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IMPROVING CANCER DIAGNOSIS AND CARE Clinical Application of Computational Methods in Precision Oncology Emily Zevon, Margie Patlak, and Sharyl J. Nass, Rapporteurs National Cancer Policy Forum Board on Health Care Services Health and Medicine Division
THE NATIONAL ACADEMIES PRESSâ 500 Fifth Street, NWâ Washington, DC 20001 This activity was supported by Contract No. 200-2011-38807 (Task Order No. 75D30118F00071) and Contract No. HHSN263201800029I (Task Order No. HHSN26300008) with the Centers for Disease Control and Prevention and the National Cancer Institute/National Institutes of Health, respectively, and by the American Association for Cancer Research, American Cancer Society, American Col- lege of Radiology, American Society of Clinical Oncology, Association of American Cancer Institutes, Association of Community Cancer Centers, Bristol-Myers Squibb, C Â ancer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Th Â erapeutics (U.S.), Inc., LIVESTRONG Foundation, Merck, National Comprehen- sive Cancer Network, Novartis Oncology, Oncology Nursing Society, and Pfizer Inc. 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: 978-0-309-49081-8 International Standard Book Number-10: 0-309-49081-2 Digital Object Identifier: https://doi.org/10.17226/25404 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. Improving cancer diagnosis and care: Clinical application of computational methods in precision oncology: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25404.
The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental insti- tution to advise the nation on issues related to science and Âechnology. t 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. 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 Â ciences S 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.
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WORKSHOP PLANNING COMMITTEE1 CHRISTOPHER R. COGLE (Chair), Professor of Medicine, Pierre Chagnon Professor of Stem Cell Biology and Bone Marrow Transplant, University of Florida; Scholar in Clinical Research, Leukemia & Lymphoma Society AMY P. ABERNETHY, Chief Medical Officer, Chief Scientific Officer, and Senior Vice President, Oncology, Flatiron Health2 CONSTANTINE GATSONIS, Henry Ledyard Goddard University Professor, Founding Chair, Department of Biostatistics, Founding Director, Center for Statistical Sciences, Brown University School of Public Health LORI HOFFMAN HÅGG, Veterans Health Administration National Program Manager, Prevention Policy, National Center for Health Promotion and Disease Prevention; National Oncology Clinical Advisor, Office of Nursing Services, Department of Veterans Affairs HEDVIG HRICAK, Chair, Department of Radiology, Memorial Sloan Kettering Cancer Center SAMIR N. KHLEIF, Director, Jeannie and Tony Loop Immuno-Oncology Lab; Biomedical Scholar and Professor of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center MIA LEVY, Director, Rush University Cancer Center; Associate Professor of Medicine, Division of Hematology and Oncology; and System Vice President, Cancer Services, Rush University System for Health DAVID MAGNUS, Thomas A. Raffin Professor of Medicine and Biomedical Ethics, Professor of Pediatrics and Medicine, and Director, Center for Biomedical Ethics, Stanford University MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer BAKUL PATEL, Associate Director, Digital Health, Center for Devices and Radiological Health, Food and Drug Administration 1 The National Academies of Sciences, Engineering, and Medicineâs planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. Â The responsibility for the published Proceedings of a Workshop rests with the workshop r Â apporteurs and the institution. 2 In February 2019, Dr. Abernethy became Principal Deputy Commissioner of Food and Drugs at the Food and Drug Administration. v
ROBERT A. WINN, Associate Vice Chancellor, Community-Based Practice; Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Illinois at Chicago; Director, University of Illinois Cancer Center Project Staff ERIN BALOGH, Senior Program Officer RUTH COOPER, Senior Program Assistant (from October 2018) NATALIE LUBIN, Senior Program Assistant (until October 2018) CYNDI TRANG, Research Assistant (until September 2018) EMILY ZEVON, Associate Program Officer (from October 2018) SHARYL J. NASS, Forum Director and Director, Board on Health Care Services vi
NATIONAL CANCER POLICY FORUM1 EDWARD J. BENZ, JR. (Chair), President and Chief Executive Officer Emeritus, Dana-Farber Cancer Institute; Richard and Susan Smith Distinguished Professor of Medicine, Genetics and Pediatrics, Harvard Medical School LUCILE L. ADAMS-CAMPBELL, Professor of Oncology, Associate Director for Minority Health and Health Disparities Research, and Senior Associate Dean, Community Outreach and Engagement, Georgetown Lombardi Comprehensive Cancer Center GARNET L. ANDERSON, Senior Vice President and Director, Public Health Sciences Division, Fred Hutchinson Cancer Research Center; Affiliate Professor, Department of Biostatistics, University of Washington KENNETH ANDERSON, Kraft Family Professor of Medicine, American Cancer Society Clinical Research Director, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute WILLIAM L. BAILEY, Vice President, Medical & Scientific Affairs Research & Development, Helsinn Therapeutics (U.S.), Inc. KAREN BASEN-ENGQUIST, Annie Laurie Howard Research Distinguished Professor, Professor of Behavioral Science, and Director, Center for Energy Balance in Cancer Prevention and Survivorship, The University of Texas MD Anderson Cancer Center CHRIS BOSHOFF, Chief Development Officer, Oncology, Global Product Development, Pfizer Inc. CATHY J. BRADLEY, Associate Dean for Research, Colorado School of Public Health, Professor and Deputy Director, University of Colorado Cancer Center OTIS W. BRAWLEY, Bloomberg Distinguished Professor, Department of Epidemiology, Bloomberg School of Public Health, Department of Oncology, School of Medicine, Johns Hopkins University ROBERT W. CARLSON, Chief Executive Officer, National Comprehensive Cancer Network 1 The National Academies of Sciences, Engineering, and Medicineâs forums and round- tables do not issue, review, or approve individual documents. The responsibility for the pub- lished Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii
NANCY E. DAVIDSON, President and Executive Director, Seattle Cancer Care Alliance; Senior Vice President, Director, and Full Member, Clinical Research Division, Fred Hutchinson Cancer Research Center; Head, Department of Medicine, Division of Medical Oncology, University of Washington GEORGE D. DEMETRI, Professor of Medicine and Director, Ludwig Center, Harvard Medical School; Senior Vice President for Experimental Therapeutics, Dana-Farber Cancer Institute; Associate Director for Clinical Sciences, Dana-Farber/Harvard Cancer Center JAMES H. DOROSHOW, Deputy Director for Clinical and Translational Research, National Cancer Institute NICOLE F. DOWLING, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention SCOT W. EBBINGHAUS, Vice President and Therapeutic Area Head, Oncology Clinical Research, Merck Research Laboratories KOJO S. J. ELENITOBA-JOHNSON, Professor, Perelman School of Medicine; Director, Center for Personalized Diagnostics and Division of Precision and Computational Diagnostics, University of Pennsylvania AWNY FARAJALLAH, Vice President, Head, US Medical Oncology, Bristol-Myers Squibb STANTON L. GERSON, Director, Case Comprehensive Cancer Center; Professor of Hematological Oncology, Case Western Reserve University; Director, University Hospitals Seidman Cancer Center LORI HOFFMAN HÅGG, Veterans Health Administration National Program Manager, Prevention Policy, National Center for Health Promotion and Disease Prevention; National Oncology Clinical Advisor, Office of Nursing Services, Department of Veterans Affairs LINDA HOUSE, President, Cancer Support Community HEDVIG HRICAK, Chair, Department of Radiology, Memorial Sloan Kettering Cancer Center ROY A. JENSEN, President, Association of American Cancer Institutes; Director, The University of Kansas Cancer Center; William R. Jewell, M.D. Distinguished Masonic Professor, Kansas Masonic Cancer Research Institute LISA KENNEDY SHELDON, Chief Clinical Officer, Oncology Nursing Society SAMIR N. KHLEIF, Director, Jeannie and Tony Loop Immuno-Oncology Lab; Biomedical Scholar and Professor of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center viii
RONALD M. KLINE, Medical Officer, Patient Care Models Group, Center for Medicare & Medicaid Innovation, Centers for Medicare & Medicaid Services MICHELLE M. LE BEAU, Arthur and Marian Edelstein Professor of Medicine and Director, The University of Chicago Medicine Comprehensive Cancer Center MIA LEVY, Director, Rush University Cancer Center; Associate Professor of Medicine, Division of Hematology and Oncology; and System Vice President, Cancer Services, Rush University System for Health J. LEONARD LICHTENFELD, Interim Chief Medical Officer, American Cancer Society NEAL J. MEROPOL, Vice President, Research Oncology, Flatiron Health MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer RANDALL A. OYER, Medical Director, Oncology, Ann B. Barshinger Cancer Institute, Penn Medicine Lancaster General Health RICHARD PAZDUR, Director, Oncology Center of Excellence; Acting Director, Office of Hematology and Oncology Products, Food and Drug Administration RICHARD L. SCHILSKY, Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology DEBORAH SCHRAG, Chief, Division of Population Sciences, Professor of Medicine, Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute LAWRENCE N. SHULMAN, Professor of Medicine, Deputy Director for Clinical Services, and Director, Center for Global Cancer Medicine, Abramson Cancer Center, University of Pennsylvania DAN THEODORESCU, Director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center VERENA VOELTER, Head, United States Oncology Clinical Development & Medical Affairs, Novartis Pharmaceuticals Corporation GEORGE J. WEINER, C.E. Block Chair of Cancer Research, Professor of Internal Medicine, and Director, Holden Comprehensive Cancer Center, The University of Iowa ROBERT A. WINN, Associate Vice Chancellor, Community-Based Practice; Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Illinois at Chicago; Director, University of Illinois Cancer Center ix
National Cancer Policy Forum Staff ERIN BALOGH, Senior Program Officer RUTH COOPER, Senior Program Assistant ANNALEE GONZALES, Administrative Assistant NATALIE LUBIN, Research Assistant MICAH WINOGRAD, Financial Officer EMILY ZEVON, Associate Program Officer SHARYL J. NASS, Forum Director and Director, Board on Health Care Services x
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 mak- ing 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: DEVEN McGRAW, Ciitizen LISA McSHANE, National Cancer Institute NATHAN PRICE, University of Washington 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 DANIEL R. MASYS, University of W Â ashington School of Medicine. 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. xi
Acknowledgments Support from the many annual sponsors of the National Academies of Sciences, Engineering, and Medicineâs National Cancer Policy Forum is crucial to the work of the forum. Federal sponsors include the Centers for Disease Control and Prevention and the National Cancer Institute/National Institutes of Health. Non-federal sponsors include the American Association for Cancer Research, American Cancer Society, American College of Â adiology, Ameri- R can Society of Clinical Oncology, Association of American Cancer Institutes, Association of Community Cancer Centers, Bristol-Myers Squibb, Cancer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Â Â Th Â erapeutics (U.S.), Inc., LIVESTRONG Foundation, Merck, National Com- prehensive Cancer Network, Novartis Oncology, Oncology Nursing Society, and Pfizer Inc. The forum wishes to express its gratitude to the expert speakers whose presentations helped further the dialogue and advance progress in the use of high-dimensional omics data, computational methods, and clinic infraÂ structures enabling precision oncology care. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. xiii
Contents ACRONYMS AND ABBREVIATIONS xix PROCEEDINGS OF A WORKSHOP 1 WORKSHOP OVERVIEW 1 NEW PARADIGM IN CANCER DIAGNOSIS AND CARE 2 Computational Technologies, 10 Machine Learning, 10 Machine Learning Applications in Radiology, 12 Health Apps, 12 TRANSLATION CHALLENGES 13 Data Quality and Completeness, 13 Risk of Bias, 15 Validation of Computational Precision Oncology, 17 Test Development and Analytical Validation Steps, 17 Statistical Validation, 18 Clinical Validation, 20 Face Validity, 21 Gaps in Reproducibility, 21 Regulatory Oversight, 23 Digital Data Standards, 23 Devices, 24 Software as a Medical Device, 25 Quantitative Imaging Devices, 28 Laboratory Developed Tests, 29 xv
xvi CONTENTS Patient Privacy, 30 General Data Protection Regulation, 31 California Consumer Privacy Act of 2018, 32 Communicating Results and Risks to Patients, 34 Challenges for Payers, 36 RESEARCH NEEDED 38 EXAMPLES OF CARE DELIVERY MODELS FOR COMPUTATIONAL PRECISION MEDICINE 40 Moffitt Cancer Center Precision Oncology Program, 40 Intermountain Healthcare Precision Oncology Program, 41 Department of Veterans Affairsâ National Precision Oncology Program, 43 University of California, 44 VanderbiltâIngram Cancer Centerâs My Cancer Genome, 46 LESSONS LEARNED FROM IMPLEMENTING COMPUTATIONAL PRECISION ONCOLOGY CARE 46 Financial Support, 46 Patient-Centered and Clinician-Friendly Design, 47 Informed Consent, 48 Improve Clinician Understanding of Omics and Analytics, 49 Standards, 49 Data Sharing, 51 Large-Scale Public Databases, 51 Incentives for Sharing Data, 52 Enabling Patient Sharing of Data, 52 Data Protection, 56 Multidisciplinary Teamwork, 56 WRAP-UP 58 REFERENCES 59 APPENDIX A: STATEMENT OF TASK 65 APPENDIX B: WORKSHOP AGENDA 67
Boxes, Figures, and Tables BOXES 1 Suggestions from Individual Workshop Participants to Improve the Translation of Computational Precision Oncology into Clinical Practice, 3 2 Overview of the First Workshop on Improving Cancer Diagnosis and Care, 7 3 Requirements for a Rigorous Validation of a Predictor, 19 4 Project GENIE, 53 5 Health 0.0 at the Massachusetts Institute of Technology, 57 FIGURES 1 The process of making a fit-for-purpose real-world dataset, 15 2 Risk-based approach to assessing importance of independent review, 27 3 Precision oncology workflow at Intermountain Healthcare, 42 4 Department of Veterans Affairsâ National Precision Oncology Program data flow, 44 5 Infrastructure of the Center for Data-Driven Insights and Innovation, 45 xvii
xviii BOXES, FIGURES, AND TABLES TABLES 1 Device Class and Premarket Requirements, 24 2 Individual Rights Under the General Data Protection Regulation and the HIPAA Privacy Rule, 33 3 Results Disclosure Communication Approaches, 35
Acronyms and Abbreviations AACR American Association for Cancer Research AI artificial intelligence CCPA California Consumer Privacy Act of 2018 CDISC Clinical Data Interchange Standards Consortium CLIA Clinical Laboratory Improvement Amendments CMS Centers for Medicare & Medicaid Services CT computed tomography EHR electronic health record EU European Union FDA Food and Drug Administration GDPR General Data Protection Regulation GENIE Genomics Evidence Neoplasia Information Exchange H&E hematoxylin and eosin HER2 human epidermal growth factor receptor 2 HIPAA Health Insurance Portability and Accountability Act of 1996 IMDRF International Medical Device Regulators Forum IT information technology xix
xx ACRONYMS AND ABBREVIATIONS LDT laboratory developed test MIT Massachusetts Institute of Technology MRI magnetic resonance imaging NCCN National Comprehensive Cancer Network NCI National Cancer Institute NIH National Institutes of Health PDF portable document format PHI protected health information SaMD Software as a Medical Device VA Department of Veterans Affairs VCF variant call file