemical action within or on the body and that is not dependent on being metabolized; Biologic: a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine applicable to the prevention, treatment, or cure of a disease; and Drug: (a) an article recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, (b) an article intended for the prevention, diagnosis, treatment, or cure of a disease, or (c) an article other than food intended to affect the structure or any function of the body. New patient therapies are becoming more complex, however. The FDA is just now beginning to deal with the issue of how to evaluate “combination products,” that is, products that are made up of components from more than one of these categories. Timely assessment of these devices is important from both a public health and an economic standpoint. The safe and effective development of such combination products requires an understanding of their failure mechanisms as well as an assessment of the risk associated with failure. Currently, devices, biologics, and drugs are all evaluated using different review standards. But for certain combination products, especially breakthrough products, it may not be clear which review standard(s) should apply. In addition, in some cases, scientific methodologies to appropriately assess some combination products may not yet exist or be fully developed, although the therapeutic endpoints for many of these products exist and are well understood (e.g., drug-eluting stents). Combination products thus pose new challenges with respect to the assessment of efficacy and safety. It is important to determine the extent, if any, to which differences in the testing

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices of combination products may create barriers to innovation or delays in bringing products to those in need. ROUNDTABLE ON BIOMEDICAL ENGINEERING MATERIALS AND APPLICATIONS The Roundtable on Biomedical Engineering Materials and Applications (BEMA) is an activity of the National Research Council (NRC) convened with the objective of bringing together government officials, industry representatives, academics, and others to discuss research, development, applications, and regulation of biomedical materials and devices. BEMA provides a forum for participants to identify opportunities for applying engineering principles to create and improve the clinical performance of medically useful materials and devices. In addition, the roundtable discusses strategies for overcoming the technical, legal, and cultural obstacles that impede the transition of new materials and devices into clinical application. BEMA achieves these objectives by: Providing a neutral setting for the exchange of information about issues related to biomaterials science, research, and practice; Identifying and discussing priority issues in the general area of biomaterials and their application in the development, manufacture, and use of medical devices; and Conducting problem-solving and issue-identification activities such as workshops that address these issues in greater depth. WORKSHOP ON SCIENCE-BASED ASSESSMENT A workshop entitled “Science-Based Assessment: Accelerating Product Development of Combination Medical Devices” was held on April 22-23, 2003, at the National Academies in Washington, D.C. (the theme was identified in BEMA meetings held the previous year). The purpose of the workshop was to discuss science-based assessment that can be used to effectively evaluate biomedical materials and combination devices. To facilitate discussion, the workshop was organized into sessions on three specific types of combination products: orthopedic repair using bone morphogenetic protein; drug-eluting stents; and cell-matrix cartilage implants. Abstracts of the presentations in each of these sessions are included in this report, as are abstracts of overarching, context-setting discussions of science-based assessment and experimental design. The agenda for the workshop is included in Appendix A and biographical sketches of the speakers are given in Appendix B. The viewgraphs presented by the speakers are reproduced, as originally supplied, on the attached CD-ROM.

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices NRC roundtables are established solely to provide open forums for discussion of emerging issues. They are prohibited by NRC policy from producing conclusions and recommendations or from offering advice to government agencies. As such, the primary purpose of this workshop was to educate the individuals who attended so that they might take this information back to their organizations and use it in their daily planning and decision making. This proceedings therefore serves primarily as a guide to those participants in remembering the content of the discussions. The abstracts of the workshop presentations and the unedited viewgraphs represent solely the viewpoints of the presenters. ACKNOWLEDGMENTS On behalf of BEMA, I would like to thank the speakers, session chairs, panelists, and attendees who participated in the workshop. The strong presence from government, industry, and academia was responsible for the success of the event and the lively discussions that took place. I would also like to thank those BEMA members who worked hard to organize this workshop and who, by their tireless efforts, brought the right people to the right place at the right time. Finally, I would like to thank the NRC staff members who were instrumental in organizing the workshop and preparing this report: Bonnie Scarborough, Toni Maréchaux, Teri Thorowgood, Emily Ann Meyer, Marta Vornbrock, Laura Toth, and Pablo Whaley. Thanks are also extended to the following individuals, who reviewed the contents of this proceedings volume: Tara Federici, AdvaMed; Jean Jacob, Louisiana State University; John Ranieri, DuPont; and Frederick Schoen, Harvard Medical School. The individual presenters are responsible for its substance. Robert M. Nerem, Chair Roundtable on Biomedical Engineering Materials and Applications

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices Contents     ABSTRACTS         SETTING THE CONTEXT   2      Use of Science-Based Assessment in the Development of Standards, John T. Watson, National Institutes of Health   2      Setting the Context: Clinician, Renu Virmani, Armed Forces Institute of Pathology   3      Science-Based Testing: Balancing Risk and Reward, Paul Citron, Medtronic, Inc.   4      Biofilms and Medical Devices, William Costerton, Montana State University   5      Testing for Safety and Efficacy: An Ethicist’s Perspective, Leonard J. Weber, University of Detroit Mercy   7     SCIENCE-BASED ASSESSMENT AND EXPERIMENTAL DESIGN   9      Science-Based Testing for Combination Devices, Aric Kaiser, U.S. Food and Drug Administration   9      Science-Based Testing for Biologics, Darin J. Weber, U.S. Food and Drug Administration   10      Using Design of Experiment Methods in the Innovation Process, James Rutledge, DataVision Statistical Consulting and Training, LLC   10      Making It Fly: Current Boeing Certification Processes, Stephen G. LaRiviere, Boeing Commercial Airplanes   12     BONE MORPHOGENETIC PROTEINS AND ORTHOPEDIC REPAIR   14      The Basic Science of Bone Morphogenetic Proteins and the Importance of Test Methods, Barbara D. Boyan, Georgia Institute of Technology   14      Bone Morphogenetic Protein Combination Products and Orthopedic Repair, Amy J. LaForte, Stryker Biotech   15      Product Development Process for a Bone Morphogenetic Protein Combination Product, William McKay, Medtronic Sofamor Danek   15     DRUG-ELUTING STENTS   18      Drug-Eluting Stents: Current Clinical Status, Robert S. Schwartz, Minneapolis Heart Institute   18

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Proceedings from the Workshop on Science-Based Assessment: Accelerating Product Development of Combination Medical Devices      Drug-Eluting Stents: Preclinical Testing Challenges, H. Semih Oktay, CardioMed Device Consultants, LLC   19      TAXUS: A Polymer-Based Paclitaxel-Eluting Stent, Ronald A. Sahatjian, Boston Scientific Corporation   20     CELL-MATRIX CARTILAGE IMPLANTS   21      Cell-Matrix Cartilage Implants: A Clinician’s Perspective, Richard D. Coutts, University of California at San Diego   21      Cell Therapy for Cartilage Repair: Present and Future, James W. Burns, Genzyme   23      Cell-Matrix Cartilage Implants for Articular Repair and Replacement, Anthony Ratcliffe, Synthasome, Inc.   24     APPENDIXES         Appendix A:   Workshop Agenda   28     Appendix B:   Biographies of Speakers and Session Chairs   31