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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. The Drug Development Paradigm in Oncology: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/24742.
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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.

Amanda Wagner Gee, Erin Balogh, Margie Patlak, and Sharyl J. Nass, Rapporteurs National Cancer Policy Forum Board on Health Care Services Health and Medicine Division

THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 This activity was supported by Contract No. 200-2011-38807 (Task Order No. 0051) and Contract No. HHSN263201200074I (Task Order No. HHSN26300052) 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 College of Radiology, American Society for Radiation Oncology, American Society of Clinical Oncology, American Society of Hematology, Association of American Cancer Institutes, AstraZeneca, Bristol-Myers Squibb, Cancer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Healthcare SA, LIVESTRONG Foundation, Merck, National Comprehensive 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:  978-0-309-45794-1 International Standard Book Number-10:  0-309-45794-7 Digital Object Identifier:  https://doi.org/10.17226/24742 Additional copies of this publication are available for sale 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 2018 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. 2018. The drug development paradigm in oncology: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24742.

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 ­echnology. 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 ­ 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.

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 partici- pants 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.

WORKSHOP PLANNING COMMITTEE1 RICHARD L. SCHILSKY (Chair), Senior Vice President and Chief Medical Officer, American Society of Clinical Oncology AMY P. ABERNETHY, Chief Medical Officer, Chief Scientific Officer, and Senior Vice President for Oncology, Flatiron Health JEFF ALLEN, President and Chief Executive Officer, Friends of Cancer Research 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 MARGARET ANDERSON, Executive Director, FasterCures, A Center of the Milken Institute MONICA M. BERTAGNOLLI, Richard E. Wilson Professor of Surgery, Harvard Medical School; Chief, Division of Surgical Oncology, Dana-Farber/Brigham and Women’s Cancer Center; Group Chair, Alliance for Clinical Trials in Oncology GIDEON BLUMENTHAL, Acting Deputy Director, Office of Hematology and Oncology Projects, Food and Drug Administration HEDVIG HRICAK, Chair, Department of Radiology, Memorial Sloan Kettering Cancer Center RONALD M. KLINE, Medical Officer, Patient Care Models Group, Center for Medicare & Medicaid Innovation, Centers for Medicare & Medicaid Services AMY McKEE, Supervisory Associate Director, Office of Hematology and Oncology Projects, Food and Drug Administration REBECCA PENTZ, Professor of Hematology and Oncology in Research Ethics, Emory University School of Medicine STEVEN PIANTADOSI, Phase One Foundation Distinguished Chair, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center MACE L. ROTHENBERG, Chief Development Officer, Oncology, Pfizer Global Product Development, Pfizer Inc. 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speak- ers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. v

DANIEL J. SARGENT, Professor of Biostatistics and Oncology, Director of Cancer Statistics, Mayo Clinic Cancer Center DEBORAH SCHRAG, Chief, Division of Population Sciences, Professor of Medicine, Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute MARC THEORET, Lead Medical Officer, Division of Oncology Products, Office of Hematology and Oncology Products, Food and Drug Administration SUZANNE L. TOPALIAN, Professor, Surgery and Oncology, Johns Hopkins University School of Medicine Project Staff ERIN BALOGH, Senior Program Officer MORGAN L. BONAME, Associate Program Officer SYLARA MARIE CRUZ, Senior Program Assistant (until June 2017) REBECCA A. ENGLISH, Program Officer CYNDI TRANG, Research Assistant AMANDA WAGNER GEE, Program Officer ANNE B. CLAIBORNE, Director, Forum on Drug Discovery, Development, and Translation SHARYL J. NASS, Director, National Cancer Policy Forum and 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 KALD A. ABDALLAH, Oncology External Alliances Leader, U.S. Medical Affairs, AstraZeneca AMY P. ABERNETHY, Chief Medical Officer, Chief Scientific Officer, and Senior Vice President for Oncology, Flatiron Health LUCILE L. ADAMS-CAMPBELL, Professor of Oncology, Associate Director for Minority Health and Health Disparities Research, Georgetown University Lombardi 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 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 CATHY J. BRADLEY, Associate Director, Cancer Prevention and Control, University of Colorado Cancer Center OTIS W. BRAWLEY, Chief Medical Officer, American Cancer Society ROBERT W. CARLSON, Chief Executive Officer, National Comprehensive Cancer Network CHRISTOPHER R. COGLE, Professor of Medicine, Pierre Chagnon Professor of Stem Cell Biology and Bone Marrow Transplant, University of Florida; Scholar in Clinical Research, Leukemia & Lymphoma Society 1 The National Academies of Sciences, Engineering, and Medicine’s 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

ROGER D. DANSEY, Senior Vice President, Clinical Research—Late Stage Development, Merck 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 KOJO S. J. ELENITOBA-JOHNSON, Professor, Perelman School of Medicine; Founding Director, Center for Personalized Diagnostics and Division of Precision and Computational Diagnostics, University of Pennsylvania STANTON L. GERSON, President, Association of American Cancer Institutes; Director, Case Comprehensive Cancer Center; Professor of Hematological Oncology, Case Western Reserve University; Director, University Hospitals Seidman Cancer Center LORI HOFFMAN HŌGG, Veterans Health Administration National Oncology Clinical Advisor and Program Manager, Prevention Policy, Department of Veterans Affairs LINDA HOUSE, President, Cancer Support Community HEDVIG HRICAK, Chair, Department of Radiology, Memorial Sloan Kettering Cancer Center LISA KENNEDY SHELDON, Chief Clinical Officer, Oncology Nursing Society; Editor, Clinical Journal of Oncology Nursing SAMIR N. KHLEIF, Professor of Medicine, Biochemistry, Molecular Biology, and Graduate Studies, Medical College of Georgia, Augusta University RONALD M. KLINE, Medical Officer, Patient Care Models Group, Center for Medicare & Medicaid Innovation, Centers for Medicare & Medicaid Services LEE M. KRUG, Disease Area Head, Lung and Head & Neck Cancer, Immuno-Oncology, Bristol-Myers Squibb FRANCOIS LAFLEUR, U.S. Head and Vice President, Medical Affairs, Helsinn Healthcare SA viii

MICHELLE M. LE BEAU, Arthur and Marian Edelstein Professor of Medicine and Director, The University of Chicago Comprehensive Cancer Center MIA LEVY, Director of Cancer Health Informatics and Strategy, Ingram Associate Professor of Cancer Research; Associate Professor of Biomedi- cal Informatics and Medicine, Vanderbilt-Ingram Cancer Center GRETA MASSETTI, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on Cancer RICHARD PAZDUR, Director, Oncology Center of Excellence; Acting Director, Office of Hematology and Oncology Products, Food and Drug Administration LISA C. RICHARDSON, Director, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention MACE L. ROTHENBERG, Chief Development Officer, Oncology, Pfizer Global Product Development, Pfizer Inc. 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, Paul A. Bunn, Jr. Endowed Chair in Cancer Research, Professor of Surgery and Pharmacology, and Director, Uni- versity of Colorado Cancer Center GEORGE J. WEINER, C. E. Block Chair of Cancer Research, Professor of Internal Medicine, Director, Holden Comprehensive Cancer Center, University of Iowa ROBERT A. WINN, Associate Vice Chancellor for Community-Based Practice; Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Illinois College of Medicine; Director, University of Illinois Health Cancer Center RICHARD C. WOODMAN, Senior Vice President and Head, North America Oncology Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation ix

WENDY A. WOODWARD, Associate Professor and Service Chief, Breast Cancer Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center National Cancer Policy Forum Staff ERIN BALOGH, Senior Program Officer PATRICK BURKE, Financial Officer NATALIE LUBIN, Senior Program Assistant (from June 2017) SYLARA MARIE CRUZ, Senior Program Assistant (until June 2017) CYNDI TRANG, Research Assistant WILLIAM SONG, Summer Intern (June 2017–July 2017) 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 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: JESSE BERLIN, Johnson & Johnson FRANKLIN G. MILLER, Weill Cornell Medical College ELDA RAILEY, Research Advocacy Network MARK RATAIN, The University of Chicago ERIC H. RUBIN, Merck Research Laboratories RAJESHWARI SRIDHARA, Food and Drug Administration 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 ELAINE LARSON, Columbia University School of Nursing. She was responsible for making certain that an indepen- xi

xii REVIEWERS dent 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.

In Memoriam This Proceedings of a Workshop is dedicated to Dr. Daniel J. Sargent, an internationally renowned statistician, a valued member of the workshop planning committee, and an irreplaceable colleague and friend. xiii

Acknowledgments Support from the many annual sponsors of the National Academies of Sciences, Engineering, and Medicine’s 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 Col- lege of Radiology, American Society for Radiation Oncology, American Society of Clinical Oncology, American Society of Hematology, Association of American Cancer Institutes, AstraZeneca, Bristol-Myers Squibb, Can- cer Support Community, CEO Roundtable on Cancer, Flatiron Health, Helsinn Healthcare SA, LIVESTRONG Foundation, Merck, National Comprehensive Cancer Network, Novartis Oncology, Oncology Nursing Society, and Pfizer Inc. The forum wishes to express its gratitude to the expert speakers whose presentations helped examine the drug development paradigm for cancer therapy. The forum also wishes to thank the members of the planning com- mittee for their work in developing an excellent workshop agenda. xv

Contents ACRONYMS AND ABBREVIATIONS xxi INTRODUCTION 1 BACKGROUND ON DRUG DEVELOPMENT AND REGULATORY REVIEW 3 Types of FDA Drug Development and Approval Pathways, 3 Ethical Requirements of Clinical Research, 11 EXPLORING THE CHALLENGES WITH TRADITIONAL CLINICAL DRUG DEVELOPMENT 12 Inefficiencies and Long Development Timelines, 12 Generalizability of Clinical Trial Results to Clinical Practice, 14 Appropriate Use of Biomarkers and Surrogate Endpoints, 15 Finding the Right Dose, 16 NEW STRATEGIES IN ONCOLOGY DRUG DEVELOPMENT 18 Patient-Centered Drug Development, 18 Informed Consent, 21 Patient Risk, 22 Mechanism-Informed Cancer Drug Development, 23 Targeting Mutations in Breast Cancer, 24 Targeting the Microenvironment in Multiple Myeloma, 25 Functional Imaging, 27 New Endpoints, 29 xvii

xviii CONTENTS Modeling, 31 Process Modeling the Drug Development Pathway, 31 Dosage Modeling, 32 Modeling Benefits and Risks, 34 Development and Use of Biomarkers in Cancer Clinical Trials, 35 Innovative Clinical Trial Designs, 41 Adaptive Designs, 42 Seamless (Continuous) Clinical Trial Designs, 43 Master Protocols, 50 Clinical Trials with Common Control Arms, 59 Issues to Consider with Innovative Clinical Trial Designs, 60 Leveraging Real-World Evidence from Clinical Practice, 66 Pragmatic Trials, 69 Using EHR Data in Studies, 70 When to Use Real-World Evidence, 72 Standardization, 75 Guidance on Standardizing and Using Real-World Evidence, 76 Patient Privacy, 77 Expanding Clinical Trial Eligibility, 77 Collaboration, 81 POTENTIAL POLICY OPPORTUNITIES 85 Innovations at CMS, 85 FDA Oncology Center of Excellence, 85 Expanded Access, 86 Cancer Moonshot, 88 EXAMPLES OF INNOVATIONS IN CANCER DRUG DEVELOPMENT 91 Development of Crizotinib, 92 Development of Avelumab, 94 Development of Pembrolizumab, 95 Development of Vemurafenib, 96 T790M EGFR Inhibitors, 98 WORKSHOP WRAP-UP 101 REFERENCES 104 APPENDIX A: STATEMENT OF TASK 115 APPENDIX B: WORKSHOP AGENDA 117

Boxes, Figures, and Tables BOXES 1 Many Suggestions Were Made by Individual Workshop Participants to Improve Cancer Drug Development, 4 2 21st Century Cures Act, 19 3 Questions Regarding the Design of Large, Seamless First-in-Human Cancer Clinical Trials, 46 4 Discussions Regarding Dose Challenges with Seamless Trials, 47 5 Lung Cancer Master Protocol Trial, 51 6 Precision Promise, 54 7 National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) Trial, 56 8 Targeted Agent Profiling Utilization Registry Study, 80 9  Contrasting Development Story of Rociletinib, a T790M EGFR A Inhibitor, 99 10  Potential Strategies to Improve the Drug Development Paradigm in Oncology Summarized by Richard Schilsky, 104 xix

xx BOXES, FIGURES, AND TABLES FIGURES 1 Drug discovery and development timeline, 13 2 Complete remission of metastatic prostate cancer in a 71-year-old man who received four cycles of 177Lu-PSMA-I&T (177Lu labeled prostate-specific membrane antigen ligand for imaging and therapy) as fifth line therapy, 29 3 Response surface design of predicted median human epidermal growth factor receptor 2 (HER2)-specific antibody responses as a function of doxorubicin (DOX) and cyclophosphamide (CY) dose combinations to produce the highest vaccine response in breast cancer, 34 4 Analysis of the benefits and risks for non-small cell lung cancer therapies, 36 5 Designs to evaluate biomarkers/subgroups, 37 6 Traditional and seamless oncology drug development paradigms, 45 7  KEYNOTE-001 dose expansion cohorts in solid tumors, The melanoma, and non-small cell lung cancer, 57 8  Pragmatic-Explanatory Continuum Indicator Summary 2 The (PRECIS-2) wheel, 70 9 Utilization of cancer drugs outpaces trial evidence contributing to the evidence gap, 73 10  crizotinib drug development timeline from 2006 to 2011, 93 The 11  Key milestones in the discovery and development of osimertinib, 100 TABLES 1 Traditional Phases of Drug Development, 9 2 Types of Expedited Drug Development Pathways for Serious Conditions Designated by the Food and Drug Administration (FDA), 10 3 Statistical Power to Detect Different Response Rates in Biomarker- Defined Subgroups in a Single-Arm Study of 100 Patients, 38

Acronyms and Abbreviations ALK amplastic lymphoma kinase ASCO American Society of Clinical Oncology BATTLE-1 Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination CAP College of American Pathologists CDER Center for Drug Evaluation and Research CDK cyclin-dependent kinases CLIA Clinical Laboratory Improvement Amendments of 1988 CMS Centers for Medicare & Medicaid Services CT computed tomography CY cyclophosphamide DOE Department of Energy DSMB data and safety monitoring board EGFR epidermal growth factor receptor EHR electronic health record EMA European Medicines Agency ER estrogen receptor xxi

xxii ACRONYMS AND ABBREVIATIONS FDA Food and Drug Administration FNIH Foundation for the National Institutes of Health HDAC histone deacetylase HER2 human epidermal growth factor receptor 2 HIPAA Health Insurance Portability and Accountability Act IND investigational new drug IRB Institutional Review Board I-SPY TRIAL Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis Lung-MAP Lung Cancer Master Protocol MRI magnetic resonance imaging NCI National Cancer Institute NCI-MATCH National Cancer Institute-Molecular Analysis for Therapy Choice NDA New Drug Application NGS next-generation sequencing OCE Oncology Center of Excellence OHOP Office of Hematology and Oncology Products ORR overall response rate OS overall survival PD-1 programmed death-1 PD-L1 programmed death-ligand 1 PERCIST PET Response Criteria in Solid Tumors PET positron emission tomography PFS progression-free survival POC proof of concept PRECIS Pragmatic-Explanatory Continuum Indicator Summary RECIST Response Evaluation Criteria in Solid Tumors START South Texas Accelerated Research Therapeutics TAPUR Targeted Agent Profiling Utilization Registry Study

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Advances in cancer research have led to an improved understanding of the molecular mechanisms underpinning the development of cancer and how the immune system responds to cancer. This influx of research has led to an increasing number and variety of therapies in the drug development pipeline, including targeted therapies and associated biomarker tests that can select which patients are most likely to respond, and immunotherapies that harness the body’s immune system to destroy cancer cells. Compared with standard chemotherapies, these new cancer therapies may demonstrate evidence of benefit and clearer distinctions between efficacy and toxicity at an earlier stage of development. However, there is a concern that the traditional processes for cancer drug development, evaluation, and regulatory approval could impede or delay the use of these promising cancer treatments in clinical practice. This has led to a number of efforts—by patient advocates, the pharmaceutical industry, and the Food and Drug Administration (FDA)—to accelerate the review of promising new cancer therapies, especially for cancers that currently lack effective treatments. However, generating the necessary data to confirm safety and efficacy during expedited drug development programs can present a unique set of challenges and opportunities.

To explore this new landscape in cancer drug development, the National Academies of Sciences, Engineering, and Medicine developed a workshop held in December 2016. This workshop convened cancer researchers, patient advocates, and representatives from industry, academia, and government to discuss challenges with traditional approaches to drug development, opportunities to improve the efficiency of drug development, and strategies to enhance the information available about a cancer therapy throughout its life cycle in order to improve its use in clinical practice. This publication summarizes the presentations and discussions from the workshop.

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