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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Page xvii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25371.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products PROCEEDINGS OF A WORKSHOP Meredith Hackmann, Theresa Wizemann, and Sarah H. Beachy, Rapporteurs Forum on Regenerative Medicine Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY­ Uncorrected Proofs —

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and Advanced Regenerative Manufacturing Institute (unnumbered contract); Akron Biotech (unnumbered contract); Alliance for Regenerative Medicine (unnumbered contract); ALS Association (unnumbered contract); American Society of Gene & Cell Therapy (unnumbered contract); Burroughs Wellcome Fund (unnumbered con- tract); California Institute for Regenerative Medicine (unnumbered contract); Centre for Commercialization of Regenerative Medicine (un­ umbered contract); Depart- n ment of Veterans Affairs (Contract No. VA268-16-C-0051); Food and Drug Admin- istration (Grant #1R13FD0066—14-01); GE Healthcare (unnumbered contract); GlaxoSmithKline (unnumbered contract); International Society for Cellular ­ herapy T (unnumbered contract); International Society for Stem Cell Research (unnum- bered contract); Johnson & Johnson (unnumbered contract); Juno Therapeutics (unnumbered contract); The Michael J. Fox Foundation for Parkinson’s Research (un­ umbered contract); National Institute of Standards and Technology (unnum- n bered contract); National Institutes of Health (Contract No. HHSN263201200074I, Order No. HHSN23600075: National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Cranio- facial Research; National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of Neurological Disorders and Stroke); The New York Stem Cell Foundation (unnumbered contract); Parkinson’s Foundation (unnumbered con- ­ tract); Takeda Development Center Americas (unnumbered contract); and United Therapeutics Corporation (#10003921). Any opinions, conclusions, or recom- mendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25371 Additional copies of this publication are available 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. Copyright 2019 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. ­ 2019. Exploring sources of variability related to the clinical translation of ­egenerative engineering products: Proceedings of a workshop. Washington, DC: r The National Academies Press. doi: https://doi.org/10.17226/25371. PREPUBLICATION COPY­ Uncorrected Proofs —

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institu- tion to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the char- ter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engi­ eering, and Medicine to provide independent, objective analysis and n a ­ dvice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY­ Uncorrected Proofs —

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typi- cally include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and ­ pinions o contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY­ Uncorrected Proofs —

PLANNING COMMITTEE ON EXPLORING SOURCES OF VARIABILITY RELATED TO THE CLINICAL TRANSLATION OF REGENERATIVE ENGINEERING PRODUCTS1 MARTHA LUNDBERG (Co-Chair), Program Director, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health KATHERINE TSOKAS (Co-Chair), Regulatory Head of Regenerative Medicine and Advanced Therapy, Johnson & Johnson BRIAN FISKE, Senior Vice President, Research Programs, The Michael J. Fox Foundation for Parkinson’s Research CATO T. LAURENCIN, Director, Institute for Regenerative Engineering; Chief Executive Officer, Connecticut Institute for Clinical and Translational Science; Distinguished Professor of Orthopedic Surgery and Chemical, Material, and Biomolecular Engineering, University of Connecticut Health Center ANNE PLANT, Chief of the Biosystems and Materials Division, National Institute of Standards and Technology KRISHNENDU ROY, Robert A. Milton Chair and Professor Technical Lead, National Cell Manufacturing Consortium, Georgia Institute of Technology SOHEL TALIB, Scientific Program Officer, California Institute for Regenerative Medicine DANIEL WEISS, Chief Scientific Officer, International Society for Cellular Therapy Forum on Regenerative Medicine Staff SARAH H. BEACHY, Senior Program Officer and Forum Director SIOBHAN ADDIE, Program Officer ARIEL MARKOWITZ-SHULMAN, Associate Program Officer (until June 2018) MEREDITH HACKMANN, Research Associate REBECCA RAY, Senior Program Assistant (until December 2018) 1  The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rap- porteurs and the institution. v PREPUBLICATION COPY­ Uncorrected Proofs —

Board on Health Sciences Policy Staff MARIAM SHELTON, Program Coordinator (from September 2018) ANDREW M. POPE, Board Director vi PREPUBLICATION COPY­ Uncorrected Proofs —

FORUM ON REGENERATIVE MEDICINE1 JAY P. SIEGEL (Co-Chair) (retired), Chief Biotechnology Officer and Head, Scientific Strategy and Policy, Johnson & Johnson SHARON TERRY (Co-Chair), President and Chief Executive Officer, Genetic Alliance JAMES C. BECK, Vice President, Scientific Affairs, Parkinson’s Foundation SANGEETA BHATIA, John J. and Dorothy Wilson Professor, Institute for Medical Engineering and Science, Electrical Engineering and Computer Science, Massachusetts Institute of Technology LUCIE BRUIJN, Chief Scientist, ALS Association GEORGE Q. DALEY, Director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute; Dean, Harvard Medical School CYNTHIA DUNBAR, Past President, American Society of Gene & Cell Therapy (until January 2019) BRIAN FISKE, Senior Vice President, Research Programs, The Michael J. Fox Foundation for Parkinson’s Research LAWRENCE GOLDSTEIN, Distinguished Professor, Department of Cellular and Molecular Medicine, Department of Neurosciences; Director, University of California, San Diego, Stem Cell Program; Scientific Director, Sanford Consortium for Regenerative Medicine; Director, Sanford Stem Cell Clinical Center, University of California, San Diego, School of Medicine ROSEMARIE HUNZIKER, Director of Tissue Engineering and Regenerative Medicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (until December 2018) SEIGO IZUMO, Global Head, Regenerative Medicine, Takeda Development Center Americas RUSSELL KELLEY, Program Officer, Interfaces in Science and Regulatory Science, Burroughs Wellcome Fund (until June 2018) AUDREY KUSIAK, Scientific Program Manager, Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs ROBERT S. LANGER, David H. Koch Institute Professor, Massachusetts Institute of Technology CATO T. LAURENCIN, Director, Institute for Regenerative Engineering; Chief Executive Officer, Connecticut Institute for Clinical and Translational Science; Distinguished Professor of Orthopedic Surgery and Chemical, Material and Biomolecular Engineering, University of Connecticut Health Center vii PREPUBLICATION COPY­ Uncorrected Proofs —

JOHN LEPORE, Senior Vice President, Research and Development Pipeline, GlaxoSmithKline MARTHA LUNDBERG, Program Director, Division of Cardiovascular Sciences, Advanced Technologies and Surgery Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (until December 2018) TERRY MAGNUSON, Sarah Graham Kenan Professor, Vice Chancellor for Research, University of North Carolina at Chapel Hill MICHAEL MAY, President and Chief Executive Officer, Centre for Commercialization of Regenerative Medicine RICHARD McFARLAND, Chief Regulatory Officer, Advanced Regenerative Manufacturing Institute JACK MOSHER, Senior Manager, Scientific Affairs, International Society for Stem Cell Research DUANQING PEI, Director General, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences THOMAS PETERSEN, Vice President, Regenerative Medicine, United Therapeutics Corporation ANNE PLANT, Chief of the Biosystems and Materials Division, National Institute of Standards and Technology DEREK ROBERTSON, Co-Founder and President, Maryland Sickle Cell Disease Association KELLY ROSE, Program Officer, Burroughs Wellcome Fund (from January 2019) KRISHNENDU ROY, Robert A. Milton Chair in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology KRISHANU SAHA, Assistant Professor, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin–Madison RACHEL SALZMAN, Society Officer, American Society of Gene & Cell Therapy (from January 2019) MARTHA SOMERMAN, Director, National Institute of Dental and Craniofacial Research, National Institutes of Health LISA STROVINK, Chief Strategy Officer, The New York Stem Cell Foundation SOHEL TALIB, Scientific Program Officer, California Institute for Regenerative Medicine KATHERINE TSOKAS, Regulatory Head of Regenerative Medicine and Advanced Therapy, Johnson & Johnson PHIL VANEK, General Manager, Cell Therapy Growth Strategy, GE Healthcare viii PREPUBLICATION COPY­ Uncorrected Proofs —

DANIEL WEISS, Chief Scientific Officer, International Society for Cellular Therapy MICHAEL WERNER, Co-Founder and Senior Policy Counsel, Alliance for Regenerative Medicine CELIA WITTEN, Deputy Director, Center for Biologics Evaluation and Research, Food and Drug Administration CLAUDIA ZYLBERBERG, Founder and Chief Executive Officer, Akron Biotech Forum on Regenerative Medicine Staff SARAH H. BEACHY, Senior Program Officer and Forum Director SIOBHAN ADDIE, Program Officer MEREDITH HACKMANN, Research Associate MICHAEL BERRIOS, Senior Program Assistant (from December 2018) REBECCA RAY, Senior Program Assistant (until December 2018) Board on Health Sciences Policy Staff MARIAM SHELTON, Program Coordinator (from September 2018) ANDREW M. POPE, Board Director ix PREPUBLICATION COPY­ Uncorrected Proofs —

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Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making its published proceedings as sound as possible and to ensure that it meets institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manu- script remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research JANE LEBKOWSKI, Regenerative Patch Technologies, LLC SOHEL TALIB, California Institute for Regenerative Medicine Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings, nor did they see the final draft before its release. The review of this proceedings was overseen by LINDA DEGUTIS, Henry M. Jackson Foundation. She was responsible for making certain that an independent examination of this proceedings was carried out in accordance with institu- tional procedures and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. xi PREPUBLICATION COPY­ Uncorrected Proofs —

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Acknowledgments The support of the sponsors of the Forum on Regenerative Medi- cine was crucial to the planning and conduct of the workshop Exploring Sources of Variability Related to the Clinical Translation of Regenerative Engineering Products and for the development of this Proceedings of a Workshop. Federal sponsors were the Department of Veterans Affairs; Food and Drug Administration; National Institute of Standards and Technol- ogy; and National Institutes of Health: National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of ­ Neurological Disorders and Stroke. Nonfederal sponsorship was provided by Advanced Regenerative Manufacturing Institute; Akron Biotech; A­ liance l for Regenerative Medicine; ALS Association; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenera- tive Medicine; Centre for Commercialization of Regenerative Medicine; GE Healthcare; GlaxoSmithKline; International Society for Cellular Therapy; ­ International Society for Stem Cell Research; Johnson & Johnson; Juno Therapeutics; The Michael J. Fox Foundation for Parkinson’s Research; ­ The New York Stem Cell Foundation; Parkinson’s Foundation; Takeda Development Center Americas; and United Therapeutics Corporation. The Forum on Regenerative Medicine wishes to express gratitude to the expert speakers who explored the factors that contribute to variability in the development and clinical application of regenerative engineering xiii PREPUBLICATION COPY­ Uncorrected Proofs —

xiv ACKNOWLEDGMENTS products. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop. PREPUBLICATION COPY­ Uncorrected Proofs —

Contents ACRONYMS AND ABBREVIATIONS xix 1 INTRODUCTION AND OVERVIEW 1 Developing Regenerative Engineering Products, 3 Organization of the Workshop and Proceedings, 8 2 SOURCES OF VARIABILITY ASSOCIATED WITH REGENERATIVE THERAPIES: LESSONS FROM CASE STUDIES 9 Case Study 1: Variability in the Use of Mesenchymal Stem Cells for Treating Cardiomyopathy, 10 Case Study 2: Sources of Variability in Preclinical and Clinical Research on Stem Cell Therapies for ALS, 14 Case Study 3: Variability in the Development of CAR T Cell Therapy, 17 Discussion, 19 3 FACTORS CONTRIBUTING TO PATIENT VARIABILITY 23 Understanding Therapeutic Mechanisms, 24 Outcome Variability in Cardiovascular Stem Cell Trials, 28 Acceptable Results from Unacceptable Variability, 32 Allogeneic Cell Therapy for Degenerative Disc Disease, 36 xv PREPUBLICATION COPY­ Uncorrected Proofs —

xvi CONTENTS 4 ADDRESSING VARIABILITY IN DONOR TISSUES AND CELLS 41 The Challenge of Variability in CAR T Cell Manufacturing, 42 Identifying and Processing Cells for Regenerative Therapies, 45 The Role of Preservation in the Variability of Regenerative Medicine Products, 49 Discussion, 53 5 ADDRESSING VARIABILITY AND MEETING QUALITY EXPECTATIONS IN THE MANUFACTURING SETTING 55 Addressing Variability in Cell and Gene Therapy Manufacturing, 57 Using Elements of Quality by Design to Manage Variability, 59 Advances in Tissue Cryopreservation, 62 Discussion, 65 6 EXPLORING VARIABILITY AND ITS IMPACT ON PRODUCT REGULATION AND OUTCOMES 69 VentriGel: A Case Example of a Regenerative Engineering Therapy, 70 Variability of Regenerative Engineering Products and the Regulatory Approval Pathway, 73 7 POTENTIAL NEXT STEPS TO CONSIDER FOR ADDRESSING VARIABILITY 77 Crosscutting Topic Discussion, 77 Final Thoughts, 80 REFERENCES 83 APPENDIXES A WORKSHOP AGENDA 87 B SPEAKER BIOGRAPHICAL SKETCHES 93 C STATEMENT OF TASK 103 D REGISTERED ATTENDEES 105 PREPUBLICATION COPY­ Uncorrected Proofs —

Boxes and Figures BOXES 1-1 Workshop Objectives, 3 1-2 Definition of Regenerative Engineering, 4 2-1 Overview of Select Phase I/II Clinical Trials of Mesenchymal Stem Cells for the Treatment of Heart Failure (as described by Ivonne Hernandez Schulman), 12 7-1 Ideas About How to Begin to Understand and Address Variability Related to the Clinical Translation of Regenerative Engineering Products, 82 FIGURES 2-1 General overview of the steps and manufacturing challenges involved in CAR T cell manufacturing, 18 4-1 Sources of variation in cell sourcing and selection, 47 xvii PREPUBLICATION COPY­ Uncorrected Proofs —

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Acronyms and Abbreviations ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis CAR chimeric antigen receptor CFU colony forming unit cGMP current good manufacturing practice CIRM California Institute for Regenerative Medicine CLL chronic lymphocytic leukemia CMC chemistry, manufacturing, and controls FDA Food and Drug Administration GDNF glial cell line-derived neurotrophic factor GMP good manufacturing practices IDCT Injectable Disc Cell Therapy IL interleukin IND investigational new drug application iPSC induced pluripotent stem cell LFOV large field of view MI myocardial infarction MSC mesenchymal stromal cell xix PREPUBLICATION COPY­ Uncorrected Proofs —

xx ACRONYMS AND ABBREVIATIONS NIH National Institutes of Health NIST National Institute of Standards and Technology PBMC peripheral blood mononuclear cell RMAT Regenerative Medicine Advanced Therapy (designation) SOP standard operating procedure PREPUBLICATION COPY­ Uncorrected Proofs —

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The emerging multidisciplinary field of regenerative engineering is devoted to the repair, regeneration, and replacement of damaged tissues or organs in the body. To accomplish this it uses a combination of principles and technologies from disciplines such as advanced materials science, developmental and stem cell biology, immunology, physics, and clinical translation. The term "regenerative engineering" reflects a new understanding of the use of tissue engineering for regeneration and also the growing number of research and product development efforts that incorporate elements from a variety of fields. Because regenerative engineered therapies rely on live cells and scaffolds, there are inherent challenges in quality control arising from variability in source and final products. Furthermore, each patient recipient, tissue donor, and product application is unique, meaning that the field faces complexities in the development of safe and effective new products and therapies which are not faced by developers of more conventional therapies. Understanding the many sources of variability can help reduce this variability and ensure consistent results.

The Forum on Regenerative Medicine hosted a public workshop on October 18, 2018, in Washington, DC, to explore the various factors that must be taken into account in order to develop successful regenerative engineering products. Invited speakers and participants discussed factors and sources of variability in the development and clinical application of regenerative engineering products, characteristics of high-quality products, and how different clinical needs, models, and contexts can inform the development of a product to improve patient outcomes. This publication summarizes the presentation and discussion of the workshop.

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