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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Exploring Novel Clinical Trial Designs for Gene-Based Therapies: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25712.
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Siobhan Addie, Meredith Hackmann, Joe Alper, 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; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; Department of Veterans Affairs (Contract No. VA268-16-C-0051); Food and Drug Administration (Grant #1R13FD0066—14-01); GE Healthcare; International Society for Cell & Gene Therapy; International Society for Stem Cell Research; Johnson & Johnson; The Michael J. Fox Foundation for Parkinson’s Research; National Institute of Standards and Technology; National Institutes of Health: National Institute of Dental and Craniofacial Research (Contract No. HHSN263201800029I; Order No. 75N98019F00847), National Institute of Diabetes and Digestive and Kidney Diseases (PO No. 75N94019P00304); The New York Stem Cell Foundation; Parkinson’s Foundation; Sanofi (Contract No. 55630791); and United Therapeutics Corporation (Contract No. 10003921). Any opinions, findings, 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-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: http://doi.org/10.17226/25712 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 2020 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. 2020. Exploring novel clinical trial designs for gene-based therapies: Proceedings of a workshop. Washington, DC: The National Academies Press. http://doi. org/10.17226/25712. 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 institution 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 charter 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. John L. Anderson 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, Engineering, and Medicine to provide independent, objective analysis and advice 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 typically 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 opinions 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 NOVEL CLINICAL TRIAL DESIGNS FOR GENE-BASED THERAPIES1 KRISHANU SAHA (Co-Chair), Associate Professor and Retina Research Foundation Kathryn and Latimer Murfee Chair, Department of Biomedical Engineering, University of Wisconsin–Madison CELIA WITTEN (Co-Chair), Deputy Director, Center for Biologics Evaluation and Research, Food and Drug Administration MILDRED CHO, Research Professor of Pediatrics and Associate Director, Center for Biomedical Ethics, Stanford University MICHAEL DeBAUN, Professor of Pediatrics and Medicine, Vanderbilt University School of Medicine CYNTHIA DUNBAR, Senior Investigator, National Heart, Lung, and Blood Institute, National Institutes of Health DEREK ROBERTSON, Co-Founder and President, Maryland Sickle Cell Disease Association KATHERINE TSOKAS, Regulatory Head of Regenerative Medicine and Advanced Therapy, Johnson & Johnson Forum on Regenerative Medicine Staff SARAH H. BEACHY, Senior Program Officer and Forum Director SIOBHAN ADDIE, Program Officer MEREDITH HACKMANN, Associate Program Officer MICHAEL BERRIOS, Senior Program Assistant Board on Health Sciences Policy Staff BRIDGET BOREL, Program Coordinator (from October 2019) MARIAM SHELTON, Program Coordinator (until October 2019) ANDREW M. POPE, Board Director 1The 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

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FORUM ON REGENERATIVE MEDICINE1 TIM COETZEE (Co-Chair), Chief Advocacy, Services and Research Officer, National Multiple Sclerosis Society KATHERINE TSOKAS (Co-Chair), Regulatory Head of Regenerative Medicine and Advanced Therapy, Johnson & Johnson 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 GEORGE Q. DALEY, Director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute; Dean, Harvard Medical School 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 AUDREY KUSIAK, Scientific Program Manager, Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs (until September 2019) ROBERT S. LANGER, David H. Koch Institute Professor, Massachusetts Institute of Technology CATO T. LAURENCIN, University Professor, Albert and Wilda Van Dusen Distinguished Professor of Orthopaedic Surgery, Professor of Chemical, Materials Science, and Biomedical Engineering; Director, The Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences; Chief Executive Officer, The Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut 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 1The 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. vii PREPUBLICATION COPY—Uncorrected Proofs

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 Biomaterials Division, National Institute of Standards and Technology KIMBERLEE POTTER, Scientific Program Manager, Biomedical Laboratory R&D Service, Office of Research and Development, Department of Veterans Affairs (from September 2019) DEREK ROBERTSON, Co-Founder and President, Maryland Sickle Cell Disease Association GRIFFIN RODGERS, Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health KELLY ROSE, Program Officer, Burroughs Wellcome Fund KRISHNENDU ROY, Robert A. Milton Chair and Professor in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology KRISHANU SAHA, Associate Professor and Retina Research Foundation Kathryn and Latimer Murfee Chair, Department of Biomedical Engineering, University of Wisconsin–Madison RACHEL SALZMAN, Society Officer, American Society of Gene & Cell Therapy JAY P. SIEGEL, Chief Biotechnology Officer and Head, Scientific Strategy and Policy, Johnson & Johnson (Retired) LANA SKIRBOLL, Vice President, Science Policy, Sanofi 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, Associate Director of Therapeutics and Industry Alliance, California Institute for Regenerative Medicine PHIL VANEK, General Manager, Cell Therapy Growth Strategy, GE Healthcare DANIEL WEISS, Chief Scientific Officer, International Society for Cell & Gene Therapy MICHAEL WERNER, Co-Founder and Senior Policy Counsel, Alliance for Regenerative Medicine viii PREPUBLICATION COPY—Uncorrected Proofs

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, Associate Program Officer MICHAEL BERRIOS, Senior Program Assistant Board on Health Sciences Policy Staff BRIDGET BOREL, Program Coordinator (from October 2019) MARIAM SHELTON, Program Coordinator (until October 2019) 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 each published proceedings as sound as possible and to ensure that it meets the 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: ALEXANDRA BEATTY, National Academies of Sciences, Engineering, and Medicine ROSEMARIE HUNZIKER, Connexon Life Science Consulting DEREK ROBERTSON, Maryland Sickle Cell Disease Association 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 LESLIE BENET, University of California, San Francisco. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with stan- dards of the National Academies and that all review comments were care- fully 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 Medicine was crucial to the planning and conduct of the workshop Exploring Novel Clinical Trial Designs for Gene-Based Therapies, 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 Institute of Dental and Craniofacial Research and National Institute of Diabetes and Digestive and Kidney Diseases. Nonfederal sponsorship was provided by the Advanced Regenerative Manufacturing Institute; Akron Biotech; Alliance for Regenerative Medicine; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenera- tive Medicine; Centre for Commercialization of Regenerative Medicine; GE Healthcare; International Society for Cell & Gene Therapy; International Society for Stem Cell Research; Johnson & Johnson; The Michael J. Fox Foundation for Parkinson’s Research; The New York Stem Cell Foundation; Parkinson’s Foundation; Sanofi; and United Therapeutics Corporation. The Forum on Regenerative Medicine wishes to express gratitude to the expert speakers who explored the design complexities and ethical issues associated with developing clinical trials for gene-based therapies. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project direc- tor would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop. xiii PREPUBLICATION COPY—Uncorrected Proofs

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Contents ACRONYMS AND ABBREVIATIONS xix 1 INTRODUCTION AND OVERVIEW 1 Organization of the Workshop and Proceedings, 4 Lessons from the Development of a Gene Therapy to Treat Children and Adults with Inherited Vision Loss, 5 2 DEVELOPING FIRST-IN-HUMAN GENE THERAPY CLINICAL TRIALS 11 Using Natural History Studies in Clinical Development, 12 Development of Gene Therapy for Spinal Muscular Atrophy, 15 Ethical Dimensions of First-in-Human Gene Transfer Trials, 17 Discussion, 19 3 UNDERSTANDING THE COMPLEXITIES OF PATIENT SELECTION, ENROLLMENT, AND THE CONSENT PROCESS 23 The Complexities of Patient Selection, Enrollment, and Consent in the Context of Hematopoietic Stem Cell Transplantation to Treat Sickle Cell Disease, 25 The Complexities of Patient Selection, Enrollment, and Consent in the Context of Gene Therapies to Treat Sickle Cell Disease, 28 The Complexities of Patient Selection, Enrollment, and Consent in the Context of Gene Therapy for Severe Combined Immunodeficiency, 31 xv PREPUBLICATION COPY—Uncorrected Proofs

xvi CONTENTS The Challenges of Using Gene Therapy to Treat Duchenne Muscular Dystrophy, 33 Patient and Family Perspectives, 35 Discussion, 38 4 DEVELOPING ENDPOINTS FOR GENE THERAPY CLINICAL TRIALS 43 Developing Endpoints for Clinical Trials, 43 Endpoints for Gene Therapy Clinical Trials in Pompe Disease, 45 A Novel Outcome Measure for Gene Therapy for a Form of Congenital Blindness, 47 Determining Optimal Endpoints for Gene Therapy in Sickle Cell Disease, 48 Discussion, 51 5 INTEGRATING GENE-BASED THERAPIES INTO CLINICAL PRACTICE: EXPLORING LONG-TERM CLINICAL FOLLOW-UP OF PATIENTS 55 Perspectives from the Food and Drug Administration on Long-Term Follow-Up Studies, 57 Long-Term Surveillance of Exposed Pediatric and Adolescent Cancer Survivors, 60 Long-Term Follow-Up for Gene and Cellular Therapies, 63 Role of the Cystic Fibrosis Foundation in Addressing Post-Approval Regulatory Obligations, 64 A Patient’s Perspective on Long-Term Follow-Up Studies, 66 Discussion, 67 6 REFLECTIONS ON THE WORKSHOP AND POTENTIAL OPPORTUNITIES FOR NEXT STEPS 69 Possible Next Steps for Improving the Design of Gene Therapy Clinical Trials, 69 Ongoing Challenges for Gene Therapy Clinical Trials, 72 Final Remarks and Summary, 72 REFERENCES 77 APPENDIXES A WORKSHOP AGENDA 83 B SPEAKER BIOGRAPHICAL SKETCHES 89 C STATEMENT OF TASK 99 D REGISTERED ATTENDEES 101 PREPUBLICATION COPY—Uncorrected Proofs

Boxes, Figures, and Table BOXES 1-1 Workshop Objectives, 4 6-1 Key Points from Individual Speakers Related to Natural History Data and First-in-Human Gene Therapy Clinical Trials, 73 6-2 Key Points from Individual Speakers Related to Patient Selection, Enrollment, and Consent, 74 6-3 Key Points from Individual Speakers Related to Developing Endpoints for Gene Therapy Clinical Trials, 75 6-4 Key Points from Individual Speakers Related to Long-Term Patient Follow-Up, 76 FIGURES 1-1 Clinical development of AAV2-RPE65 (Luxturna), 6 3-1 Bone marrow stem cell strategies for sickle cell disease, 29 3-2 Autologous bone marrow stem cell–targeted gene editing to treat sickle cell disease, 30 5-1 Framework to assess the risk of gene therapy–related delayed adverse events, 58 xvii PREPUBLICATION COPY—Uncorrected Proofs

xviii BOXES, FIGURES, AND TABLE TABLE 5-1 Pediatric Cancer Survivor Cohort Characteristics, 61 PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations AAV adeno-associated virus ADA adenosine deaminase BEST Biomarkers, EndpointS, and other Tools CAR T chimeric antigen receptor T cell CCSS Childhood Cancer Survivor Study CFTR cystic fibrosis transmembrane conductance regulator CLL chronic lymphocytic leukemia DDT drug development tool DMD Duchenne muscular dystrophy FDA Food and Drug Administration GAA acid alpha-glucosidase GVHD graft-versus-host disease IRB institutional review board MLMT multi-luminance mobility test xix PREPUBLICATION COPY—Uncorrected Proofs

xx ACRONYMS AND ABBREVIATIONS NCATS National Center for Advancing Translational Sciences NCI National Cancer Institute NeuroNEXT National Network for Excellence in Neuroscience Clinical Trials NHLBI National Heart, Lung, and Blood Institute NIH National Institutes of Health RPE65 retinal pigment epithelium 65 SCID severe combined immunodeficiency SJLIFE St. Jude Lifetime SMA spinal muscular atrophy PREPUBLICATION COPY—Uncorrected Proofs

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Recognizing the potential design complexities and ethical issues associated with clinical trials for gene therapies, the Forum on Regenerative Medicine of the National Academies of Sciences, Engineering, and Medicine held a 1-day workshop in Washington, DC, on November 13, 2019. Speakers at the workshop discussed patient recruitment and selection for gene-based clinical trials, explored how the safety of new therapies is assessed, reviewed the challenges involving dose escalation, and spoke about ethical issues such as informed consent and the role of clinicians in recommending trials as options to their patients. The workshop also included discussions of topics related to gene therapies in the context of other available and potentially curative treatments, such as bone marrow transplantation for hemoglobinopathies. This publication summarizes the presentation and discussion of the workshop.

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