Exploring Novel
Clinical Trial Designs for
Gene-Based Therapies
PROCEEDINGS OF A WORKSHOP
Siobhan Addie, Meredith Hackmann, Joe Alper, 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; 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: 978-0-309-67298-6
International Standard Book Number-10: 0-309-67298-8
Digital Object Identifier: http://doi.org/10.17226/25712
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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.
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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, Senior Board Director
___________________
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.
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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, 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
___________________
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.
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
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, Senior 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 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:
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 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 standards of the National Academies 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 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 Regenerative 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 director would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop.
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Contents
Organization of the Workshop and Proceedings
2 DEVELOPING FIRST-IN-HUMAN GENE THERAPY CLINICAL TRIALS
Using Natural History Studies in Clinical Development
Development of Gene Therapy for Spinal Muscular Atrophy
Ethical Dimensions of First-in-Human Gene Transfer Trials
3 UNDERSTANDING THE COMPLEXITIES OF PATIENT SELECTION, ENROLLMENT, AND THE CONSENT PROCESS
The Challenges of Using Gene Therapy to Treat Duchenne Muscular Dystrophy
Patient and Family Perspectives
4 DEVELOPING ENDPOINTS FOR GENE THERAPY CLINICAL TRIALS
Developing Endpoints for Clinical Trials
Endpoints for Gene Therapy Clinical Trials in Pompe Disease
A Novel Outcome Measure for Gene Therapy for a Form of Congenital Blindness
Determining Optimal Endpoints for Gene Therapy in Sickle Cell Disease
Perspectives from the Food and Drug Administration on Long-Term Follow-Up Studies
Long-Term Surveillance of Exposed Pediatric and Adolescent Cancer Survivors
Long-Term Follow-Up for Gene and Cellular Therapies
Role of the Cystic Fibrosis Foundation in Addressing Post-Approval Regulatory Obligations
A Patient’s Perspective on Long-Term Follow-Up Studies
6 REFLECTIONS ON THE WORKSHOP AND POTENTIAL OPPORTUNITIES FOR NEXT STEPS
Possible Next Steps for Improving the Design of Gene Therapy Clinical Trials
Ongoing Challenges for Gene Therapy Clinical Trials
Boxes, Figures, and Table
BOXES
6-2 Key Points from Individual Speakers Related to Patient Selection, Enrollment, and Consent
6-4 Key Points from Individual Speakers Related to Long-Term Patient Follow-Up
FIGURES
1-1 Clinical development of AAV2-RPE65 (Luxturna)
3-1 Bone marrow stem cell strategies for sickle cell disease
3-2 Autologous bone marrow stem cell–targeted gene editing to treat sickle cell disease
5-1 Framework to assess the risk of gene therapy–related delayed adverse events
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 |
CNS | central nervous system |
DDT | drug development tool |
DMD | Duchenne muscular dystrophy |
Dx | diagnosis |
FDA | Food and Drug Administration |
GAA | acid alpha-glucosidase |
GT | gene therapy |
GVHD | graft-versus-host disease |
HL | Hodgkin lymphoma |
HLA | human leukocyte antigen |
IRB | institutional review board |
MLMT | multi-luminance mobility test |
NCATS | National Center for Advancing Translational Sciences |
NCI | National Cancer Institute |
NDI | National Death Index |
NeuroNEXT | Network for Excellence in Neuroscience Clinical Trials |
NHL | non-Hodgkin lymphoma |
NHLBI | National Heart, Lung, and Blood Institute |
NIH | National Institutes of Health |
RPE65 | retinal pigment epithelium 65 |
SCD | sickle cell disease |
SCID | severe combined immunodeficiency |
SJLIFE | St. Jude Lifetime cohort |
SMA | spinal muscular atrophy |