THE DRUG DEVELOPMENT
PARADIGM IN
ONCOLOGY
PROCEEDINGS OF A WORKSHOP
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
Washington, DC
www.nap.edu
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
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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.
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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 speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
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
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 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.
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
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 Biomedical 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, University 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
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
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:
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 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 ELAINE LARSON, Columbia University School of Nursing. She was responsible for making certain that an indepen-
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.
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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 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.
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 committee for their work in developing an excellent workshop agenda.
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Contents
BACKGROUND ON DRUG DEVELOPMENT AND REGULATORY REVIEW
Types of FDA Drug Development and Approval Pathways
Ethical Requirements of Clinical Research
EXPLORING THE CHALLENGES WITH TRADITIONAL CLINICAL DRUG DEVELOPMENT
Inefficiencies and Long Development Timelines
Generalizability of Clinical Trial Results to Clinical Practice
Appropriate Use of Biomarkers and Surrogate Endpoints
NEW STRATEGIES IN ONCOLOGY DRUG DEVELOPMENT
Patient-Centered Drug Development
Mechanism-Informed Cancer Drug Development
Targeting Mutations in Breast Cancer
Process Modeling the Drug Development Pathway
Development and Use of Biomarkers in Cancer Clinical Trials
Innovative Clinical Trial Designs
Seamless (Continuous) Clinical Trial Designs
Clinical Trials with Common Control Arms
Issues to Consider with Innovative Clinical Trial Designs
Leveraging Real-World Evidence from Clinical Practice
When to Use Real-World Evidence
Guidance on Standardizing and Using Real-World Evidence
Expanding Clinical Trial Eligibility
POTENTIAL POLICY OPPORTUNITIES
FDA Oncology Center of Excellence
Boxes, Figures, and Tables
BOXES
1 Many Suggestions Were Made by Individual Workshop Participants to Improve Cancer Drug Development
3 Questions Regarding the Design of Large, Seamless First-in-Human Cancer Clinical Trials
4 Discussions Regarding Dose Challenges with Seamless Trials
5 Lung Cancer Master Protocol Trial
7 National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) Trial
8 Targeted Agent Profiling Utilization Registry Study
9 A Contrasting Development Story of Rociletinib, a T790M EGFR Inhibitor
FIGURES
1 Drug discovery and development timeline
4 Analysis of the benefits and risks for non-small cell lung cancer therapies
5 Designs to evaluate biomarkers/subgroups
6 Traditional and seamless oncology drug development paradigms
7 The KEYNOTE-001 dose expansion cohorts in solid tumors, melanoma, and non-small cell lung cancer
8 The Pragmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) wheel
9 Utilization of cancer drugs outpaces trial evidence contributing to the evidence gap
10 The crizotinib drug development timeline from 2006 to 2011
11 Key milestones in the discovery and development of osimertinib
TABLES
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 |
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 |