STEM CELL

THERAPIES

Opportunities for Ensuring the Quality
and Safety of Clinical Offerings

SUMMARY OF A JOINT WORKSHOP

by the Institute of Medicine,
the National Academy of Sciences, and
the International Society for Stem Cell Research

Adam C. Berger, Sarah H. Beachy, and Steve Olson, Rapporteurs

Board on Health Sciences Policy
Institute of Medicine

Board on Life Sciences
Division on Earth and Life Studies

    INSTITUTE OF MEDICINE AND
NATIONAL RESEARCH COUNCIL
                         OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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ST M CEL S EM C LL T ER PIE TH RA ES Opportun O nities fo Ensuri or ing the Quality Q and S Safety of Clinica Offerin f al ngs SUMMARY OF A JOINT WORKSHOP by the Institute of Medicine, the National Aca ademy of Sciences and s, the International Society for Stem Cell Research C Ad C. Berge Sarah H. Beachy, and St dam er, B teve Olson, R Rapporteurs Board on Heealth Science s Policy Institu of Medicin ute ne Board on Life Scien o nces Division on Earth and Life Studies E fe

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001 NOTICE: The workshop that is the subject of this workshop summary 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. This project was supported by contracts between the National Academy of Sciences and the Alliance for Regenerative Medicine (unnumbered contract); California Institute for Regenerative Medicine (unnumbered contract); The Ellison Medical Foundation (Contract No. OP-CW-0405-13); Howard Hughes Medical Institute (unnumbered contract); International Society for Stem Cell Research (unnumbered contract); and U.K. Academy of Medical Sciences (unnumbered contract). The project was also sponsored by the Presidents’ Committee Funds of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13: 978-0-309-30300-2 International Standard Book Number-10: 0-309-30300-1 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. For more information about the National Academy of Sciences, visit the NAS home page at: http://www.nasonline.org. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America COVER: Fluorescence microscopy of pluripotent mouse stem cells undergoing differentiation into a variety of cell lineages. Photo credit: Pablo Perez-Pinera, Jonathan Brunger, Farshid Guilak, and Charles Gersbach, Duke University. Suggested citation: IOM (Institute of Medicine) and NAS (National Academy of Sciences). 2014. Stem cell therapies: Opportunities for ensuring the quality and safety of clinical offerings. Washington, DC: The National Academies Press.

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The Na ational Academy of Sciences is a private, nonp s profit, self-perpe etuating society of y distingu uished scholars engaged in scie entific and engin neering research dedicated to the h, ance of science and technology and to their use for the general welfare. Upon the furthera a authorit of the charter granted to it by the Congress in 1863, the Acade ty emy has a mand date that req quires it to advis the federal go se overnment on sc cientific and tech hnical matters. D Dr. Ralph J. Cicerone is preesident of the Na ational Academy of Sciences. y The Nattional Academy of Engineering was establishe in 1964, unde the charter of the y ed er Nationa Academy of Sciences, as a pa al S arallel organizattion of outstandi engineers. It is ing t autonom mous in its adm ministration and in the selection of its members sharing with t i s, the Nationa Academy of Sciences the res al S sponsibility for advising the feederal governmeent. The Naational Academy of Engineerin also sponsors engineering p y ng s programs aimed at d meeting national needs, encourages edu g ucation and reseearch, and recoggnizes the super rior achievements of engine eers. Dr. C. D. Mote, Jr., is pres M sident of the Nattional Academy of y ering. Enginee The Insstitute of Mediccine was established in 1970 by t National Ac the cademy of Scienc ces to secur the services of eminent memb of appropri ate professions in the examinati re o bers ion of polic matters perta cy aining to the heealth of the pub blic. The Institu acts under t ute the responsibility given to the National Ac t cademy of Sciennces by its congr ressional charter to r be an ad dviser to the fed deral governmen and, upon its o nt own initiative, to identify issues of o s medical care, research, and education. Dr. Harvey V. Fi l D ineberg is presiddent of the Institu ute of Mediicine. The National Research Council was organized by the National Acade h o e emy of Sciences in s 1916 to associate the broad community of science and technology w the Academy o b y d with y’s purpose of furthering knowledge and advising the fe es ederal governme Functioning in ent. g accorda ance with genera policies deter al rmined by the AAcademy, the Co ouncil has become the prin ncipal operating agency of bo the Nationa Academy of Sciences and the g oth al Nationa Academy of Engineering in providing servic to the gover al E p ces rnment, the publ lic, and the scientific and engineering com e mmunities. The C Council is admiinistered jointly by both Ac cademies and the Institute of Me e edicine. Dr. Ralp J. Cicerone an Dr. C. D. Mo ph nd ote, Jr., are chair and vice ch c hair, respectively of the Nationa Research Cou y, al uncil. w www.national l-academies.o org

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PLANNING COMMITTEE1 R. ALTA CHARO (Chair), Warren P. Knowles Professor of Law and Bioethics, School of Law and Department of Medical History and Bioethics, School of Medicine and Public Health, University of Wisconsin–Madison ROBIN ALI, Professor of Human Molecular Genetics, Institute of Ophthalmology, University College London, UK I. GLENN COHEN, Professor of Law and Co-Director of the Petrie– Flom Center for Health Law Policy, Biotechnology and Bioethics, Harvard Law School, Cambridge, MA ELLEN G. FEIGAL, Senior Vice President, Research and Development, California Institute for Regenerative Medicine, San Francisco, CA FRED H. GAGE, Vi and John Adler Professor, Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA LAWRENCE S. B. GOLDSTEIN, Distinguished Professor and Director of the University of California, San Diego, Stem Cell Program, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA GEOFF MACKAY, Chief Executive Officer, Organogenesis, Inc., Canton, MA AMY COMSTOCK RICK, Chief Executive Officer, Parkinson’s Action Network, Washington, DC IRVING L. WEISSMAN, Director, Institute of Stem Cell Biology and Regenerative Medicine; Director, Ludwig Center at Stanford; Professor, Departments of Pathology and Developmental Biology and Neurosurgery, Stanford University School of Medicine, Stanford, CA Institute of Medicine and National Research Council Staff ADAM C. BERGER, Project Director KEEGAN SAWYER, Program Officer SARAH H. BEACHY, Associate Program Officer Y. CRYSTI PARK, Senior Program Assistant MEREDITH L. HACKMANN, Senior Program Assistant (from January 2014) 1 Planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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International Society for Stem Cell Research Staff NANCY WITTY, Executive Director HEATHER ROOKE, Scientific Director vi

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BOARD ON HEALTH SCIENCES POLICY JEFFREY KAHN (Chair), Levi Professor of Bioethics and Public Policy, Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD ELI ADASHI, Professor of Medical Science, The Warren Alpert Medical School, Brown University, Providence, RI WYLIE BURKE, Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle ROBERT M. CALIFF, Director, Duke Translational Medicine Institute; Professor of Medicine, Vice Chancellor for Clinical and Translational Research, Duke University Medical Center, Durham, NC KATHLEEN A. DRACUP, Professor, School of Nursing, University of California, San Francisco MICHAEL EHLERS, Senior Vice President, Chief Scientific Officer of Neuroscience, Pfizer Inc., Cambridge, MA NAOMI L. GERBER, University Professor, Center for the Study of Chronic Illness and Disability, George Mason University, Fairfax, VA LEWIS R. GOLDFRANK, Herbert W. Adams Professor and Chair, Department of Emergency Medicine, New York University School of Medicine; Director of Emergency Medicine, Bellevue Hospital Center and New York University Langone Medical Center STEVEN E. HYMAN, Director, Stanley Center, Broad Insitute of Harvard University and the Massachusetts Institute of Technology, Cambridge, MA HARRY T. ORR, Director, Institute of Human Genetics; Tulloch Professor of Genetics, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis SHARON TERRY, President and Chief Executive Officer, Genetic Alliance, Washington, DC REED V. TUCKSON, Managing Director, Tuckson Health Connections, LLC, Edina, MN CLYDE YANCY, Magerstadt Professor of Medicine and Chief, Division of Cardiology, Northwestern University Feinberg School of Medicine; Associate Director, Bluhm Cardiovascular Insitute, Northwestern Memorial Hospital, Chicago, IL vii

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Board on Health Sciences Policy Staff ANDREW M. POPE, Director ADAM C. BERGER, Senior Program Officer SARAH H. BEACHY, Associate Program Officer Y. CRYSTI PARK, Senior Program Assistant MEREDITH L. HACKMANN, Senior Program Assistant (from January 2014) DONNA RANDALL, Administrative Assistant viii

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BOARD ON LIFE SCIENCES JAMES P. COLLINS (Chair), Virginia M. Ullman Professor of Natural History and the Environment, Arizona State University, Tempe ENRIQUETA C. BOND, Former President, Burroughs Wellcome Fund, Marshall, VA ROGER D. CONE, Professor and Chairman, Department of Molecular Physiology and Biophysics; Director, Vanderbilt Institute for Obesity and Metabolism; Vanderbilt University Medical Center, Nashville, TN SEAN EDDY, Group Leader, Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, VA SARAH C. R. ELGIN, Viktor Hamburger Professor of Arts & Sciences, Department of Biology, Washington University, St. Louis, MO DAVID R. FRANZ, Former Commander, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD LOUIS J. GROSS, James R. Cox and Alvan and Sally Beaman Distinguished Professor of Ecology and Evolutionary Biology and Mathematics; Director, National Institute for Mathematical and Biological Synthesis; Director, Institute for Environmental Modeling; University of Tennessee, Knoxville ELIZABETH HEITMAN, Associate Professor of Medicine and Anesthesiology, Vanderbilt University Medical Center, Nashville, TN JOHN G. HILDEBRAND, Regents Professor, University of Arizona, Tucson RICHARD A. JOHNSON, Retired Partner, Arnold & Porter, LLC, Washington, DC JUDITH KIMBLE, Vilas Professor, Howard Hughes Medical Institute Investigator, University of Wisconsin–Madison CATO T. LAURENCIN, University Professor, University of Connecticut Health Center, Farmington ALAN I. LESHNER, Chief Executive Officer, American Association for the Advancement of Science, Washington, DC KAREN E. NELSON, President, J. Craig Venter Institute, Rockville, MD ROBERT M. NEREM, Parker H. Petit Distinguished Chair for Engineering in Medicine; Institute Professor Emeritus, Georgia Institute of Technology, Atlanta CAMILLE PARMESAN, Professor, University of Texas, Austin; National Marine Aquarium Chair, Plymouth University, Plymouth, UK ALISON G. POWER, Professor, Cornell University, Ithaca, NY ix

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MARGARET RILEY, Professor, University of Massachusetts; President and Founder, Massachusetts Academy of Sciences, Amherst JANIS C. WEEKS, Professor, University of Oregon, Eugene MARY WOOLLEY, President, Research!America, Alexandria, VA Board on Life Sciences Staff FRANCES E. SHARPLES, Director KEEGAN SAWYER, Program Officer x

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Reviewers This workshop summary 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 workshop summary 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 process. We wish to thank the following individuals for their review of this workshop summary: I. Glenn Cohen, Harvard Law School Susan Howley, Christopher & Dana Reeve Foundation Mahendra Rao, National Institutes of Health Celia Witten, U.S. Food and Drug Administration Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by Caswell Evans, University of Illinois at Chicago, and Harold J. Fallon, University of Alabama at Birmingham School of Medicine. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments xi

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xii REVIEWERS were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the rapporteurs and the institution.

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Acknowledgments The support of the sponsors of Stem Cell Therapies: Opportunities for Ensuring the Quality and Safety of Clinical Offerings was crucial to the planning and conduct of the workshop and the development of the workshop summary report. Sponsorship was provided by the Alliance for Regenerative Medicine; California Institute for Regenerative Medicine; The Ellison Medical Foundation; Howard Hughes Medical Institute; In- ternational Society for Stem Cell Research; the Presidents’ Committee Funds of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine; and U.K. Academy of Medi- cal Sciences. The planning committee and staff wish to express their gratitude to the expert speakers whose presentations helped outline the challenges and opportunities for ensuring the quality and safety of stem cell thera- pies. The staff also wish to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank project staff, who worked diligently to de- velop both the workshop and the resulting summary. xiii

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Contents ABBREVIATIONS AND ACRONYMS xix 1 INTRODUCTION AND THEMES OF THE WORKSHOP 1 Background, 3 Themes of the Workshop, 6 Organization of the Report, 7 2 STEM CELL THERAPIES—KNOWNS AND UNKNOWNS 9 Stem Cells as Regulated Therapeutics, 10 Clinical Offerings Using Stem Cells, 12 3 PATIENTS’ EXPERIENCES 17 Medical Tourism: Patients Seeking Stem Cell Treatments, 18 Patients Seeking Unproven or Unregulated Treatments, 20 One Patient’s Experiences, 23 4 COMPARATIVE REGULATORY AND LEGAL FRAMEWORKS 25 Regulatory and Legal Frameworks in the United States, 26 Regulatory and Legal Frameworks in Italy, 30 Regulatory and Legal Frameworks in Japan, 33 Regulatory and Legal Frameworks in Mexico, 35 Regulatory and Legal Frameworks in China, 37 Suggested Improvements for Regulation, 38 xv

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xvi CONTENTS 5 THE ROLES OF PROFESSIONAL SOCIETIES 41 The Society for Assisted Reproductive Technology, 42 The International Society for Stem Cell Research, 44 The International Society for Cellular Therapy, 45 6 MOVING FORWARD 49 What Is the Most Important Problem?, 51 What Needs to Be Known?, 52 What Could Be Done?, 53 A Continued Dialogue, 54 REFERENCES 55 APPENDIXES A Workshop Agenda 61 B Speaker Biographical Sketches 67 C Statement of Task 79 D Registered Attendees 81 E Glossary 85

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Boxes, Figures, and Table BOXES 1-1 Stem Cell Potential, 2 1-2 Objectives of the Workshop Developed by the Planning Committee, 3 2-1 Considerations from Individual Speakers for Assessing Treatment Effectiveness and Communicating with Patients, 9 3-1 Summary from Individual Speakers About Discussions on Regulation and Patients’ Expectations, 17 4-1 Summary Points from Individual Speakers About Regulatory and Legal Issues Related to Stem Cell Therapies, 25 5-1 Potential Contributions of Professional Societies and Other Organizations as Suggested by Individual Speakers, 41 6-1 Proposed Solutions to Challenges Encountered with Unproven Stem Cell Therapies as Suggested by Individual Speakers, 49 FIGURES 2-1 The tone of news media reports that covered stem cell therapies has been largely positive, 13 xvii

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xviii BOXES, FIGURES, AND TABLE 4-1 A new approval system under consideration in Japan would create earlier patient access to cellular therapy products, 35 TABLE 1-1 Number of Clinical Trials Under Way Using Stem Cells, 5

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Abbreviations and Acronyms AIDS acquired immunodeficiency syndrome ASRM American Society for Reproductive Medicine CAS Chinese Academy of Sciences CEO chief executive officer CIRM California Institute for Regenerative Medicine COFEPRIS Comisión Federal para la Protección contra Riesgos Sanitarios (Mexico) EMA European Medicines Agency FDA U.S. Food and Drug Administration FTC Federal Trade Commission GMP good manufacturing process IOM Institute of Medicine IRB institutional review board ISCT International Society for Cellular Therapy ISSCR International Society for Stem Cell Research MHLW Ministry of Health, Labor, and Welfare (Japan) MS multiple sclerosis NAS National Academy of Sciences PMDA Pharmaceuticals and Medical Devices Agency (Japan) xix

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xx ABBREVIATIONS AND ACRONYMS SART Society for Assisted Reproductive Technologies U.S. United States