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
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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 contract); California Institute for Regenerative Medicine (unnumbered contract); Centre for Commercialization of Regenerative Medicine (unnumbered contract); Department of Veterans Affairs (Contract No. VA268-16-C-0051); Food and Drug Administration (Grant #1R13FD0066—14-01); GE Healthcare (unnumbered contract); GlaxoSmithKline (unnumbered contract); International Society for Cellular Therapy (unnumbered contract); International Society for Stem Cell Research (unnumbered contract); Johnson & Johnson (unnumbered contract); Juno Therapeutics (unnumbered contract); The Michael J. Fox Foundation for Parkinson’s Research (unnumbered contract); National Institute of Standards and Technology (unnumbered 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 Craniofacial 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 contract); Takeda Development Center Americas (unnumbered contract); and United Therapeutics Corporation (#10003921). Any opinions, conclusions, or recommendations 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: 978-0-309-48909-6
International Standard Book Number-10: 0-309-48909-1
Digital Object Identifier: https://doi.org/10.17226/25371
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Suggested citation: 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: https://doi.org/10.17226/25371.
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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 in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Cell-Therapy Characterization and Manufacturing, 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 rapporteurs and the institution.
Board on Health Sciences Policy Staff
MARIAM SHELTON, Program Coordinator (from September 2018)
ANDREW M. POPE, Board Director
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
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
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
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 Cell-Therapy 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
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
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Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments 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 manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings:
Although the reviewers listed above provided many constructive comments 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 institutional procedures and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
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Acknowledgments
The support of the sponsors of the Forum on Regenerative Medicine 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 Technology; 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; Alliance for Regenerative Medicine; ALS Association; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative 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
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.
Contents
Developing Regenerative Engineering Products
Organization of the Workshop and Proceedings
2 SOURCES OF VARIABILITY ASSOCIATED WITH REGENERATIVE THERAPIES: LESSONS FROM CASE STUDIES
Case Study 1: Variability in the Use of Mesenchymal Stem Cells for Treating Cardiomyopathy
Case Study 3: Variability in the Development of CAR T Cell Therapy
3 FACTORS CONTRIBUTING TO PATIENT VARIABILITY
Understanding Therapeutic Mechanisms
Outcome Variability in Cardiovascular Stem Cell Trials
4 ADDRESSING VARIABILITY IN DONOR TISSUES AND CELLS
The Challenge of Variability in CAR T Cell Manufacturing
Identifying and Processing Cells for Regenerative Therapies
The Role of Preservation in the Variability of Regenerative Medicine Products
5 ADDRESSING VARIABILITY AND MEETING QUALITY EXPECTATIONS IN THE MANUFACTURING SETTING
Addressing Variability in Cell and Gene Therapy Manufacturing
Using Elements of Quality by Design to Manage Variability
Advances in Tissue Cryopreservation
6 EXPLORING VARIABILITY AND ITS IMPACT ON PRODUCT REGULATION AND OUTCOMES
VentriGel: A Case Example of a Regenerative Engineering Therapy
Variability of Regenerative Engineering Products and the Regulatory Approval Pathway
7 POTENTIAL NEXT STEPS TO CONSIDER FOR ADDRESSING VARIABILITY
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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 practice |
| IDCT | Injectable Disc Cell Therapy |
| IL | interleukin |
| IND | investigational new drug |
| iPSC | induced pluripotent stem cell |
| LFOV | large field of view |
| MI | myocardial infarction |
| MSC | mesenchymal stromal cell |
| NIH | National Institutes of Health |
| PBMC | peripheral blood mononuclear cell |
| RMAT | Regenerative Medicine Advanced Therapy (designation) |
| SOP | standard operating procedure |
