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The Drug Development Paradigm in Oncology: Proceedings of a

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GET THIS BOOK Amanda Wagner Gee, Erin Balogh, Margie Patlak, and Sharyl J. Nass, Rapporteurs;
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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
Copyright National Academy of Sciences. All rights reserved.

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.
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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 speak-
ers. 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
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

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 A Contrasting Development Story of Rociletinib, a T790M EGFR
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 The KEYNOTE-001 dose expansion cohorts in solid tumors,
melanoma, and non-small cell lung cancer, 57
8 The Pragmatic-Explanatory Continuum Indicator Summary 2
(PRECIS-2) wheel, 70
9 Utilization of cancer drugs outpaces trial evidence contributing to the
evidence gap, 73
10 The crizotinib drug development timeline from 2006 to 2011, 93
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

Proceedings of a Workshop
INTRODUCTION1
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 biomarker2 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 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
1 The planning committee’s role was limited to planning the workshop. The Proceedings
of a Workshop was prepared by the rapporteurs as a factual account of what occurred at the
workshop. Statements, recommendations, and opinions expressed are those of individual
presenters and participants and are not necessarily endorsed or verified by the National
Academies of Sciences, Engineering, and Medicine. They should not be construed as reflect-
ing any group consensus.
2 In this proceedings, a biomarker is defined as “a characteristic that is objectively measured
and evaluated as an indicator of normal biological processes, pathogenic processes, or pharma-

cologic responses to an intervention” (NASEM, 2016a, p. 26).

2 THE DRUG DEVELOPMENT PARADIGM IN ONCOLOGY
of efforts—by patient advocates, the pharmaceutical industry, and the

Food and Drug Administration (FDA)—to accelerate the development and
evaluation 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 Cancer Policy Forum, in collaboration with the Forum on Drug
Discovery, Development, and Translation, developed a workshop, The
Drug Development Paradigm in Oncology. The workshop was held on
December 12–13, 2016, at the National Academies of Sciences, Engineer-
ing, and Medicine in Washington, DC. 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 cancer therapy
throughout its life cycle in order to improve its use in clinical practice.3
Many workshop speakers discussed potential strategies for improving cancer
drug development, including
• patient-centered drug development that prioritizes patient needs

and employs patient-reported outcomes;
• biologically informed strategies in drug development, including
the use of biomarkers to select patients most likely to respond to
treatments and surrogate endpoints that are informed by a drug’s
mechanism of action;
• more flexible, efficient, and continuous clinical trial designs that
can evaluate multiple interventions in different patient populations,
expand testing to larger numbers of patients when agents show
initial promise, and conscientiously and efficiently manage limited
patient availability and clinical trial resources; and
• expanding clinical trial eligibility and leveraging the use of real-
world data to better understand how drugs perform in clinical
practice.
3 Although
some workshop speakers noted that improving the efficiency of drug develop-
ment could potentially result in lower drug development costs, particularly as therapies are
targeted to smaller patient populations, a detailed analysis of the cost of drug development
was beyond the scope of this workshop.

PROCEEDINGS OF A WORKSHOP 3
This proceedings is a summary of the presentations and discussions

at the workshop. A broad range of views and ideas were presented, and a
summary of individual suggestions to improve cancer drug development is
provided in Box 1. The workshop statement of task is in Appendix A and
the workshop agenda is in Appendix B. The webcast and speakers’ presenta-
tions have been archived online.4
BACKGROUND ON DRUG DEVELOPMENT

AND REGULATORY REVIEW
A number of workshop speakers discussed the goals of oncology drug
development, the traditional phased approach to drug development, the
regulatory processes for review and evaluation of new cancer therapies, and
the ethical standards for clinical research.
Mark Ratain, director of the Center for Personalized Therapeutics
and associate director for clinical sciences at The University of Chicago
Comprehensive Cancer Center, summarized the goals of oncology drug
development as
• demonstrating a therapy’s anticancer activity;

• identifying target populations likely to respond to the therapy;
• determining dosage and schedule that optimizes the benefit-to-risk
ratio; and
• identifying individual patient factors that necessitate dose modifica-
tion, such as age, body size, organ function, and molecular features
affecting a drug’s disposition or interaction with a drug target.
Types of FDA Drug Development and Approval Pathways

Ratain said that oncology drug development traditionally proceeds
through distinct, chronologic phases (see Table 1). G. K. Raju, executive
director of Pharmaceutical Manufacturing Initiatives at the Massachusetts
Institute of Technology, added that FDA weighs the risks and benefits when
deciding if drugs should be approved for use in clinical practice.
Marc Theoret, lead medical officer in FDA’s Office of Hematology and
Oncology Products (OHOP), said that the agency has two categories of
4 See http://www.nationalacademies.org/hmd/Activities/Disease/NCPF/2016-DEC-12.
aspx (accessed February 21, 2017).

BOX 1
Many Suggestions Were Made by Individual Workshop
Participants to Improve Cancer Drug Development
Addressing Inefficiencies in the Traditional Drug Development

Paradigm
• Make efficiency—gaining precision and speed, reducing waste,
and preserving scientific rigor—the primary goal of improving drug
development. (Schilsky)
• Devote more attention and resources to cancer therapies that are
likely to have a substantial impact on patient outcomes by using
methods to identify and drop ineffective drugs at an earlier stage of
development. (Woodcock)
Focusing on Patient-Centered Drug Development

• Ensure patients are at the center of drug development by incorpo-
rating their feedback and priorities in drug development programs
and by focusing on drugs that improve quality of life and provide
meaningful symptom control. (Ratain, Schilsky, Sigal, Woodcock)
• Collect real-world data using modern technologies, such as health
apps, social media, or wearables, to help patients and clinicians
distinguish among treatment options that may have similar efficacy
but different impacts on quality of life. (Koehler, Matrisian, Pentz,
Sigal)
• Consider opportunities for improving informed consent, while also
ensuring patient privacy, including broad consent to use patients’
electronic health record (EHR) data collected at participating facili-
ties and the use of opt-out consent strategies. (Brown)
• Allow for flexibility in determining a patient’s tolerance of risk related
to the use of new cancer drugs, given that more efficient drug
development may come with more uncertainty regarding safety and
efficacy. (Joffe, Matrisian, Raju, Rockhold, Tendler)
Establishing More Meaningful Endpoints in Drug Development

• Invest in the development, validation, and use of intermediate
endpoints and surrogate endpoints to measure tumor burden and
patient response to new cancer therapies—both quantitatively and
qualitatively—in order to identify effects earlier in drug develop-
ment and to improve the efficiency of clinical trials. (Anderson,
Blumenthal, Joffe, Redman, Woodcock)
• Design studies with endpoints that reflect both efficacy and futility.
(Redman)

• Improve standardized criteria for imaging interpretation to guide

clinical trial design and patient care. (Anderson, Weber)
• Use new imaging approaches for in vivo assessment of a drug,
including the assessment of antitumor effects and whether a drug
is reaching its target. (Schilsky, Weber)
• Use a variety of appropriate endpoints to evaluate different types of
therapies in the different subtypes of cancer. (Flaherty)
Using Modeling and Evaluating Biomarkers and Companion

Diagnostics
• Use modeling to estimate the minimum active dose and to deter-
mine the range of active and tolerable doses, rather than estimating
the maximum tolerated dose. (Piantadosi, Ratain)
• Determine more precise dosing information by collecting some
pharmacokinetic data in late-stage trials, accounting for clinical
variables among diverse populations, using expanded cohorts to
assess appropriate dosing for long-term drug use, and making
formulation improvements for oral cancer drugs. (Harvey)
• Invest in research aimed at finding better pharmacodynamic bio-
markers and use physiology-based modeling. (Harvey, McKee)
• Increase the use of modeling to facilitate improved decision making
by data and safety monitoring boards (DSMBs). (Joffe, Raju)
• Develop an explicit plan for biomarker analysis as part of oncology
clinical trial designs, including plans to ensure sufficient statistical
power to determine treatment effects given expected biomarker
prevalence both within and among patient populations. (Redman)
• Improve the evaluation of diagnostic performance to predict patient
response to therapy, with the understanding that a companion
diagnostic will be inextricably linked with the therapy after Food and
Drug Administration (FDA) approval. (Woodcock)
• Weigh competing factors when deciding whether and when to
develop a companion diagnostic (e.g., financial investment, risk tol-
erance, medical and scientific justifications, ethical considerations,
regulation, and insurance coverage). (Flaherty, Rothenberg, Rubin,
Topalian)
Using Innovative Clinical Trial Designs

• Employ an iterative process to seamless drug development in order
to balance efficiency with an accurate assessment of risk. (Keegan,
McKee)
• Use master protocols to investigate multiple clinical questions simul-
taneously, standardize data collection, and promote efficiencies in
continued

BOX 1 Continued
drug development by keeping the same clinical trial network and

protocol in place as trials are modified over time. (Sridhara, Theoret)
• Consider adaptive master protocols when assessment with tradi-
tional clinical trial designs is difficult, such as for new diagnostics,
novel therapeutic mechanisms and regimens, and combination
therapies. (Woodcock)
• Encourage scientific rigor in master protocols by consistently evalu-
ating the statistical analysis plan, including safety information from
earlier patients in analyses, and scheduling sponsor meetings with
FDA proactively. (Theoret)
• Promote the use of seamless trial designs that have enhanced flex-
ibility and the ability to respond quickly to striking signals of efficacy
that emerge in the drug development process. (Schilsky)
• Increase efficiency, minimize bias, and prevent reactive responses
to interim results by establishing preplanned criteria for modifi-
cations in adaptive clinical trial designs. (Keegan, Piantadosi,
Sridhara)
• Recognize that adaptive trial designs may lengthen the trial timeline
and can be difficult to launch and manage. (Feltquate, Schilsky)
• Better align trial designs with the questions under evaluation, and
balance scientific rigor with flexibility to adapt to new information.
(Harvey, Ratain, Schilsky)
• Determine the types and reliability of signals for positive and nega-
tive drug effects and consider drug effect size in different patient
populations, particularly for seamless designs. (Feltquate, Joffe,
Rothenberg)
• Incentivize investigators and drug sponsors to spend more time on
preclinical and early clinical research to ensure that clinical trials are
as informative and targeted as possible. (Schilsky)
• Conduct more efficient clinical research through multi-sponsor col-
laborations that use the same control arm while evaluating similar
research questions. (McKee, Sridhara)
• Consider opportunities to use expanded access programs to sup-
port approval for new therapies with safety or pharmacodynamics
data. (Lemery)
Decision Making and Oversight of Clinical Trials

• Recognize that the decision-making processes in seamless trial
designs are more complex due to the altered benefit–risk analyses
and the need for rapid continuation or expansion decisions. (Joffe)

• E
nsure the independence of DSMBs to assess the data and provide
oversight for a seamless trial design. (Rockhold)
• U
se central Institutional Review Boards (IRBs) for oversight of
seamless trials, with appropriate methodological expertise and the
ability to rapidly review protocol modifications in coordination with
DSMBs, patients, and clinicians. (Flaherty, Joffe)
• A
ddress gaps in knowledge about seamless and adaptive trial
designs among existing members of DSMBs and IRBs and ensure
an adequate workforce pipeline by recruiting the involvement of new
participants in DSMBs and IRBs, especially statisticians with clinical
trial expertise. (Piantadosi, Rockhold, Rothenberg)
• U
se integrated regulatory approval processes, such as the newly
instituted parallel approval process of FDA and the Centers for
Medicare & Medicaid Services for devices and diagnostics or FDA’s
Oncology Center of Excellence for review of combination products.
(Kline, Woodcock)
Leveraging Real-World Evidence from Clinical Practice

• S everal participants suggested that real-world evidence could be
used to:
o evaluate drugs that enter the market through expedited approval
mechanisms to build the evidence base and to determine sub
sequent indications, label updates, and potential combination
therapies. (Koehler)
o assess the effects of new cancer drugs on the use and impact
of other treatment modalities, such as surgery and radiation
therapy. (Bertagnolli)
o characterize the safety and effectiveness of drugs in clinical
practice. (Koehler, Sridhara)
o evaluate eligibility criteria for clinical trials inform future trial
designs with expanded eligibility. (Brown, Redman)
o discover and validate biomarkers. (Ratain)
• L ink and analyze data from real-world sources carefully in order to
prevent misinterpretation of the findings. (Brown)
• C reate FDA guidance on real-world evidence, including delineation
of which drug development scenarios it is most applicable to, data
quality requirements, data management and dataset production
requirements, optimal analytic approaches, and how data could be
represented on a drug label. (Abernethy)
• Incentivize postmarket learning and data sharing through new pay-
ment models. (Brown)
continued

BOX 1 Continued
• se postmarketing surveillance to update drug labels, espe-

U
cially with information that is relevant for children, rare popula-
tions, or individuals with comorbidities. (Rothenberg)
• Perform confirmatory work either sequentially or in parallel with
postmarket learning, such as determining appropriate dosing
for a given population after a new drug enters the market.
(Ratain, Schilsky)
Using More Inclusive Clinical Trial Eligibility Criteria

• Make clinical trials more accessible to a larger number and
variety of patients by following suggestions from recent working
groups to reevaluate standard exclusion criteria for trials. (Ison,
Schilsky)
• Allow patients with pediatric cancers to enroll in clinical trials of
novel cancer drugs. (Kline, Rothenberg)
• Make the inclusion of patients with human immunodeficiency
virus the default option in clinical trial eligibility and require
justification for exclusion. (Sharon)
• Plan expanded access program principles in advance, as a
way to facilitate access for patients excluded from the trial,
either because of eligibility criteria or geographic location.
(Lemery, Theoret)
Increasing Collaboration Among Stakeholders

• Align the culture of industry with the changing science of drug
development, and minimize barriers to information sharing and
collaboration to facilitate learning across the drug life cycle.
(Schilsky)
• Use the new funding and infrastructures that will be available
through the Cancer Moonshot. (Schilsky)
• Create partnerships to evaluate biomarkers for predicting rare
but serious toxicities. (Blumenthal)
• Expand collaboration to address the growing complexity of
cancer diagnostics and treatments. (Blumenthal, Fogarty,
Sigal)
• Facilitate collaboration among drug sponsors to efficiently
develop the most effective agents for important classes of new
drugs that are likely to be used in smaller patient populations.
(Rothenberg)

TABLE 1 Traditional Phases of Drug Development

Phase 0 Nonclinical pharmacology and toxicology studies.
Phase I Small studies to assess safety and determine the appropriate dose of an
investigational new drug (IND).
Phase II Preliminary research into effectiveness of an IND, either in a single arm
study or compared to placebo or standard of care, conducted on small
numbers of patients with the targeted disease. Safety, dosing, and short-
term side effects are also studied.
Phase III Studies in larger and more varied patient populations, if efficacy is
demonstrated in Phase II.
Phase IV Postmarketing studies to amass more complete information on an
approved drug’s safety, effectiveness, and optimal use.
SOURCES: Ratain and Theoret presentations, December 12 and 13, 2016; FDA,
2014a.
drug approvals: regular and accelerated approvals. Regular and a ccelerated

approvals both require substantial evidence of safety and efficacy based
on adequate and well-controlled trials, he said. The endpoints for regu-
lar approval require direct evidence of clinical benefit—such as extend-
ing survival, improving physical functioning, or relieving tumor-related
symptoms—or an effect on an established surrogate endpoint. Theoret said
there is no comparative effectiveness requirement for regular approvals.
He said that accelerated approval is intended for products that treat
serious or life-threatening illnesses and address an unmet medical need.
There are four types of expedited drug development pathways at FDA—fast
track, breakthrough therapy, priority review, and accelerated approval (see
Table 2). Theoret noted that all FDA pathways for expediting clinical devel-
opment and review of a new drug consider the available therapies to treat
the target disease to determine whether there is an unmet medical need, i.e.,
if the new therapy appears to provide an improvement or advantage over
available therapies (FDA, 2014c).
Theoret said that expedited pathways are widely used in oncology drug
development: 42 percent of all Breakthrough Therapy Designation requests
submitted to the FDA Center for Drug Evaluation and Research (CDER)
between 2012 and 2014 were submitted to OHOP and one-third of the
Breakthrough Therapy Designation requests to OHOP were granted. In
addition, from 2014 to 2015, half of the 24 OHOP approvals of new
molecular entities were accelerated approvals (FDA, 2015).

TABLE 2 Types of Expedited Drug Development Pathways for Serious

Conditions Designated by the Food and Drug Administration (FDA)
Fast track Granted when a drug demonstrates the potential to address an
designation unmet medical need for treatments, which may be based on
nonclinical information in an early stage of development. Allows
rolling submission of the marketing application based on observed
preclinical or clinical activity, and initiates frequent communication
with FDA to rapidly resolve arising issues.
Breakthrough Granted when preliminary clinical evidence indicates a new
therapy drug may demonstrate substantial improvement over an existing
designation treatment, and may have an effect on a clinically significant
endpoint. Allows for frequent meetings with FDA based on
overwhelming clinical activity and, if the observed activity holds in
continued follow-up or subsequent studies, then an expedited review
of the application will be conducted.
Priority Designation granted when a sponsor submits an application (new
review or supplemental) that, if approved, would provide a significant
improvement in safety or effectiveness. Ensures an expedited time of
review of the application, and requires FDA action within 6 months.
Accelerated Approval for when a drug demonstrates meaningful therapeutic
approval benefit over existing treatments. Endpoints based on unestablished
surrogate endpoints or intermediate clinical endpoints.
Confirmatory trials ongoing at the time of approval.
SOURCES: Theoret presentation, December 13, 2016; FDA, 2014c.
In line with the expedited pathways for drug evaluation and approval,
there is also interest in more flexible and efficient mechanisms for cancer
drug development, Theoret said (see section titled New Strategies in
Oncology Drug Development). Staff from FDA’s OHOP recently authored
an article outlining an evolving drug development paradigm, indicating
their willingness to consider alternatives to the traditional phased drug
development process (Prowell et al., 2016; Theoret et al., 2015), said Janet
Woodcock, director of CDER at FDA.
“Based on better scientific understanding of the biological under-
pinnings of cancer and the host response to cancer, some investigational
products are demonstrating a very large magnitude of antitumor activity
very early on in drug development. These unprecedented response rates
have brought us into this new era of oncology drug development; the
lines between distinct trial phases are becoming blurred, and a single trial
may serve as the entire clinical drug development program supporting at

least an initial FDA approval,” Theoret said. He added that “discrete drug
development objectives might not be evaluated in [sequential] stand-alone
trials, but will be evaluated seamlessly in cohorts within an existing trial in
some cases, in treatment refractory settings with clear, high unmet medical
need.” For example, a single-arm trial demonstrating a treatment effect on
a surrogate endpoint may provide the preliminary and primary evidence
for an accelerated approval, while confirmatory trials are ongoing, he said.
Ethical Requirements of Clinical Research

Steven Joffe, associate professor of medical ethics and health policy
at the University of Pennsylvania Perelman School of Medicine, outlined
the ethical requirements for clinical research (Emanuel et al., 2000). For
example, a clinical trial should have social or scientific value and should be
conducted appropriately so it results in scientifically valid conclusions. The
protocol for a clinical trial also needs to undergo an independent ethics
review by an Institutional Review Board (IRB)5 prior to study launch,
to ensure that adequate informed consent is obtained from participating
patients, and that there is fair selection of clinical trial participants. Joffe
added that a clinical trial should also have a favorable benefit-to-risk ratio
for the individual patients participating in the research, as well as for future
patients who stand to gain from the results of the research.
Frank Rockhold, professor of biostatistics and bioinformatics at the
Duke Clinical Research Institute, noted that the ethical imperatives for
clinical research are defined in the Declaration of Helsinki,6 which states
that the risks to participants in clinical trials must be continuously moni-
tored, assessed, and documented by researchers. When the risks are found
to outweigh the potential benefits, or when there is conclusive proof of
definitive outcomes, researchers need to assess whether to continue, modify,
5 An IRB is a panel of scientists and non-scientists in hospitals and research institutions
that oversees clinical research. IRBs approve the clinical trial protocols, which describe the
type of people who may participate in the clinical trial, the schedule of tests and procedures,
the medications and dosages to be studied, the length of the study, the study’s objectives, and
other details. IRBs make sure that the study is acceptable, that participants have given con-
sent and are fully informed of the risks, and that researchers take appropriate steps to protect
patients from harm (FDA, 2014a).
6 The Declaration of Helsinki outlines ethical principles for conduct of human subjects
research, written by the World Medicine Association for the medical community (WMA,
2017).

or immediately stop the study. Rockhold added that data and safety moni-
toring boards (DSMBs)7 serve this purpose and are integral to the ethical
conduct of clinical trials. He noted that at certain intervals during the trial,
the DSMB integrates interim data and determines if the benefit–risk ratio
to continuing the trial is still favorable, and if there is still clinical equipoise,
which he defined as a state of genuine uncertainty about the advantages or
disadvantages of each therapeutic arm in a clinical trial.
EXPLORING THE CHALLENGES WITH

TRADITIONAL CLINICAL DRUG DEVELOPMENT
A number of workshop participants discussed common challenges
with the traditional approach to drug development, such as inefficiencies
and long development timelines, a lack of clinically relevant information,
the use of inappropriate endpoints, and inaccuracies in selecting dosages
of therapies.
Inefficiencies and Long Development Timelines

Ellen Sigal, chair and founder of Friends of Cancer Research, reminded
workshop participants that, on average, it takes more than 10 years of test-
ing, starting with approximately 5,000 to 10,000 compounds, to develop a
single new FDA-approved drug (AACR, 2011) (see Figure 1).
Although gaps in understanding the basic science of cancer are partly
responsible for the arduous process of the traditional drug development
process, Sigal said that the low success rate and long time frames in clinical
drug development can also be attributed to inefficiencies from lack of data
sharing among companies and academic institutions.
Ratain noted that it is particularly undesirable when a drug fails
late in the development timeline, after tremendous amounts of time and
resources have been invested. “It is okay to fail as long as one fails pretty
quickly,” he said, but frequently that does not happen. Failure can be due
to a n
umber of factors, Ratain said, such as not identifying the right dosage
7 A DSMB is a “group of individuals with pertinent expertise that reviews on a regular

basis accumulating data from one or more ongoing clinical trials. The [DSMB] advises the
sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the
trial, as well as the continuing validity and scientific merit of the trial” (FDA, 2006). They
are also known as data monitoring committees or Data and Safety Monitoring Committees.

FIGURE 1 Drug discovery and development timeline.

NOTE: FDA = Food and Drug Administration; IND = investigational new drug; Mfg. = manufacturing; NDA = New Drug Application.

SOURCES: Sigal presentation, December 12, 2016; AACR, 2011.
13
or the population likely to respond well to the therapy, as well as failing to

identify individual patient factors that influence how effective or toxic the
therapy is. Woodcock said that more effective ways to identify and drop
ineffective drugs at an earlier stage of development would improve the
success rate for drug development and reduce its cost, so more focus and
resources can be devoted to interventions that will have a substantial impact
on a disease, including drugs that can potentially cure disease. Often these
interventions will be combinations of new agents, which are challenging to
study, she noted.
Ratain added that inefficient trial designs and misunderstandings of
governmental regulations or corporate bureaucracy can delay the onset
or lengthen the duration of clinical trials. Clinical trial designs with more
patients, sites, or data than necessary can also contribute to inefficiencies
and extra expense. In addition, if historical controls are used to compare
the therapy’s effectiveness, the results may not be reliable in current patient
populations, Ratain said. In some cases, “we are treating patients without
really learning anything,” he said.
Joffe noted that in order to make the drug development process
faster, it is necessary to have a discussion about the ethical trade-offs that
may result. He said that it takes time to collect data that meet traditional
thresholds for safety and efficacy, and that accepting a faster pace of drug
development requires changes to the amount of information gathered to
inform these decisions. Two rationales have been used to support faster
drug development, Joffe said: (1) some of the evidence requirements in the
traditional drug development process add little or no value to information
about a drug’s safety and efficacy; or (2) less evidence about safety and
efficacy for drug approvals is acceptable in exchange for speed. Joffe said
that it is important to be explicit about the rationale for increasing the
speed of drug development, and to support the rationale with evidence-
based information. Joffe added that if regulatory approvals are made more
quickly based on less information on safety and efficacy, confirmatory
studies will need to be completed in the postmarketing setting to gather
additional information.
Generalizability of Clinical Trial Results to Clinical Practice

When a drug receives FDA approval, there is often uncertainty about
which patient populations in clinical practice will most benefit from a
drug, said Maria Koehler, vice president of oncology strategy, innovation,

and collaborations at Pfizer Inc. This is because clinical trials often enroll
patients who are healthier than many patients in clinical practice settings,
who frequently have multiple comorbidities (IOM, 2013). She noted that
the problem is also exacerbated by low participation rates in trials and a lack
of diversity in cancer clinical trial enrollments (Chen et al., 2014; IOM,
2010). Therefore, payers often require additional testing and confirmation
of clinical trial results in more representative populations in order to make
coverage decisions, she said.
Appropriate Use of Biomarkers and Surrogate Endpoints

As cancer is further defined by genetic mutations, several speakers
noted that reliable biomarkers and surrogate endpoints will be key in regula-
tory and clinical decision making. Woodcock stressed that the “traditional
Phase I, II, III progression cannot really provide enough information in our
current era of precision medicine, as cancers are splintered into multiple
subgroups and treatment categories” usually based on their underlying
genetics. She added that often the scientific knowledge about biomarkers
to predict patient response to therapies is evolving concurrently with the
development of a therapy, and unless that information is incorporated into
the drug testing protocol, development of such companion diagnostics
will lag behind that of new drugs. “In general, we get agents on the market
where the maturity and our understanding of the diagnostic component
is still not [sufficient], and we really do not know everything we need to
know,” she said.
Several participants pointed out the inadequacy of commonly used
endpoints to assess patient response in clinical trials, including the Response
Evaluation Criteria in Solid Tumors (RECIST). Wolfgang Weber, chief of
the molecular imaging and therapy service at the Memorial Sloan K ettering
Cancer Center, pointed out that the RECIST criteria were originally
adopted in the 1970s based on the primary technologies to detect tumor
changes at that time. These criteria are based on biomedical imaging results
to assess changes in tumor size and number within a period of time follow-
ing treatment. Disease progression is assumed when tumors increase in size,
or if new tumors develop.
Weber noted several challenges when using RECIST criteria to deter-
mine patient response. Although RECIST criteria have been shown to
correlate with patient survival and other clinical outcomes (Eisenhauer et
al., 2009; Miller et al., 1981; Therasse et al., 2000; Wolchok et al., 2009),

there is a large degree of variability in patient responses. Some patients

who do not show a response based on the criteria have extended periods of
survival, while some responders have shortened periods of survival (Bruzzi
et al., 2005; Johnson et al., 2006). Weber said that unless a therapy has
an unusually strong and immediate impact on tumors, large numbers
of patients in clinical trials are needed in order for RECIST criteria to
reliably predict improved outcomes. Weber added that the criteria entail
subjective judgment, and often cannot distinguish between scar tissue and
viable tumor. The criteria also cannot measure metastases at all sites (e.g.,
bone) and may not be able to distinguish between slow-growing and stable
tumors, Weber said (Thatcher et al., 2005; Therasse et al., 2000).
RECIST criteria can also be problematic for evaluating immuno-
therapies, which can initially cause an increase in tumor size before causing
tumor regression (NASEM, 2016b; Wolchok et al., 2009), said Eric Rubin,
vice president and therapeutic area head in oncology early development at
Merck Research Laboratories. This increase in size is thought to be due to
infiltrating immune cells, which is associated with therapeutic response,
Rubin said. Sigal added that “immunotherapy is a new world, and we can-
not rely on old standards.” Given the new developments in technologies
and treatments, Gideon Blumenthal, acting deputy director of OHOP,
suggested that there may be better quantitative and qualitative metrics to
assess tumor burden and response to different therapies. Woodcock added,
“The classic types of endpoints that have been used may not capture the
effect properly, and may not help us in understanding the activity of an
immunotherapy, so other endpoints are going to have to be devised.”
Woodcock also stressed using endpoints that consider the patient per-
spective. “Survival is really important in oncology, but so is quality of that
survival,” she said, and suggested increased use of quality-of-life endpoints
in clinical drug development. “Drug development has to be driven by
the patients,” Sigal added, suggesting that such development take a more
patient-oriented approach, rather than a product-oriented approach.
Finding the Right Dose

Traditionally, investigators have determined the dose of a new drug
by starting with small test doses in patients and gradually increasing the
amount of those doses until patients develop serious adverse reactions, said
Steven Piantadosi, Phase One Foundation distinguished chair of the Samuel
Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center.

“Most of what we do in oncology is dose escalation under the ordinary

belief that more drug is better,” Piantadosi said. However, that is not neces-
sarily the case because the traditional “maximum tolerated dose”8 model is
not appropriate for many of the newer classes of cancer drugs, which have
stronger biological effects with relatively fewer toxicities compared with
traditional chemotherapy, he said.
R. Donald Harvey, director of the Phase I Clinical Trials Section at the
Winship Cancer Institute and associate professor of hematology/medical
oncology and pharmacology at Emory University, added, “We look for
the ceiling all the time in early drug development, but really understand-
ing the basement is critical,” especially for therapeutics composed of
monoclonal antibodies. For these drugs, modeling based on how effectively
these antibodies attach to target receptors can predict the lowest dose
needed to generate a response, Harvey said. Rubin called this the “mini-
mally effective dose.” Harvey pointed out that the relationship between dose
exposure and effects, both positive and negative, is rarely known before a
new agent is tested in a first-in-human clinical trial. That relationship is
further refined with subsequent trials, but even in Phase III trials, as many
as 85 percent of patients require dose reductions (Postel-Vinay et al., 2011).
Ratain noted that historically, oncology drugs were intravenous chemo-
therapy drugs with a narrow range between effectiveness and toxicity. “So
we would push them to the maximum tolerated dose and then we would
back off if we went too far. But we are now in an era where we have drugs
that do not have a narrow therapeutic index and we should have different
dose testing paradigms for them,” he said.
Amy McKee, supervisory associate director at OHOP, said dose opti-
mization is further complicated by bioavailability of oral agents. When
chemotherapy drugs are given intravenously, bioavailability of the drugs
given is not an issue. In contrast, bioavailability is of vital importance with
oral cancer therapies, she said.
Piantadosi added that dosing designs for single agents do not extend
satisfactorily to combination therapy development. Harvey agreed, and
noted that the maximum tolerated dose does not often apply when com-
8 Maximum tolerated dose is “the highest dose of a drug or treatment that does not cause
unacceptable side effects. The maximum tolerated dose is determined in clinical trials by
testing increasing doses on different groups of people until the highest dose with accept-
able side effects is found.” See https://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid=546597 (accessed May 18, 2017).

bining therapies, or expanding drugs into different types of patient popu-

lations. Multiple schedules for different combination therapies are rarely
explored in a comparative fashion, he added.
Harvey said a Phase I trial of vemurafenib and ipilimumab in com-
bination was stopped early due to liver toxicity (Ribas et al., 2013). “It is
the first Phase I trial I can recall reading about in the New England Journal
of Medicine that was a negative trial [because] there were overlapping
toxicities that were not predicted before that trial opened,” he said. Joffe
and Piantadosi noted that life-threatening side effects have occurred when
drugs in the same class have been combined, such as immunotherapy com-
binations or combinations of targeted therapies. The toxicities associated
with the combinations were not evident in early-phase testing.
NEW STRATEGIES IN ONCOLOGY DRUG DEVELOPMENT

Many workshop speakers provided suggestions and examples of new
strategies in oncology drug development, including
• patient-centered drug development;

• mechanism-informed drug development;
• new, clinically relevant endpoints;
• modeling to improve the development pathway, more accurately
predict optimal dosing, and calculate benefit–risk ratios;
• innovative trial designs;
• leveraging real-world evidence from clinical practice;
• expanding trial eligibility; and
• collaboration among stakeholders.
Patient-Centered Drug Development

“The patient should always come first [in drug development],” Sigal
said. She suggested that patients work with FDA in meaningful ways to
ensure their needs are met by clinical trials for drug development, and added
that an objective of the 21st Century Cures Act (see Box 2) is to incorporate
patient perspectives into the regulatory process and address patients’ unmet
medical needs. Other opportunities to incorporate patients into the drug
development process include FDA’s Patient-Focused Drug Development
Initiative (FDA, 2017e) and the Patient-Centered Outcomes Research

BOX 2
21st Century Cures Acta
Ellen Sigal, chair and founder of Friends of Cancer Research,

provided an overview of the 21st Century Cures Act (Cures). Cures
provides funding to the Department of Health and Human Services,
the National Institutes of Health, and the Food and Drug Admin-
istration (FDA) to support discovery and advances in biomedical
sciences and precision medicine, as well as the promotion of col-
laborative research and the development of young emerging scien-
tists. Sigal said that Cures has a number of provisions to streamline
FDA’s drug approval processes, includingb
• increasing the focus on patients in drug development by

requiring FDA to publish a brief statement on patient experi-
ence data that was part of the new medication application.
• advancing new drug therapies by requiring FDA to estab-
lish a process to qualify drug development tools (methods,
materials, or measures that aid drug development and
regulatory review) as reliable for use in supporting approval
or investigational use of a drug.
• modernizing trial design and evidence development by
requiring FDA to issue guidance addressing the use of novel
clinical trial design in the development and review of drugs,
and to evaluate and issue guidance on the use of evidence
from sources other than clinical trials to support approval of
a drug for a new indication.
• increasing patient access to therapies and information
by allowing FDA to rely on a summary of clinical data to
approve a supplemental application for a medication, for
certain indications. Upon request, FDA must also facilitate
development and expedite review of regenerative advanced
therapies, including cell therapies, therapeutic tissue engi-
neering products, and human cell and tissue products.
• improving scientific expertise and outreach at FDA by
granting FDA additional hiring authority for scientific, techni-
cal, or professional positions that support the development,
review, and regulation of medical products.
a Public Law 114-255.

b See https://www.congress.gov/bill/114th-congress/house-bill/34 (accessed June
21, 2017).

Institute.9 “Patients want efficacy, but they also want quality of life,” Sigal
stressed, suggesting that drug development incorporate patient-reported
outcomes as a means to assess quality of life. Woodcock agreed that using
quality-of-life endpoints that consider patient perspectives would improve
drug development. Ratain agreed, noting that in addition to assessing
tumor response in clinical trials, there should be assessment of meaningful
symptom control or relief through patient-reported outcomes.
Sigal also stressed the importance of real-world clinical data to patients
and clinicians when making decisions about treatments that have similar
efficacy, but may have different impacts on quality of life. These impacts
may be detected by analyzing real-world data from clinical practice, such
as patient-reported outcomes in electronic health records (EHRs). Lynn
Matrisian, chief research officer of the Pancreatic Cancer Action Network,
agreed, noting that “real-world evidence is something patients really care
about.” Koehler added that real-world evidence can facilitate patient-
centered drug development by
• focusing on broader populations and outcomes that are important

to patients;
• better informing and engaging patients through patient portals
located in EHRs;
• facilitating identification of patients who are eligible for trials, b etter
coordination of their health information, and enabling their partici-
pation in clinical trials;
• accelerating broad access to new medications; and
• promoting precision medicine in community care settings.
Several workshop participants also discussed the importance of patient-

reported outcomes and related ethical considerations in patient-centered
drug development. Rebecca Pentz, professor of research ethics at Emory
School of Medicine, suggested developing and deploying new health appli-
cations that facilitate collection of patient-reported outcomes, such as the
side effects of their treatments. “We are in a new era of social media and
apps. That is what people are going to be using, so we are going to have to
adapt and [collect] adverse events that way with the proper controls,” she
said. Jeffrey Brown, associate professor in the Department of Population
Medicine at the Harvard Pilgrim Health Care Institute at Harvard Medical
9 See http://www.pcori.org (accessed May 21, 2017).

School, pointed out that many health apps do not have privacy policies and
patients are not aware of this. “We . . . need to use health apps because they
are the future, but we have to think about some of these privacy issues,”
Brown said.
Informed Consent
Brown said that ethicists have differing opinions on whether and how
patient consent should be obtained for the use of their data for research
purposes. He noted that some ethicists view it acceptable to use some
patient data in research without consent when there is minimal risk to the
patient or in cases of public health activities. Some ethicists do not believe
that any patient data should be used for research purposes without express
patient consent, Brown said. Other ethicists propose that the default option
should be to allow patient data to be used in research, but to offer patients
the opportunity to “opt out” of using their data in studies. “There is debate
about this in the ethical field and we need to move forward, come to con-
sensus, and come up with a solution,” he said.
Brown noted that obtaining informed consent from patients for studies
that use data collected from EHRs and other sources of real-world data can
be challenging. He suggested it might be feasible to have patients agree
that if they enter a hospital or other medical facility that uses EHRs, they
automatically agree to share their EHR data for research purposes. “That
may be needed for a pragmatic, clustered randomized clinical trial,” he said.
He noted that garnering such consent is currently difficult to accomplish
because of current regulations that restrict access to patient information for
research, such as the Privacy Rule promulgated under the Health Insurance
Portability and Accountability Act (HIPAA) (IOM, 2009).
Brown suggested using broad consent forms for research on patient
data in EHRs, similar to those used for patient consent for future research
on patients’ biospecimens. He said that many patients do not have concerns
with such broad consent forms, with the exception of a minority of patients
who have expressed the concern that others will profit from the use of their
biospecimens in research (Grady et al., 2015).
John Burch, a member of the Mid-America Angels Capital Investment
Network, suggested using patient-centered repositories of patient data. “Not
the clinician’s EHR, but the patient’s own EHR,” he stressed. A patient could
put his or her data into the repository, own and control the use of the data,
and could make the data available for research, he said. Pentz noted that this

could serve the patient well, and there would be an ethical advantage to hav-
ing patient-centered repositories of data. “From an ethical standpoint, it is
the patient’s information and they would be empowered to use and control
it,” she said.
Patient Risk
Joffe noted that there is increasing pressure to accelerate cancer drug
development in order to provide patients who have life-threatening diseases
with earlier access to promising new therapies. But he said an analysis of
more than 100 Phase I cancer clinical trials found that faster approaches
to escalating doses in studies was linked to increased toxicity rates, without
improving efficacy (Koyfman et al., 2007).10 “In this case, it was hard to
make the argument that these accelerated designs were better for patients
than traditional designs,” Joffe said.
Joffe added that reports of life-threatening autoimmune reactions to
immunotherapies have recently emerged, many of which did not become
apparent until these agents entered the market after accelerated FDA
approval.11 He cautioned that “as we move more quickly and have smaller
numbers of patients involved in our drug development programs, we are
going to be much more reliant on the postmarketing period to get a sense
of what the safety data are.” He noted that the 21st Century Cures Act has
provisions aimed at speeding FDA approval of new drugs, but cautioned
that there are ethical concerns about whether accelerating cancer drug
development will lower the bar for patient safety (Kaplan, 2016). Brown
suggested that the goal should not simply be acceleration of drug develop-
ment, but rather optimizing data collection and getting the right data at
the right time. “We have to get the right data for the right patient without
putting them at undue risk,” he said.
Joffe stressed that the push for speed and accelerated approvals “has
trade-offs we can decide to make, and by ‘we’ I do not just mean the clini-
cians, investigators, and statisticians, but also the patients and the broader
community. We can decide to accept those increased risks to get that
speed.”
10 The study results may not be applicable for newer cancer therapies, such as targeted
therapies and immunotherapies.
11 See https://www.nytimes.com/2016/12/03/health/immunotherapy-cancer.html
(accessed May 21, 2017).

However, the ethical considerations regarding patient risk are complex

because patients vary in how much risk they are willing to assume in return
for a possible benefit, said Joffe, Raju, Rockhold, and Craig Tendler, vice
president of Late Development and Global Medical Affairs in Oncology at
the Janssen Pharmaceutical Corporation. Raju noted that regulators make
decisions on whether to approve drugs based on results in populations of
patients, but individual patients “should be doing their own benefit–risk
analyses together with their clinicians and their circumstances.” He also
said that individual patient preferences for and tolerances of risk vary
over time.
Matrisian agreed, and added that how fast a disease is progressing and
how serious it is can alter patients’ perspectives of their risk and whether
the risk of the drug is greater than the risk of having the disease itself. She
noted that patients with the most lethal cancers, which have 5-year survival
rates of less than 50 percent and cause more than half of U.S. cancer-related
deaths each year, could have a very different perspective on the benefit–risk
ratio than patients with cancers that have a greater than 90 percent 5-year
survival rate.
Mechanism-Informed Cancer Drug Development

Mary Redman, associate member of the Clinical Research Division at
the Fred Hutchinson Cancer Research Center, suggested more time be spent
on the discovery phase of drug development in order to better understand
the biology that underpins a therapy’s mechanism of action. In addition to
early testing aimed at determining dose and the patient population most
likely to respond to a treatment, Kenneth Anderson, director of the Lebow
Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma
Center at the Dana-Farber Cancer Institute, suggested that researchers
conduct more preclinical modeling studies with genetic analyses to guide
later clinical trials. For example, such biologic explorations have informed
drug development by assessing which patients with breast cancer are most
likely to respond to an epidermal growth factor receptor (EGFR) inhibi-
tor, and by providing a better understanding of the ways in which various
compounds block the growth of multiple myeloma cells in the bone marrow
microenvironment of the tumor. In addition, Weber said that functional
imaging can confirm mechanisms of action in both mouse models and in
patients by showing, at an early stage of drug development, whether a drug
is reaching its target and affecting tumor growth.

Targeting Mutations in Breast Cancer

A number of cancer therapies target specific genetic mutations that
drive cancer growth, such as EGFR inhibitors. Some of EGFR inhibitors
initially failed in clinical trials because they were not effective in a broad
population of patients, said Richard Finn, associate professor of medicine
at the David Geffen School of Medicine at the University of California,
Los Angeles. For example, one EGFR inhibitor, gefitinib, was initially not
shown to be effective in clinical trials for patients with lung cancer. Further
research demonstrated that gefitinib did improve progression-free survival
in patients whose tumors had specific EGFR mutations compared to stan-
dard chemotherapy (Maemondo et al., 2010). In 2015, FDA approved
gefitinib as a first-line treatment for patients with metastatic non-small cell
lung cancer whose tumors harbor specific genetic mutations.12
Instead of repeating this pathway of development, Finn said that the
development of palbociclib—a selective inhibitor of the cyclin-dependent
kinases (CDK) 4 and 6—began by proactively determining the types of
breast cancer cells that are most likely to respond to this therapy prior to
initiating clinical trials. By testing a large library of cell lines, Finn and his
colleagues demonstrated that estrogen receptor-positive (ER-positive) breast
cancer cells responded best to palbociclib. They also demonstrated that the
therapy interacted synergistically with antiestrogen treatments, suggesting
breast cancer patients receiving antiestrogen treatments would receive addi-
tional benefits if they were to receive palbociclib as well (Finn et al., 2009).
These findings led to a Phase I study conducted in 2008. In 2009,
the Phase II study known as PALOMA-1/TRIO 18 was initiated, which
randomized women with estrogen receptor-positive, human epidermal
growth factor receptor 2 (HER2)-negative advanced breast cancer to either
palbociclib plus letrozole13 versus letrozole alone. Palbociclib plus letrozole,
compared with letrozole alone, extended median progression-free survival
by approximately 10 months (Finn et al., 2015). Shortly after the trial
ended in 2015, Pfizer Inc. received accelerated approval of palbociclib as a
first-in-class CDK inhibitor for treatment of ER-positive breast cancer, in
12 See https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm454678.
htm (accessed May 21, 2017).
13 Letrozole is an aromatase inhibitor that inhibits the growth of estrogen-dependent breast
cancer cells. See https://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=42086


combination with letrozole. This has since been confirmed in a Phase III
study (Finn et al., 2016).
During the Phase II study, Finn recalled the deliberation by the spon-
soring team to determine which patients to enroll. They were concerned
that they might not see a significant effect if all patients presenting with
ER-positive cancer were enrolled. At the same time, they thought they
might miss a treatment benefit if they selectively enrolled patients with
mutations affecting proteins that interact with CDKs and might be driving
cancer growth. Thus, they included two sequential cohorts in PALOMA-1/
TRIO 18: the first cohort included patients with ER-positive/HER2-
negative breast cancer, while the second cohort included only patients with
ER-positive/HER2-negative breast cancer who also had amplification of
cyclin D1, loss of p16, or both.
Finn pointed out that if they had limited patient selection in initial
trials of palbociclib to only patients who had these additional biomarkers,
the study would have generated positive outcomes, “but we would
have missed the other 80 percent of patients who might benefit from a
compound like this.” These deliberations about defining the right study
population is relevant to the design of future trials, and is reflective of the
choices that sponsors must make in drug development, said Finn and Mace
Rothenberg, chief development officer of oncology at Pfizer Inc.
Finn noted that since palbociclib’s approval, several other CDK inhibi-
tors have progressed from the laboratory to Phase III studies, including
ribociclib (Hortobagyi et al., 2016).14 “The greatest advances in patient
outcomes have come from integrating biology into clinical practice and
critical use of preclinical models can guide that process. They can help us
design hypothesis-driven Phase I/Phase II studies,” Finn concluded.
Targeting the Microenvironment in Multiple Myeloma

Anderson reported on how multiple myeloma has served as a paradigm
for targeting the microenvironment of cancer cells. Because the cancerous
cells in this blood cancer can be routinely accessed, researchers can more
easily model interactions between the tumor and the host, he said. This has
enabled discovery and validation of novel agents, alone and in combina-
tion, that can overcome conventional drug resistance. Since 2003, FDA
14 Ribociclib was approved by FDA in March 2017. See https://www.fda.gov/drugs/
informationondrugs/approveddrugs/ucm546438.htm (accessed May 21, 2017).

has approved 18 new drugs for multiple myeloma, and patients with mul-
tiple myeloma are living three to four times as long as they did previously,
Anderson reported. “It is fair to say that there are some patients now who
end up having a normal life span,” he said.
In traditional drug development, academic laboratories complete basic
cancer biology research that can suggest new pathways and mechanisms
of action for how cancer grows and spreads, Anderson explained. Industry
then discovers new agents that act on these pathways and develops these
agents further with preclinical testing before working with academia to
conduct clinical trials. However, the development of innovative drugs for
multiple myeloma has instead used a more efficient, collaborative approach,
with academia conducting more drug discovery and validation work along
with input from patients and industry. This has resulted in quicker transla-
tion of treatments to clinical practice, Anderson said.
For example, Anderson’s lab showed that lenaliodmide, a derivative of
thalidomide, affects the tumor microenvironment primarily by stimulating
the host’s immune response against the cancer, but also by blocking adhe-
sion of cells and inhibiting the generation of blood vessels. Research also
demonstrated that triggering protein degradation mediated thalidomide’s
effects on tumor cells. These findings fostered the development of additional
drugs targeting protein degradation in different areas of the cell (Krönke et
al., 2014; Lu et al., 2014; Winter et al., 2015).
Conversely, by focusing on the importance of preventing protein
degradation in order to destroy cancer cells using proteasome inhibitor
bortezomib, investigators were able to devise drug combinations that could
inhibit that protein degradation in multiple ways and achieve higher efficacy
in some patients. Anderson said that such combination approaches with
different classes of drugs that have different mechanisms of action have
been quite effective in multiple myeloma. “Combinations of novel agents,
predicated [by] preclinical science, have achieved unprecedented results,”
said Anderson. For example, when bortezomib was combined with histone
deacetylase (HDAC) inhibitors to block both proteasomal and aggresomal
protein degradation, dramatic suppression of multiple myeloma tumor cell
growth occurred (Catley et al., 2006). This finding led to a Phase III trial
testing the combination of an HDAC inhibitor with bortezomib, and the
first FDA-approved HDAC inhibitor, panobinostat (Richardson et al.,
2013; San-Miguel et al., 2014).
Anderson said that although immunotherapy directed at blocking the
checkpoint inhibitor programmed death-1 (PD-1) has not been effective

in multiple myeloma, preclinical research suggests that combinations with

lenalidomide may drive a response (Görgün et al., 2015).
Anderson noted that some mechanistic preclinical findings are relevant
not only to multiple myeloma, but to other cancers as well. For example,
preclinical findings suggest that there is synergy in combining a proteasome
inhibitor with protein kinase B inhibitors—also known as Akt inhibitors—
in multiple myeloma, prostate cancers, and other cancers. “The correlative
science can inform going forward clinically, not only in one disease, but
more broadly,” he said.
Functional Imaging
Weber discussed the use of functional imaging as a diagnostic tool to
assess tumor response to treatments. He reported on the preclinical and
clinical uses of functional imaging to assess tumor response to therapeutic
agents, including assessment of tumor characteristics (e.g., blood perfusion
and glucose metabolism) through magnetic resonance imaging (MRI) and
positron emission tomography (PET). Weber stressed that functional imag-
ing can overcome many of the limitations of traditional imaging approaches
and RECIST criteria. Unlike traditional imaging, functional imaging can
distinguish between scar tissue and viable tumor tissue; detect tumors in
bone and other areas that are difficult to image with computed t omography
(CT) scans or traditional MRI; quantify relevant physiological and bio-
chemical changes; and show tumor responses more quickly, Weber said
(Johnson et al., 2016). In addition, PET also can be used to assess whether
an agent has hit its target, he added.
Because of the widespread use of PET-CTs for tumor staging, imag-
ing technologies and the infrastructure to make imaging agents are also
available throughout the country, Weber added (Buck et al., 2010). Weber
noted that because PET infrastructure is in place at most institutions, the
technology is primed for application in drug development. “We now have
the opportunity to go beyond glucose imaging [with fluorodeoxyglucose]
and look into molecules that are of interest in drug development,” he said.
Traditional imaging is generally done infrequently (e.g., before therapy
begins and then several months later), leading to a loss of information about
the tumor status and changes in growth between those two widely spaced
time points. By contrast, innovative PET imaging can document details
during that interim time period, such as the location of the therapy and
its concentration at tumor sites, and whether it interacts with the intended

target. While some of that information can be determined by examining a

patient’s biopsied tumor tissue shortly after therapy, the advantage of PET
imaging is that “you can do whole-body imaging studies [at different time
points] and look at not only one site, one small biopsy, but all metastatic
lesions in a particular patient,” Weber said, with radiologic technologists
able to complete whole-body scans of patients within 15 minutes.
He said that theranostics, which he defined as use of the same or a very
similar compound to both image and treat tumors, can maximally take
advantage of PET technology. For example, he discussed a theranostic that
combines a radioactive compound with an agent targeting prostate-specific
membrane antigen. This theranostic agent led to the disappearance of bone
metastases after four cycles of treatment in a patient with metastatic prostate
cancer (Heck et al., 2016), shown by PET scans taken after each treatment
cycle (see Figure 2). “It is a striking example of how effective this targeted
radiotherapy can be if you have the right target and the right drug to treat
it,” Weber said.
Weber also noted the ability to use PET for optimizing drug dosage by
demonstrating in patients the concentrations of drug at the actual tumor
site. This could help distinguish among several drugs in the same class, such
as the PARP inhibitors olaparib and iniparib. Iniparib failed in Phase III
clinical trials (Mateo et al., 2013), and PET imaging later showed that the
molecule does not inhibit PARP at clinically relevant doses at the tumor
site while olaparib, which has FDA approval for the treatment of ovar-
ian cancer, is able to do so (Michel et al., 2017). Similarly, the technique
has been used to determine biologically relevant doses of androgen- and
estrogen-receptor inhibitors in Phase II clinical trials (Rathkopf et al., 2013;
Wang et al., 2016).
Weber also stressed that such molecular imaging could serve as a com-
panion diagnostic that aids in the selection of patients for cancer treatments.
“The technical feasibility to develop a molecular diagnostic is no longer the
limiting factor,” he said. Weber noted that there is a large toolbox of cancer-
relevant molecular diagnostics, but use in clinical care requires validation
and FDA approval for in vivo companion diagnostics, and greater partici-
pation of cancer centers with the ability to develop or use these molecular
probes in clinical trials, according to Weber. Having oncologists with expe-
rience in diagnostic radiology and nuclear medicine will also be critical for
translating this technology into clinical care, he added.
Anderson and Weber stressed the need for standardized criteria for
use of imaging as biomarkers to enable uniform, consistent interpretation

FIGURE 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.
SOURCES: Weber presentation, December 12, 2016; Reprinted and modified from
The Journal of Urology, 196, Heck, M. M., M. Retz, C. D’Alessandria, I. Rauscher,
K. Scheidhauer, T. Maurer, E. Storz, F. Janssen, M. Schottelius, H.-J. Wester, J. E.
Gschwend, M. Schwaiger, R. Tauber, and M. Eiber, Systemic radioligand therapy with
177Lu labeled prostate specific membrane antigen ligand for imaging and therapy in
patients with metastatic castration resistant prostate cancer, 382-391, Copyright 2016,
with permission from Elsevier and the American Urological Association.
of results that can accurately inform clinical trial designs and patient care.
Weber noted that such criteria have been developed for PET imaging of
tumors—PET Response Criteria in Solid Tumors (PERCIST)—and could
be used in clinical trials (Wahl et al., 2009).
New Endpoints
Several workshop participants discussed the need to develop new end-
points to assess therapeutic responses more quickly, compared with current
endpoints used in cancer clinical trials, such as progression-free and overall
survival. For example, Anderson said that patients with multiple myeloma
may have a progression-free survival rate of 7 to 10 years when they are

treated with a three-drug therapy. If new therapies improve their survival

rate by 50 percent, it will take more than a dozen years to see that improve-
ment in a clinical trial. “Patients cannot wait for that and we cannot afford
these long trials,” he said. “We need a metric that will be able to tell us at
18 months what the outcome will be at 10 years,” he added. However,
Joffe cautioned that although use of surrogate markers could make drug
development more efficient, there is a risk of misleading outcomes: “There
is a trade-off between careful and rigorous evaluation and speed of time to
approval and clinical use,” he said.
Redman said that more time should be spent identifying and validating
intermediate and surrogate endpoints in order to obtain results earlier and
to decrease the numbers of patients needed to complete trials. She suggested
designing studies with endpoints that reflect both efficacy and futility, which
is the inability of a clinical trial to show statistically significant changes in
outcomes between treatment and control arms. She stressed evaluating futil-
ity separately from efficacy because there are different statistical standards
and methodologies to demonstrate that a trial is unable to differentiate any
effect versus a trial definitively showing no effect of the treatment.
A number of workshop participants discussed the need to have the
flexibility to choose appropriate endpoints based on the type of trial, treat-
ment, and disease. Keith Flaherty, director of the Henri & Belinda Termeer
Center for Targeted Therapy at the Massachusetts General Hospital Can-
cer Center, said that for BRAF-targeted treatments, measuring complete
responders—and not partial responders—more closely predicted patient
outcomes. Flaherty therefore suggested taking into consideration the disease
area, mechanism of action, and treatment type to better inform endpoint
choice: “Eighteen percent of the patients had complete response to BRAF/
MEK combination therapy. So for us, I have made the case that we focus
on complete response rate in early studies of BRAF/MEK treatments [when
making decisions about which agents to test further], but I am not sug-
gesting that is going to work for immunotherapy combinations,” Flaherty
said. He added that “specificity by mechanism [and] by disease are variables
that are going to expand and get more complicated, and I do not think we
should be trying to create a single platform.”
Patricia Keegan, director of FDA’s Division of Oncology Products 2,
added that response rate is more appropriate for assessing immunotherapies
in melanoma than for lung cancer, the latter of which might need durability
of response or progression-free survival endpoints. Anderson added that the
Foundation for the National Institutes of Health (FNIH) recently initiated

a public–private collaboration among basic and clinical researchers, officials

at FDA, and representatives from industry to develop a white paper15 on the
use of minimal residual disease in multiple myeloma as an alternative end-
point to progression-free survival. Companies are providing de-identified
data from clinical trials to create a database that should enable the group
to develop such a metric, Anderson reported. Ratain noted that researchers
have successfully modeled early outcomes in randomized clinical trials that
suggested “time-to-tumor-growth” was a valuable outcome measure to assess
(Claret et al., 2009; Wang et al., 2009).
Modeling
Many workshop participants discussed the concept of modeling in a
variety of contexts throughout the workshop. Several participants discussed
how process modeling can help researchers predict the optimal drug devel-
opment pathway for a therapy, as well as dosage modeling to determine
optimal dosing for a therapy or combinations of therapies. In addition,
DSMBs and FDA can use benefit–risk modeling to better ascertain the
potential benefits and risks of an investigational new drug when making
decisions about whether clinical trials should proceed, and whether it
should receive FDA approval for use in clinical practice.
Finn cautioned that models are subject to inherent biases and need to
be carefully constructed. For example, he pointed out that the development
of EGFR inhibitors included preclinical models that used tumor cell lines
that were highly dependent on epidermal growth factor. Finn said that
these cell lines were not representative of the range of tumors seen in vivo,
and that the EGFR pathway is much more complex than initial modeling
suggested.
Process Modeling the Drug Development Pathway

Piantadosi suggested the use of process modeling to help determine
how a drug should proceed through the development pipeline, particularly
for combination therapies. He noted that the overall drug development
process can be characterized using Bayesian probability statistics, such as
estimating the statistical power and error in each individual step in the drug
15 See http://clincancerres.aacrjournals.org/content/early/2017/04/26/1078-0432.CCR-
16-2895 (accessed May 22, 2017).

development process. He pointed out that although randomized Phase II

trials have become quite popular, researchers “should be careful because if
they are designed with poor error properties, they can degrade the drug
development pipeline.” He noted that “the optimal pipeline does not
necessarily result from a sequence of seemingly optimal individual clinical
trials,” because the more steps there are, the more opportunities there are for
statistical error and lack of reliability due to underpowered studies. Ratain
said that with good process models, “one can make drug development deci-
sions sooner” and noted the need for more quantitative analyses to inform
oncology drug development (Claret et al., 2009).
Dosage Modeling
Piantadosi said that the best dosing designs are guided by mathematical
dosage modeling, especially for combination therapies. “[Dosage] models
are essential because they embody knowledge from outside the experimental
realm, enabling incorporation of key ancillary information into dose find-
ing,” such as pharmacokinetic data or patient characteristics, he said.
Piantadosi suggested that dosage modeling can be used to help titrate
a therapy’s dose to meet a prespecified outcome. He also suggested that
researchers use dosage modeling to ascertain the range of active and tolera-
ble doses, and to define the minimum active dose rather than the maximum
tolerated dose. “Our old clinical designs were not defective, but were highly
optimized for the types of questions we had for agents in development then.
New questions require new designs,” Piantadosi said.
Piantadosi noted that optimizing dosing for combination therapies is
particularly complex because it requires determination of dose–response
curves for multiple agents (Tighiouart et al., 2014, 2017). He added that
this can require approximately four times more study participants compared
to a standard dose escalation trials for a single agent. “Our conventional
dose escalation approaches are unlikely to adequately solve the problem,”
he said, and added that investigating interactions between or among drugs
in combination therapies is expensive, so investigators need to know in
advance whether interactions are expected and design their clinical trials
accordingly. “With drug combinations, we will need larger designs and we
have no alternative but to pay the price when those drug interactions are
clinically important,” he said.
He noted that there is no standard dosage modeling approach for
such dosing, and gave examples of several possibilities. One approach,

called envelope simulation, uses regions of possible doses on a hypothetical

dose–response curve, and is continually updated as real data accumulate.
He added that simulated envelope data gradually lose their influence on the
predicted outcome as it is populated with actual data. With sufficient data,
the distribution of peak dose estimates gradually narrows with high preci-
sion. This method can be generalized to more than one therapy, provided
investigators can construct a plausible dose–response curve, Piantadosi said.
Another dosage modeling approach is the surface design method,
which is widely used to optimize multiple variables in industrial or chemi-
cal processes, but is not often used in clinical trials, Piantadosi said. Surface
design relies on systematically generating responses as control variables
are changed, and fitting the responses on a flexible surface to determine
optimum dosing. Piantadosi said this method is simple, reliable, and can
be applied using a minimal sample size at each design point (Myers et al.,
2016). Researchers used the surface design method to optimize the doses
of doxorubicin and cyclophosphamide and a tumor vaccine to produce the
highest response in patients with breast cancer (Emens et al., 2009) (see
Figure 3).
A third dosage model, factorial designs, is another underused tool for
studying combination therapy dosing and is well-suited to studying treat-
ment interactions, Piantadosi said. These factorial designs are especially effi-
cient and require small patient sample sizes when no interactions between
the treatments are being tested simultaneously, Piantadosi noted.
“With [dosage] models, one can begin to make predictions about what
would happen with changes in dose and schedule, which I think are abso-
lutely critical,” Ratain said. Sigal added that as the information gathered
becomes more complex with combination therapies, the ability to integrate
that information into dosage models will help researchers and regulators
make sense of the totality of evidence. Flaherty noted that when modeling
the dosing of combinations, one cannot assume “each drug is pulling its
own weight the same way. We need to be biased in our dose exploration.”
For example, Flaherty pointed out that for MEK/PI3K-targeted combina-
tion therapy, giving equal weight to the contribution of each targeted treat-
ment in the combination does not make sense because both preclinical and
clinical studies have found that the PI3 kinase inhibitor is ineffective as a
single agent (Garrett et al., 2011).
Keegan said, “We are not doing a good job of picking optimum doses
despite about half a decade’s worth of experience with continual reassess-
ment models for picking doses. Nobody is really taking a good look at

FIGURE 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.
NOTE: Shown in color is the resulting surface fitted to the responses; the red region
represents the maximum response.
SOURCES: Piantadosi presentation, December 12, 2016; Emens et al., 2009, reprinted
with permission. © 2009 American Society of Clinical Oncology. All rights reserved.
whether that has actually yielded better dosing information. We probably

now have a critical mass of information that would tell us if we are better
at picking doses with this type of model[ing].”
Modeling Benefits and Risks

Benefit–risk modeling can help DSMBs assess whether to continue a
trial after interim results have been analyzed by examining ethical consid-
erations, such as whether the benefits of the trial outweigh potential risks
to patients. Joffe suggested benefit–risk modeling should account for the
properties and the performance of various study designs under multiple
sets of assumptions in order to better protect trial participants and future
patients. “This is work that statisticians do that I think is going to be very
important,” he said.

Joffe said that assessing the risks of harm and potential benefits of a drug
agent has often relied on the clinical judgment of experts on the DSMB,
but benefit–risk modeling during an ongoing trial could help the DSMBs
integrate the vast amount of data they need to review and lend more rigor
to their discussions. He noted that researchers have made recent advances in
quantifying and modeling predictable harms and benefits in clinical trials,
and he suggested that leveraging these advances would help to foster more
rigorous and reproducible decision making within DSMBs. He added that
new methods to prevent or treat a harm, or to identify patients who are not
at risk of developing severe side effects from a treatment, could be incor-
porated in these benefit–risk models with updated appropriate weighting.
Raju noted that FDA weighs risks and benefits when assessing whether
to approve a therapy, but these assessments traditionally have been made
from a qualitative review of the evidence. He suggested that FDA use a
more quantitative approach by estimating the impact a therapy will have
on both the length and quality of life for a patient (Raju et al., 2016a).
For example, he performed a benefit–risk analysis on 22 FDA decisions
for drugs used to treat non-small cell lung cancer (Raju et al., 2016b) (see
Figure 4). In this analysis, he calculated the estimated benefit–hazard ratio
for each therapy’s primary endpoint, the estimated benefit of each therapy,
and total risk exposure compared to the control arm, as well as FDA’s deci-
sion for each therapy. He found that the analyses of estimated risks and
benefits were able to distinguish among the therapies that had been FDA
approved from the therapies that had been approved through the acceler-
ated approval pathway but were later withdrawn from the market. Raju has
conducted those analyses in nine other cancers, but noted that the quality of
data for adverse event reporting limits the benefit–risk model. He said that
the benefit of conducting these analyses is that it provides the rationale for
FDA decision making, and added that this type of benefit–risk modeling
could also inform earlier development decisions and trial designs, as well as
at later stages when more data have been collected.
Development and Use of Biomarkers in Cancer Clinical Trials

Redman stressed that clinical trials for cancer drug development need
to include an explicit plan for biomarker analysis. Woodcock added that
“more formal exploration of the performance of [biomarker-based] diag
nostics predicting patient response [should] be incorporated into clinical

FIGURE 4 Analysis of the benefits and risks for non-small cell lung cancer therapies.
(a): First line therapy. (b): Non first line therapy.
NOTE: Afa = afatinib; Ale = alectinib; ALK+ = anaplastic lymphoma kinase-positive;
Bev = bevacizumab; Cer = ceritinib; Cet = cetuximab; Cri = crizotinib; EGFR = epi-
dermal growth factor receptor; Erl = erlotinib; Gef = gefitinib; Nec = necitumumab;
Niv = nivolumab; NSq = nonsquamous; ORR = overall response rate; OS = overall sur-
vival; Osi = osimertinib; PD-L = programmed death-ligand; Pemb = pembrolizumab;
PFS = progression-free survival; Ram = ramucirumab; Sq = squamous.
SOURCES: Raju presentation, December 13, 2016; Raju et al., 2016b.

trials of therapeutics. Understanding that diagnostic and its performance is

going to be critical going forward.”
Redman suggested several different approaches to incorporate bio
markers into a clinical trial design. Investigators can use a standard trial
design in which all eligible patients are enrolled in the trial and the primary
analysis is conducted in an unselected or minimally selected population.
Secondary analyses of the trial would then include biomarker evaluation.
She added that investigators use this design when a treatment is expected
to have an effect in the overall patient population, but there are candidate
biomarkers they wish to evaluate further.
When there is a strong rationale for using a biomarker to predict
patient response in which only the subgroup of patients with that biomarker
is likely to benefit from the treatment, Redman said that subgroup-focused
designs may be a better option. She described three clinical trial designs
that include biomarker analysis as a main objective (see Figure 5). The first
approach is to include all study participants in the primary evaluation,
but to include an analysis of the treatment effect in a biomarker-defined
subgroup as a coprimary objective of the trial. Another option is to evalu-
ate treatment response within a biomarker-defined subgroup of patients
and compare it to the entire study population. Redman said that the final
option, called the targeted or master protocol design, is where investigators
specify biomarker-defined patient subgroups and treatment response is eval-
Overall Population-focused Subgroup-focused

Majority α to entire study population Majority α to subgroup
Subgroup Subgroup
Split type I error?
Entire Study
Entire Study
Population
Population
Targeted or Master Protocol Design
“Positive” “Positive” “Negative” Independent studies

Subgroup 1 Subgroup n Subgroup
FIGURE 5 Designs to evaluate biomarkers/subgroups.

NOTE: A type I error occurs if the null hypothesis is rejected when it is actually true
in the population (it is also referred to as α or false-positive) (Banerjee et al., 2009).
SOURCE: Redman presentation, December 12, 2016.

uated in each specific subgroup. If multiple biomarker-defined subgroups

are part of the trial design, they are treated as independently conducted
trials, Redman said.
Redman cautioned against using clinical trial designs that narrow
patient participation by biomarker status if they may exclude patients who
could benefit from the treatment being tested. She noted that most bio-
markers are not binary categories (i.e., a patient either has a biomarker or
does not have a biomarker). Instead, most biomarkers tend to be continuous
variables, with varying amounts of a specific biomarker in a tumor sample.
Because of this, Redman said that it can be difficult to establish appropriate
thresholds for biomarker-based patient selection in clinical trials.
Another challenge with biomarker-determined subgroup analyses of
clinical trial data is that the smaller size of each subgroup decreases the
statistical reliability of the data, Redman noted. In a hypothetical Phase I
clinical trial involving 100 patients, even if the prevalence of a biomarker
is 50 percent, there is poor statistical power to detect a 20 percent differ-
ence in response rates between biomarker-negative and biomarker-positive
patients (see Table 3). Even within a Phase III study with 400 patients,
either large responses or prevalent biomarkers are necessary to detect differ-
ences in treatment response by biomarker status, she stressed. She said that
investigators should design their biomarker studies with sufficient statistical
power by considering the prevalence of a biomarker and expected treatment
response, which will help determine the size of the patient population
needed for the clinical trial.
TABLE 3 Statistical Power to Detect Different Response Rates in

Biomarker-Defined Subgroups in a Single-Arm Study of 100 Patients
Percentage with N-Marker Power to Detect Difference Response Rate of:
Marker Positive 20% 35% 50%
10% 10 14% 57% 64%
20% 20 43% 91% 99%
30% 30 61% 97% 99%
40% 40 70% 98% 99%
50% 50 73% 99% 99%
NOTES: Based on an example with response rate of 10 percent in “marker negative”
group. One-sided t-test at the p = 0.05 level; N = 100.

Some workshop participants discussed the challenge of deciding when

to use biomarkers in a study, including how to identify all patients who
might benefit from a treatment, as well as consideration of resources and
timing to develop a companion diagnostic. Suzanne Topalian, director of
the Melanoma Program at the Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins University, inquired about the appropriate timing
of the development of a companion diagnostic: “Should this be done from
the very beginning or do we run the risk of excluding patient populations
that might benefit?” Rubin said that it takes about 1 year to validate a
promising biomarker test in the laboratory, which is a risky time invest-
ment because the drug may not go to market, so “you are not really sure
you need the biomarker.” He added that despite best efforts, diagnostic test
development often lags behind that of the therapeutic (NASEM, 2016a),
even within companies that have divisions for specialty diagnostics. Rubin’s
approach has been to conduct standard trials but ensure that these trials
have enough statistical power to address prespecified hypotheses regarding a
potential biomarker subgroup of interest. He added that determining which
biomarkers are appropriate evolves over time as more information is gener-
ated from studies, with some single biomarker tests now being replaced by
genomic biomarker signatures.
Rothenberg framed the question of when to begin diagnostic test
development as: “Do we know enough [about the biomarker test] to pull
the trigger and modify the clinical trial design? If we do, are we missing out
on a patient population who can benefit? If we do not, are we diluting the
effect in the selected group of patients so it will be a false-negative study?”
Rothenberg stressed that a number of factors influence this decision, includ-
ing medical, scientific, ethical, regulatory, and payer issues: “All of these
things come to bear in trying to [devise] the best possible decision given
the information that you have, and knowing the field is moving rapidly
forward. The longer you wait to make that decision, the more you are mak-
ing a decision not to do it.”
Flaherty said that prospectively studying biomarkers is better than
studying them retrospectively. For companies with limited resources, he
suggested designing studies whose primary objective is to determine efficacy
of a treatment in patients whose biomarker status suggests that they are
likely to respond to the intervention “and then circle back later to explore
whether a broader population might respond.” However, he suggested
that companies with more resources conduct larger trials in which there is
enough statistical power to detect whether certain biomarkers in subgroups

of patients predict response to treatment. “That is the ideal solution, but

I do not see that being executed across much of the field,” Flaherty said.
Finn noted that the PALOMA-1/TRIO-18 clinical trial changed
patient enrollment criteria midway into the study to specifically select only
ER-positive and HER2-negative patients who had biomarkers for ampli-
fication of cyclin D1, loss of p16, or both (Finn et al., 2015). He said that
this change slowed down the study, but investigators were concerned that
if the study did not limit patients by biomarker status, there may not have
been sufficient numbers of responsive patients to discern efficacy of the
treatment. If he were to redo the study, he said he would have included all
ER-positive and HER2-negative patients, and then stratified them by their
cyclin D1 and p16 biomarker status and conducted subgroup analyses.
Several speakers highlighted the lack of standards for complex omics-
based tests increasingly being used in cancer drug development (IOM,
2012). “It is a little bit of the Wild West, but validation of these tests is
incredibly important because if we are going to make informed decisions
on treatment for patients, it is important these tests work,” Sigal said. “We
all need to operate using the same standards,” she stressed, and added that
the current standards of the College of American Pathologists (CAP) and
Clinical Laboratory Improvement Amendments of 1988 (CLIA)16 are not
sufficient for these complex tests.
Woodcock noted that one of the challenges is that companies, aca-
demic institutions, and oversight bodies have not made it a priority to
ensure diagnostic test validity: “Patients will be disadvantaged by the fact
that [there is no ownership of these diagnostic tests], and there is not the
kind of round-robin concordance and proficiency [testing] that needs to
happen—nobody establishes reference standards and other things that are
needed. It is a huge problem, but there is not one entity that owns this
problem.” Sigal suggested that CAP and FDA work together to achieve
concordance in standards for these complex diagnostic tests “because it is
really going to hurt everyone if we do not.”
Ratain noted that the molecular pathology community has focused on
technical issues in the development and analytical validation of biomarker
tests, but there are other issues with clinical implementation and quality
assurance, such as whether tumor samples are tested consistently at the
same stage of diagnosis, because metastatic samples are likely to yield dif-
16 See https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.
html?redirect=/CLIA (accessed May 24, 2017).

ferent results than early-stage tumors. “We really do have to move beyond
CAP and CLIA, and there are many companies selling diagnostic tests from
CLIA-certified laboratories that have little or no clinical validity, and payers
are paying for them,” Ratain said.
Flaherty described the efforts that were undertaken in advance of
the National Cancer Institute-Molecular Analysis for Therapy Choice
(NCI-MATCH) clinical trial to ensure validation and standardization of
the test used to assess patients’ biospecimens for genomics biomarkers at
four different institutions (see section on Innovative Clinical Trial Designs).
This entailed using the same testing platform in each laboratory and hav-
ing all the laboratories involved undergo proficiency testing using the same
reference samples, with oversight by the FDA Center for Devices and
Radiological Health, Flaherty said. Near the end of the NCI-MATCH trial,
two for-profit laboratories underwent the same proficiency testing so they
could also be involved with the study. The end result was a high degree of
concordance across these academic and commercial laboratories using a
platform that tested hundreds of genes, he said.
Innovative Clinical Trial Designs

Many participants discussed innovations in clinical trial designs
for cancer drug development. These include adaptive protocols that are
amended based on new findings, seamless protocols that more easily
transition between the different phases of drug testing, master protocols
that enable the testing of multiple drugs and/or biomarkers in multiple
diseases simultaneously, and clinical trials with common control arms.
Many features of these designs can overlap and be included in a single
clinical trial. In addition, some workshop participants discussed the unique
challenges faced in innovative, seamless designs (see section on Issues to
Consider with Innovative Clinical Trial Designs). The three categories of
challenges highlighted and discussed were determining when and if a trial
should progress by defining endpoints and appropriately using statistical
analyses; decision making and oversight, particularly when those decisions
need to be made rapidly for complex trials; and evaluating benefit and risk
by balancing potential advantages with incomplete information, taking
advantage of postmarket learning, and deciding when single-arm studies
are warranted.

Adaptive Designs
Rajeshwari Sridhara, director of the Division of Biometrics V at CDER,
reported on the different types of adaptive study designs that investigators
have used to assess clinical tests. Adaptive studies can be broadly grouped
into two main categories. One category—sequential designs—involves
analyzing and reviewing the data at periodic prespecified time points in a
study and deciding whether to continue the trial based on the results. At
these points, investigators can also decide to amend the study to increase the
sample size or to narrow the clinical trial to a subset of patients. The second
category—Bayesian design—uses probability theory to assess the likelihood
that the accruing trial data suggest a trend that require adjustments to the
study protocol.
A subcategory of adaptive study designs is an adaptive enrichment pro-
tocol that uses biomarkers to predict response to a therapy. With adaptive
enrichment trials, all patients are tested for a potential predictive biomarker
when they are treated with a therapeutic agent or standard of care. If an
interim analysis finds that the biomarker predicts response to treatment, then
the biomarker is used to stratify patients—those who are biomarker neg-
ative are no longer accrued into the trial, while those who are biomarker posi-
tive are randomized to the therapeutic agent or standard of care.
Sridhara stressed that an adaptive design by definition enables pre-
planned study design modifications based on blinded or unblinded interim
results. Adaptive designs can be used for exploratory or confirmatory
studies. With exploratory adaptive studies, “you can explore as much as you
want without adjusting for multiple looks [or] multiple adaptations to gen-
erate hypotheses to be further tested. There is a lot of leeway here,” Sridhara
said. By contrast, she said that confirmatory adaptive studies require careful
planning to specify decision rules for each trial adaptation and to ensure
that they are statistically valid, Sridhara reported. “We are not saying you
cannot have many adaptations, but you need to prespecify your threshold
when you are thinking of this adaptation,” she said, emphasizing that the
requirement is for specifying the thresholds that would alter the course of
the treatment, rather than specifying the expected change. Piantadosi noted
that the rationale for prespecifying whenever possible is to reduce bias and
statistical errors in subsequent statistical analyses of the trial data.
Richard Schilsky, senior vice president and chief medical officer of the
American Society of Clinical Oncology (ASCO), noted that having prespec-
ified adaptive designs can be challenging or counterintuitive because “part

of the issue of being able to adapt your trial design might be in response to
information that you cannot foresee or anticipate and only become aware
of it during the course of the trial.”
Finn added that the need to prespecify depends on the context of the
study. If a randomized Phase II trial that is intended to collect data that
can be used to mitigate risk in a subsequent Phase III trial has a strong
hypothesis, scientific rationale, and trend, it would be acceptable to not
preregister adaptations, he said. David Feltquate, head of early clinical
development in oncology at Bristol-Myers Squibb, noted that analysis of
results from single-arm studies often preempts design changes to ongoing
randomized studies, such as a change in endpoint or study size, illustrating
the practice of making an adaptation that is not prespecified.
Keegan said that prespecifying adaptations can increase efficiency
and enable more appropriate decision making. She said that evaluating
results at specific time points to assess whether the hypothesis needs to be
altered is more appropriate than an open-ended enrollment without pre-
specified cohort sizes and evaluation time points. For example, an early
prespecified assessment of the use of response rate as an endpoint could
indicate that progression-free survival may be a more reliable endpoint, and
in an adaptive trial this change can be made, she said.
Rockhold suggested using what is known about the mechanism of
action of agents to model and predict potential results that would require
modification of a study design. If predictive modeling is not performed,
investigators respond reactively to unexpected results because no response
procedure has been defined, he said.
Feltquate noted that although adaptive designs aim to make trials more
efficient, the embedded feedback loops in which new data are analyzed and
findings are incorporated into study amendments can be time consuming.
“Our experience is that it adds an enormous amount of time onto the learn-
ing that goes on, unless you choose a surrogate endpoint, such as functional
imaging, that can give you a much quicker answer. Otherwise, I do not see
adaptive trials as having a lot of utility, but instead they have an opportunity
to provide false negative signals, causing us to stop something too early in
the testing process,” he said.
Seamless (Continuous) Clinical Trial Designs

Several workshop participants described opportunities to create a more
seamless drug development paradigm. Theoret illustrated a seamless drug

development paradigm that blurs the traditional phases of development,

and instead includes overlapping evaluation of pharmacology, exploratory
testing, and confirmatory testing, including an earlier assessment of efficacy
in the process (see Figure 6). He noted that FDA is receptive to consider-
ing opportunities to use seamless drug development designs in appropriate
circumstances, and noted that he and other FDA colleagues had recently
authored a perspective with a conclusion that a “desire to provide earlier
access to highly effective drugs should encourage further use of seamless
expansion-cohort trials, particularly as drugs with unprecedented levels of
efficacy advance into clinical trials” (Prowell et al., 2016).
Harvey added that the advantage of seamless clinical trial designs is
that they result in “much more efficient drug development, and need a
much lower patient sample size to define activity of drugs across different
areas.” But Harvey stressed that seamless designs are not appropriate for all
agents, and noted a number of design questions that have been proposed by
Theoret and FDA colleagues (see Box 3). “There are gaps in seamless drug
development that we need to mind,” he said.
Ratain suggested that cancer drug development move from the tradi
tional phased approach to a “learn and confirm” framework (Badenas,
2010; Sheiner, 1997). With the phased approach, Ratain said that proof
of concept is usually not demonstrated until the end of a Phase II trial,
FDA approval is not sought until after a Phase III trial, and there are transi-
tion times between each trial. With a more continuous drug development
paradigm, Ratain said that proof of concept is part of the learning stage,
and is immediately followed by testing to confirm the findings, with FDA
approval sought after the confirmatory stage. Ratain said that a confirm-
ing trial would include randomization, a control arm, a pharmacokinetic
study, and clinical endpoints, akin to a Phase III trial, but that learning
would continue by studying the agent in more heterogeneous patients, in
escalating dosages, or by randomly assigning patients to different dosage
regimens.
Ratain said that the learn-and-confirm drug development framework
would have three overlapping phases, which he labeled alpha, beta, and
gamma. The aim of the alpha phase would be to demonstrate proof of
concept and the range of active and tolerable doses. This phase would
rapidly escalate the dose in groups of one to two patients until there is
evidence of activity and expected (mechanism-related) or unexpected (off-
target) toxicity. At this point, randomized dose escalation would be used
to assign patients to pharmacologically active and plausibly safe doses to

FIGURE 6 (A) Traditional and (B) seamless oncology drug development paradigms.
SOURCES: Theoret presentation, December 13, 2016; Reprinted from Clinical Cancer
Research, © 2015, 21(20):4545-4551, Theoret, M. R., L. H. Pai-Scherf, M. K. Chuk,
T. M. Prowell, S. Balasubramaniam, T. Kim, G. Kim, P. G. Kluetz, P. Keegan, and R.
Pazdur, Expansion cohorts in first-in-human solid tumor oncology trials, with permis-
sion from the American Association for Cancer Research.

BOX 3
Questions Regarding the Design of Large, Seamless
First-in-Human Cancer Clinical Trials
• I s there a compelling rationale for including multiple expansion

cohorts?
• Is the sample size range consistent with the stated objectives
and endpoints?
• Is there an appropriate statistical analysis plan for all stated
endpoints?
• Are the eligibility criteria appropriately tailored to the expansion
cohorts?
• Is there a defined end to the trial, in terms of both efficacy and
futility?
• Is there a system in place to communicate with all investigators
in a timely fashion?
• Does the informed consent reflect the current knowledge of
safety and efficacy of the investigational drug and other agents
in the same class?
• If the trial might be used for regulatory approval, is there an
independent oversight committee?
• If the trial might be used for regulatory approval, has there been
communication with regulatory agencies?
SOURCES: Harvey presentation, December 13, 2016; Prowell et al., 2016.
assess if greater efficacy is achieved with doses greater than the minimal
effective dose (see Box 4 for more information on the challenges of dosing
in seamless clinical trials).
The beta phase would include a randomized dose-ranging design that
would assign patients to doses under consideration for labeling, based on
the results of the alpha phase. The gamma phase, similar to the traditional
Phase III trial, would confirm acceptable safety and efficacy at the selected
dose or doses by using an adaptive randomized trial to confirm the results
of the beta phase. Ideally, Ratain said that the gamma phase would have an
80 percent chance of leading to a drug approval.
He said that all three phases of development could theoretically fall
under the umbrella of a single protocol. “It can all be done in a continuous
paradigm,” Ratain said, with the next steps only implemented after the

BOX 4
Discussions Regarding Dose
Challenges with Seamless Trials
R. Donald Harvey, director of the Phase I Clinical Trials Sec-

tion at the Winship Cancer Institute and associate professor of
hematology/medical oncology and pharmacology at Emory Univer-
sity, stressed that seamless trials for accelerated approvals often
test new agents in small patient populations. This results in rapid
dose determinations for drug licensing trials based on responses
in small numbers of patients. He noted that the dose determination
in a traditional Phase I trial typically dictates what follows in subse-
quent trials in which the dose is refined, and pressure to determine
the dose from data gathered from an initial small group of patients
“creates a situation where we have lots of opportunity for getting
it wrong.” He noted that dose determination is more challenging
with oral than intravenous therapies because they have variable
bioavailability and may be affected by food, gastric pH, or other
gastrointestinal alterations. But efforts to gather more information
to make dosing more accurate and to consider factors such as food
effects are more difficult once a drug is on the market, as patients
are not usually willing to commit to being in studies that address it
rather than receive a commercially available agent. “I do not want
to rain on any parades because I do believe there is a lot of value
in accelerating drug development, but we do have challenges,”
Harvey stressed.
Harvey found that since 2011, there have been 28 new Food
and Drug Administration (FDA) approvals of oral cancer drugs, 11 of
which were accelerated approvals. During the same time period,
FDA has required 78 postmarketing trials, which averages 3 trials
per drug. Five of these postmarketing studies were dose finding
studies that indicated lower optimal doses than those specified
on the FDA label. Thirty trials studied drug–drug interactions, 19
studies were completed in patients with impaired liver or kidney
function, and 2 were studies of food effects, he said (FDA, 2017b;
HHS, 2017).
Harvey suggested several strategies for optimizing dose
precision, including formulation changes to improve bioavailability
and to ensure drug effects remain more constant despite gastro
intestinal conditions. He added that an earlier and more complete
understanding of the effects of food and concomitant medications
continued

BOX 4 Continued
on dosing is needed, and limited pharmacokinetic data should be col-

lected in late-stage trials. He also suggested that FDA approve multiple
doses for differing populations. These doses should be optimally defined
by these populations’ clinical variables. In addition, Harvey pointed out
that chronic administration of cancer drugs is often approached by giv-
ing standard doses initially, but subsequently many patients need dose
reductions after 1–2 months in order to tolerate the drug over longer
periods of time. In these situations where the dose-limiting toxicity that
stops escalation in a Phase I study is different in the acute phase set-
ting versus the chronic setting, he suggested a weighting approach that
determines dosing going forward and uses expanded cohorts to assess
the appropriate chronic dosing so statistically valid assessments can be
made. Alternatively, patients can be randomized in a Phase II study that
compares different dosing regimens.
Harvey also noted that genetic predictors of targets can sometimes
overcome concerns about how oral medications will interact with food
or other drugs because lower doses are usually needed to be effec-
tive in those patients with treatment response biomarkers. “If you dial
in the sensitivity based on genetic testing, you can then potentially alter
the dose,” he said. But solubility is often a problem with tyrosine kinase
inhibitors used in targeted cancer therapies. He suggested increasing
efforts to overcome that problem, to make drugs more available in the
body. “You have to decide to really invest in trying to make this formula-
tion right, but sometimes people would rather just fail early,” and aban-
don the potential drug rather than improve its formulation, Harvey said.
Suzanne Topalian, director of the Melanoma Program at the Sidney
Kimmel Comprehensive Cancer Center at Johns Hopkins University,
protocol is amended based on what has been learned. This protocol would
be reviewed like a traditional protocol, with the understanding that it will
be amended as the data accrue and before subsequent parts of the study are
activated. “It is all done as a single, efficient but phased trial,” Ratain said.
“This way oncology drug development can be efficient without sacrificing
scientific rigor.”
There also has to be clarity on how information and responsibilities are
handed off from investigators from one phase to the other, Ratain added.
“Operationally in industry, the same group may not be responsible for

asked whether seamless trials could incorporate dose optimization test-

ing in multiple patient groups with different variables so that a separate
trial would not be required later after the drug is approved. Harvey
responded that for drugs with great activity, such optimization can be
done as part of a seamless master protocol trial without the need to write
an additional protocol to address it. Gideon Blumenthal, lead medical
officer in thoracic, head, and neck cancers at FDA’s Office of Hematology
and Oncology Products (OHOP), concurred, noting that he has seen this
done within master protocols that are still accruing patients despite mul-
tiple FDA approvals. But such optimization testing “spans many different
kinds of expertise, disciplines, and teams. So operationally we have to
think about how best to apply our resources to make sure information
is being shared across teams, divisions, and disciplines to ensure that
operationally the drug looks good.”
Mark Ratain, director of the Center for Personalized Therapeutics
and associate director for clinical sciences at The University of Chicago
Comprehensive Cancer Center, suggested first determining if an agent
has a narrow or wide therapeutic range, and then adjusting dosing
designs accordingly. He added that for agents showing high efficacy with
little to no serious adverse effects (those with a wide therapeutic index),
single-arm studies with no control group would be appropriate for a reg-
istration study as long as patients were randomized for a dose-ranging
study. This would enable researchers to skip having a randomized Phase
III trial of the agent with a large number of control patients. “If the drug
looks so good and all the doses look great, then we do not need a toxic
control group,” he said.
But recognizing current gaps in a mechanistic understanding
of dosing, Amy McKee, acting deputy office director at OHOP, sug-
gested investing in research aimed at finding better pharmacodynamic
biomarkers.
preclinical, early clinical, late clinical, registrational, and life cycle develop-
ment for a single medicine.” We will have to coordinate these efforts across
groups, he said. Rothenberg agreed, saying, “It really is incumbent upon us
to make sure we see things from end to end and coordinate.” He suggested
reaching across organizational silos to ensure coordination. “We can try
and have more formal and extensive discussions to make sure drugs we are
getting from the early development laboratories are drugs that are going to
be meaningful and successful in the clinic,” Rothenberg said.
Schilsky asked how much confirming needs to be done before a drug

enters the market with a learn-and-confirm strategy, and what aspects of

confirming can be completed after market entry. Ratain said that dose
optimization could be performed as a postapproval study, because often
the best dose for a drug is not determined at the time of drug approval,
but after the drug enters the market. However, the current business model
for pharmaceutical companies does not incentivize postapproval dosing
research because the results may indicate that a lower dose is needed, lead-
ing to lower drug revenues. “If we changed our pricing models to bundled
payments per patient or per treatment course, companies would feel more
comfortable optimizing dose after approval,” Ratain said.
Master Protocols
Sridhara said that master protocols enable the conduct of complex
clinical trials because multiple diseases, treatments, and/or biomarkers
can be assessed in one overarching protocol. “With master protocols, you
are trying to answer multiple questions, or you have multiple objectives,”
Sridhara said. For example, investigators may use a master protocol to test
one treatment on multiple types of cancer, or to test multiple treatments
on a single type of cancer, or even to test multiple types of treatments on
multiple types of cancer.
Many master protocols are seamless clinical trials with adaptive
design features to enable investigators to set up evolving treatment arms of
a single trial protocol. With a master protocol, tested agents can be more
rapidly advanced for further study if they are showing good responses or
can be discarded if they do not demonstrate efficacy and replaced with
new agents that undergo testing, without stopping the entire protocol,
Woodcock said.
Master protocols usually have a centralized governance structure,
including central IRBs, DSMBs, independent review committees, and data
and biospecimens repositories, said Sridhara.
Examples of trials that use a master protocol design include the Lung
Cancer Master Protocol (Lung-MAP) (see Box 5), Precision Promise (see
Box 6), the NCI-MATCH trial (see Box 7), as well as the BATTLE-1
(Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer
Elimination) trial (Kim et al., 2011) and the I-SPY TRIAL (Investigation
of Serial Studies to Predict Your Therapeutic Response with Imaging and
Molecular Analysis) for breast cancer (I-SPY, 2017).
Sridhara described the KEYNOTE-001 trial as a Phase I dose-

BOX 5
Lung Cancer Master Protocol Trial
Mary Redman, associate member of the Clinical Research

ivision at the Fred Hutchinson Cancer Research Center, described
D
the Lung Cancer Master Protocol (Lung-MAP) trial, which uses
an umbrella master protocol and adaptive trial design. This trial is
an example of an innovative public–private partnership in which
multiple drugs from several different companies can be tested in
multiple subpopulations of patients within the same trial.
The Lung-MAP trial was designed as a Phase II/III trial, over-
seen by a public−private collaboration among institutions participat-
ing in the National Cancer Institute’s (NCI’s) National Clinical Trials
Network, the Foundation for the National Institutes of Health (FNIH),
a number of patient advocacy organizations, and a number of phar-
maceutical companies. Prior to trial entry, patients with squamous
non-small cell lung cancer receive biomarker profiling with next
generation sequencing, and are placed into subgroups based on
the biomarker profiles of their tumors (see figure). The companies
whose drugs are being tested are providing three-quarters of the
funding for the trial, including funding for the sequencing and new
biopsies when patients experience disease progression. This will
enable Lung-MAP to accrue patients at community sites without the
resources to do such screening and repeat biopsies. By providing a
“one-stop” platform, the trial aims to improve the timelines for clini-
cal trials by maximizing the number of eligible patients in a single
protocol. Lung-MAP began accruing patients in June 2014 and will
eventually be deployed at more than 500 sites in the United States
and Canada (NCI, 2016).
The protocol has been amended multiple times to stay current
with advances in lung cancer treatment and also to remove the
standard-of-care control arm from the master protocol, Redman
reported. The trial was also modified from a Phase II/III design to
trial that includes both Phase II and Phase III. Redman said that
this change was made in order to include a screening phase in
which an investigational therapy is evaluated as a single-arm trial.
This has reduced the number of patients who needed to be tested,
Redman noted, and helps improve efficiency if investigational drugs
are found to be either highly effective or highly ineffective. Additional
modifications to the protocol have been proposed to better incor-
porate immunotherapies, Redman said, and to open the trial to any
continued

BOX 5 Continued
histology provided the tumor is positive for the biomarker being tested.
These proposed modifications would add screening for immunotherapy
combinations with some exploratory biomarker testing.
Redman said that the Lung-MAP protocol has been described as
having several advantages (Herbst et al., 2015; Lung-MAP Clinical Tri-
als, 2017), including
• E nrollment efficiency—Grouping multiple drugs and biomarkers

under a single trial increases the probability that patients will be
eligible for the trial based on their biomarker profile, and includes
a trial arm for patients who do not match any of the existing bio-
markers being tested so that all patients tested could be enrolled.
• Operational efficiency—The single master protocol can be
amended as needed as drugs enter and exit the study.
• Consistency—Every drug entered into the trial will be tested in
an identical manner.
• Predictability—If prespecified efficacy and safety criteria are
met, the drug and accompanying companion diagnostic will be
approved by the Food and Drug Administration.
• Patient benefit—The goal is to bring safe and effective drugs to
patients sooner than they might otherwise be available, and to
enroll every patient who is profiled for the study.

Previously-treated Stage IV or Recurrent
Squamous Non-Small Cell Lung Cancer
Centralized NGS* Biomarker Profiling
NGS*-Biomarker Sub-studies Non-NGS-Matched Sub-studies
Biomarker 1 Positive …Biomarker n Positive Not Biomarker 1-n
Sub-study 1 …Sub-study n Non-Match

Biomarker-driven Biomarker-driven Sub-study
Stage 1: Targeted Therapy Targeted Therapy
R
Investigational Investigational
Therapy 1 Therapy n Non-match Standard of
Investigational Care
Therapy
Stage 2: R R
Investigational Standard of Investigational Standard of
Therapy 1 Care Therapy n Care
Design: Primary Endpoint: Sample Size:

Biomarker Non-match Unchanged
Phase II ->III Phase II: Response Phase II: 40

Phase III: OS Phase III: 150-200
Lung-MAP trial schematic, December 2015.
NOTE: NGS = next-generation sequencing; OS = overall survival.
*Or other biomarker testing for targeted therapies.

53
BOX 6
Precision Promise
Lynn Matrisian, chief research officer of the Pancreatic Cancer

Action Network, reported on the Precision Promise clinical trial for
patients with metastatic pancreatic cancer. This trial was designed under
the auspices of the Pancreatic Cancer Action Network, and anticipates
enrolling patients in 2017 at 12 different sites (Pancreatic Cancer Action
Network, 2017). In this exemplar of patient-centered drug development,
patients with pancreatic cancer may receive three types of cancer treat-
ments currently showing promise: immunotherapies, biomarker-driven
therapies that target genetic mutations in tumors, and stromal disruptive
therapies. The study has a master protocol design that enables patients
who progress on one type of treatment to immediately switch to another
treatment, with some patients potentially receiving all three treatments
in succession (see figure).
“The concept is that each patient should have as much benefit from
these three approaches as possible. We want patients to try all three
approaches if they can and move through them very rapidly,” Matrisian
said. The trial will also assess the impact of supportive care on patient
outcomes. Biomarker discovery and validation is also incorporated into
the master protocol. “This pushes the modern trial design envelope from
a patient perspective,” Matrisian said.
SOURCE: Matrisian presentation, December 13, 2016.

Study designed for pancreatic cancer patients.

NOTE: CR = complete response; DDR = DNA damage response; Gem/abx = gemcitabine and abraxane; HA = hyaluronan; MATCH =
National Cancer Institute-Molecular Analysis for Therapy Choice; PD = progressive disease; PDA = pancreatic ductal adenocarcinoma;
Plat.Tx = platinum-based treatment; PR = partial response; SD = stable disease; TAPUR = Targeted Agent Profiling Utilization Registry
Study.
SOURCE: Matrisian presentation, December 13, 2016.

55
BOX 7
National Cancer Institute-Molecular Analysis
for Therapy Choice (NCI-MATCH) Trial
Rajeshwari Sridhara, director of the Division of Biometrics V at

the Center for Drug Evaluation and Research and Keith Flaherty,
director of the Henri & Belinda Termeer Center for Targeted Therapy
at the Massachusetts General Hospital Cancer Center, described
the NCI-MATCH clinical trial. This trial is an exploratory trial that
analyzes patients’ tumors with next-generation sequencing to
determine whether they contain an actionable mutation, or a genetic
abnormality for which a targeted drug exists (NCI, 2017a). Enroll-
ment is not limited to patients with specific types of cancer; rather,
by their tumors’ biomarker status (NCI, 2017a).
This complex master protocol study opened for enrollment in
August 2015 and currently has 30 different treatment arms in which
the mutations present in a patient’s tumor sample are matched to a
targeted treatment (NCI, 2017a). Patients whose cancers progress
while on an experimental therapy have the option of having their
tumor sequenced again and being placed in a different treatment
arm if reanalysis suggests that another treatment arm may be more
appropriate.
All participating clinical laboratories will run the same validated
sequencing tests on the tumor samples, with defined standard oper-
ating procedures to ensure accurate results.
SOURCES: Sridhara and Flaherty presentations, December 12, 2016.
expansion cohort master protocol, in which pembrolizumab was tested in

patients with different types of solid tumors (see Figure 7). With this type
of trial, an agent can undergo dose escalation in patients and the protocol
can be amended to expand the number of patients with the specific tumor
type(s) to include those who are most likely to respond to the agent. Dose-
expansion cohort trials have prespecified starting and stopping criteria,
Sridhara said, as well as predetermined thresholds that indicate when the
next cohort should be added. Sridhara noted that patient protection “is of
utmost importance in these studies as they expose patients to unknown
safety risks,” and it is important to specify how safety results will be com-
municated to investigators, Sridhara said.

FIGURE 7 The KEYNOTE-001 dose expansion cohorts in solid tumors, melanoma, and non-small cell lung cancer.
NOTE: IPI = ipilimumab; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; Q2W = once every 2 weeks; Q3W = once

every 3 weeks.
57
SOURCES: Sridhara presentation, December 12, 2016; Khoja et al., 2015.

Woodcock also suggested that adaptive master protocols be used to

test single agents as an efficient means to determine dose. Woodcock noted
that industry has not often used adaptive trial designs “because you lose a
certain amount of control” with the way they are set up. “With an adap-
tive design, you agree up front that you will take certain actions based on
the data as they accumulate. You lose control because you do not get to
decide at the time the data accrue, but instead have to more or less decide
in advance what you are going to do. But there are tremendous advantages
to adaptive designs and they add to the seamlessness of drug development,”
Woodcock said.
Theoret discussed several advantages of expanding cohorts under a
master protocol clinical trial. The main advantages are earlier evaluation
of efficacy endpoints, standardized data collection, and the potential to
expedite the development of the drug because there is no need to reapply
to FDA with a new investigational new drug, undergo an IRB review of
an entirely new protocol, or re-engage a clinical trial network each time
changes are made to the protocol (Theoret et al., 2015). Woodcock added
that “a highly involved master protocol could evaluate some of the things
we are not doing that well on right now, such as studying new diagnostics
and how they perform, new therapies and regimens, and combination
therapies.” She noted that master protocols are especially important for
development and validation of diagnostics “because you probably have to
do this in an adaptive fashion to be efficient and actually learn maximally
about the diagnostic.”
However, Theoret also described some limitations and disadvantages
of this approach. For example, the original statistical analysis plan might
not be adequately detailed to justify the sample size of the subgroups or the
objectives of the subgroups in the overall development plan, Theoret said.
Another challenge is the potential for safety concerns related to smaller
and more heterogeneous populations used in the study arms. He suggested
updating protocols and informed consent documents with safety informa-
tion gathered from previously treated patients, as well as informing IRBs of
emerging safety information. He added that disease-specific safety monitor-
ing may be needed for different disease-specific cohorts. He also noted that
unlike for the traditional, “phased” development program pathway, when
investigators deploy expansion-cohort master protocols with the intent of
an accelerated approval, there are no predefined milestone meetings with
FDA to discuss progress to date and how to proceed going forward. “It
is incumbent upon sponsors to contact FDA to set up these meetings at

the appropriate points in their development so that various issues can be

addressed without delay,” Theoret said.
Another challenge with expansion cohort master protocols is that case
report forms17 may vary in the level of detail required (e.g., an early-phase
trial versus a registrational trial). He suggested considering whether case
report forms need to be updated based on the specific objective of the
expansion cohort. Theoret also stressed the need to ensure independent
oversight of master protocols. “Oftentimes, an adequate and well-controlled
trial with 300 or 400 patients will have an independent panel to address not
just the potential for efficacy objectives, but ongoing safety evaluations. In
this type of trial design, consideration for independent oversight should be
considered early on,” said Theoret.
Clinical Trials with Common Control Arms

Sridhara pointed out that comparing various interventions using the
same patient group as the control arm can save time and resources. In a
hypothetical example, she said that the use of a common control arm when
testing two interventions would reduce the number of patients needed for
a trial by at least one-third.
Sridhara added that a common control arm could have been used for
evaluating investigational therapies in patients with renal cell carcinoma,
a relatively rare cancer. Recently, five concurrent studies from five sponsors
were evaluating investigational therapies in patients with advanced renal
cell carcinoma. In each of these studies, the control arm was treatment
with the current standard of care, sunitinib. Many resources could have
been saved if the control arm was shared among all five studies, Sridhara
noted. McKee agreed and stressed, “We do not have enough patients for
all of these trials.” However, many sponsors have been reluctant to pursue
a master protocol that would enable them to use a common control arm.
Echoing what Woodcock said earlier, Rubin reiterated that reluctance may
be rooted in companies not wanting to relinquish control of the study.
“Companies like to pick the sites and make sure they have the best quality
data, and they might not agree with the overall approach,” he said, but
17 A case report form is “a printed, optical, or electronic document designed to record all
of the protocol-required information to be reported to the sponsor on each trial subject.” See
https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf (accessed May 22, 2017).

added that such cross-company collaboration “is something that should

be worked on.”
Issues to Consider with Innovative Clinical Trial Designs

Several workshop speakers discussed issues that need be considered
when designing new clinical trials for oncology drug development, includ-
ing what type and amount of information is needed to progress in drug
development, who is involved in decision making, and evaluation of the
benefits and risks of novel investigational agents.
Information needed to progress in drug development Rothenberg said

seamless clinical trial designs and accelerated drug development programs
raise several new questions, including what kind of information is needed
for a study to progress from one stage to another; how strong and statisti-
cally reliable does that information need to be; and if a surrogate endpoint
is used, how much certainty about the relationship between the surrogate
endpoint and clinical outcome is needed?
He added that the determining which endpoints to use can be challeng-
ing. The relationships among outcomes such as progression-free survival,
overall survival, restricted mean survival times, durability of response, and
meaningful symptom control are not always well-established and may differ
among cancer subtypes and treatment regimens.
Feltquate noted that “as we move toward seamless drug development,
discerning true positive from true negative signals will become even more
important.” He reported that when one of the first dose escalation studies
for a cancer immunotherapy targeting the PD-L1 receptor in patients was
completed, five types of cancer (melanoma, kidney, lung, prostate, and
colorectal) were initially included. This testing demonstrated unusually
large response rates in patients—between 20 and 30 percent—at a time
when standard of care therapies provided response rates of approximately
15 percent. Even though the trial included relatively small groups of
patients, the unusually large response rates seen in three of the five types
of cancer led investigators to amend the study to expand testing to patients
with more types of cancer. The results from this Phase I study led the
researchers to acquire Breakthrough Therapy designation from FDA and
they proceeded directly from their Phase I study to a randomized Phase III
study in multiple tumor types (Robert et al., 2015).
Feltquate reported on another strong signal that occurred in one

patient—a durable complete response—in Phase I trial of a PD-L1 inhibi-

tor (Brahmer et al., 2010). This patient with colorectal cancer was found to
have a genetic mutation (microsatellite instability) that drove the response
to the drug, Feltquate said. This finding led researchers to test the treatment
in other patients whose cancer shared the same genetic mutation. These
patients also had unusually high responses, which led to the drug receiving
Breakthrough Therapy designation for this indication. “It was one patient
at first so you can call it an anecdote, but there was good science tied to
this, and that led to doing prospective work showing a very large signal,”
Feltquate said. “If you have a few patients with outstanding responses,
that can be more convincing than more patients with somewhat equivocal
responses,” he said.
Feltquate also noted that researchers are sometimes confronted with
false-negative signals, such as lack of activity in single-agent therapies. For
example, initial tests of elotuzumab, which preclinical studies suggested
would stimulate the immune response to multiple myeloma tumor cells,
found little biological activity at any of the evaluated doses. However, there
were biological reasons for suspecting this agent would perform better when
combined with lenalidomide. This combination was tested in a Phase I
study and found to have robust activity that was confirmed with a subse-
quent Phase III study in a larger group of patients with multiple myeloma
(Richardson et al., 2014).
Feltquate referred to several other studies showing large signals when
various immunotherapies are combined. These studies have shown more
complete responses or near-complete responses than what was seen with
either agent alone. In some cases there is a doubling of the response rate
when two immunotherapies are combined compared with when they are
used singly in patient populations that have response biomarkers for the
therapies. “What is notable is we are seeing these big signals in small sample
sizes,” Feltquate stressed, raising the question of whether the signals are real
and should justify a rapid drug development and approval process for the
immunotherapies, perhaps skipping Phase II trials.
Feltquate suggested that focusing on adequate sample size, clinically
meaningful effects, and key clinically or biologically defined subsets may
decrease chances of acting on false-positive and false-negative results, for
both single therapies as well as combination therapies, which are increas-
ingly being tested.
Joffe added that “Size matters. If there is a very large effect size, then a
seamless design is unlikely to lead you to the wrong decision. But if you are

talking about something that has a small-to-moderate effect size, then I think
there is a very high risk of mistaken decisions based upon seamless designs.”
He noted that there will be increasing pressure to use seamless trials when
there are smaller and more moderate effect sizes, but stressed that “the designs
and decisions that are made along the way really have to be contingent on the
effect sizes that emerge at various stages of the pathway.” He cautioned that a
plan for making decisions about whether a seamless trial progresses needs to
be deliberate in order to ensure that ethical requirements are met to protect
patients participating in the trials and to make the safest decisions possible
for future recipients of the treatments being tested.
Decision making and oversight Seamless clinical trials raise new issues
related to decision making processes, including who should be making
the decision to advance clinical testing and what stakeholder input should
be solicited. Joffe pointed out that with rapid protocol modifications and
seamless study designs, it is challenging for IRBs to quickly assess the risks
and benefits to patients in the trials. “We are going to need highly special-
ized and nimble central IRBs to make this a practicality,” he said.
“Who should be at the table when new data—very early or intermedi-
ate data—are emerging regarding a therapy and what its real limitations
may be?” Flaherty asked, adding, “Physicians and patients both are going to
gravitate toward the best available option, even when it may not really be a
great one,” especially when patients have advanced, life-threatening diseases
and there is an unmet need for an effective therapy. “Others need to be
involved in this discussion,” Flaherty said, and suggested having a small set
of representative stakeholders present for such discussions. Flaherty added
that it is not in FDA’s purview to provide such input, and that patients
and investigators tend to be biased in favor of proceeding to the next stage.
Rockhold noted that an independent DSMB needs to assess the data
and provide oversight in a continuous trial design, in order to adequately
address ethical concerns and protect patients and make sound scientific
decisions. He cited a paper written by FDA staff that found that indepen-
dent DSMBs provide important quality control in seamless clinical trials
(Prowell et al., 2016). Rockhold added that to maintain independence and
minimize bias, Principal Investigators and sponsors of a study should not
be on a DSMB, particularly for seamless trial designs. However, “there is
a fine line between independence and ignorance. You do not want to pick a
[DSMB] that is so independent, its members are never allowed to talk to
the people doing the research . . . sometimes people carry the concept of

conflict of interest too far and they want people who are so removed they
do not actually understand what is going on,” Rockhold said.
Joffe suggested that it would be appropriate to have Principal Investiga-
tors on DSMBs for single-center studies, but for multicenter studies, having
all the investigators participate on a DSMB could pose a potential conflict
of interest. He added that in hybrid Phase I/II or Phase II/III studies, there
are defined points where the investigator or sponsor is part of decision
making process about whether to continue the trial. He suggested that
investigators and sponsors should also be involved in decision making at
similar transition points in seamless trials. “These sorts of transition points
cannot all be decided by the DSMB with all the sponsors and investigators
blinded as to what is going on with the data,” he said.
Rockhold added that a DSMB review of a seamless trial aimed at
answering multiple questions involves assessing much more information
than it would for a typical trial asking a single question. “Somebody gives
you 5,000 pages of tables of interim data, so one of the challenges for a
DSMB is to outline upfront which is the right information to focus on,”
he said. An advantage to having a DSMB established for Phase II or earlier
studies is that “You now have a single group of people who are quite knowl-
edgeable about the product, [and] once it gets into Phase III testing, [they]
know what safety issues to expect,” Rockhold added.
Rockhold also suggested there be more clarity on the communication
pathways in seamless trial designs. “If an independent [DSMB] wants to
drop a group from testing, which requires changing the protocol, they
might notify the IRB or the steering committee. Who they should notify
has to be completely specified upfront to protect patients adequately,” he
said.
An additional challenge with accelerated seamless trials and knowing
when to transition from one phase to another is whether decision makers are
“keeping up to date with changes in scientific understanding,” Rothenberg
said. “I do not think clinical development is able right now to keep up with
the rapidly evolving science, so how do we keep clinical evaluation from
being the bottleneck?” Woodcock asked.
One participant suggested developing training programs for data safety
monitors to stay current with newer technologies, study designs, and sta-
tistical methods. “I do not think we have a structure or framework now to
train this new generation of monitors to do adequate monitoring jobs,” the
participant said. Rockhold noted that DSMB training programs are being
established based on recommendations from Duke University’s Clinical

Trials Transformation Initiative.18 However, the challenge is recruiting

potential members to DSMB training programs, said Rockhold. “Being on
[DSMBs] is not going to be a high-volume, lucrative career, so you have
to find people who really want to do it,” he said. He noted that some have
suggested an internship program for DSMB members so that they can
observe what happens during DSMB meetings prior to becoming an actual
member: “This is an important issue because when you set up a [DSMB],
there is always the same list of seven names that come up and I think some
of them desperately want to retire. So it is a challenge and as designs become
more complex and involved, the greater the challenge.” Piantadosi added
that there is also a paucity of trained clinical trial statisticians, due to a large
migration of statisticians into the bioinformatics field.
Evaluation of benefits and risks Woodcock commented that “we all

agree that the development of knowledge around an investigational drug is
a continuum that might be a steep learning curve at first, then it levels off
a little, but it never stops.” For example, researchers are still uncovering the
best way to use the heart medicine digoxin, which has been on the market
for decades, she said. However, an FDA approval decision is a binary deci-
sion. “So where do we cut that? The answer unfortunately is ‘it depends,’”
Woodcock said. It depends on the clinical situation, including the number
and quality of alternative therapies, as well as dosing and toxicity of the
agent balanced against potential benefit and burden of disease. If the agent
is showing unprecedented benefit, it may be granted Breakthrough Therapy
designation; however, if it shows only incremental improvement, “usually
you want to have more information because none of these drugs are a free
lunch—there is always some toxicity,” she said, adding that “we try to lay
out these considerations in a semi-quantitative way so hopefully there will
be some stable balance of benefit and harms where the benefits come out
ahead.”
Keegan added that “FDA agrees with the need to consider alternative
trial designs and methods to evaluate new drugs, but all of these come with
certain risks and considerations. It is important to evaluate the science and
how we are extrapolating—to recognize those as risks and consider that
the evaluation of the clinical development program needs to be an iterative
process.” McKee commented that “no one paradigm is going to fit every-
18 See https://www.ctti-clinicaltrials.org/projects/data-monitoring-committees-dmcs

one’s needs, and we at FDA are trying to be as flexible as we can so that

we get both the game changers on the market and the incremental benefit
products on the market.” Piantadosi stressed that “the pipelines we use for
development [need to] be designed explicitly for the clinical setting and
for the properties of the drugs under study, rather than to reflexively say we
need to have a seamless design. I would like to see us take control over the
nature of the pipeline and make sure that it will produce the kind of product
that we expect.” Redman added that “phase of development is just a signi-
fier in terms of where you are in the development of a regimen. But it does
not necessarily dictate exactly how you are going to investigate a regimen.”
“It is a balance—you get one chance in drug development. If you take
the wrong dose into your pivotal trials and fail, there is no second chance.
But at the same time, we work in a very competitive environment, so we
have to balance these things. We need to recognize that when we bring
a drug to market, we never have full certainty,” noted Rothenberg. He
emphasized that “we need to know enough to be able to accurately char-
acterize the benefit–risk relationship for the patients” and pointed out that
the established process of postmarketing surveillance leads to regular label
updates, usually based on experience of the drug when used in children, in
individuals who have liver or kidney dysfunction, or in other rare patient
populations.
Brown stressed that “much of what we know about medications we
learn after their approval for market, so how can we continue to learn in the
postmarket environment as well?” He suggested changing payment models
to promote better flow of data so that postmarket learning can take place. “If
Medicare required something, it would happen pretty quickly. Every clini-
cian likes to get paid and they will submit the required information, and then
every insurance company in the country will follow suit,” he said. He also
suggested using adaptive licensing,19 which some European countries use.
Brown noted that if more effort was devoted to monitoring and
19 Adaptive licensing describes the progressive or staggered approval of a medicine based on
a prospectively planned process. This iterative approach enables a medicine to be authorized

for use in a restricted patient population, following which the authorization may be extended
to a broader patient population (e.g., by labeling adaptation) after the collection of additional
clinical evidence. The approach allows access to medicines earlier in areas of unmet medical
need, while still protecting the more general public from risks associated with the product
until further data can be assembled. The staggered approval also allows for a more educated
value assessment by reimbursement authorities before a product is made available to a larger
patient population (Taylor Wessing LLP, 2017).

documenting adverse reactions or other unexpected findings of a drug in

the postmarket setting, it would “change the benefit–risk calculation, but
we have to convince ourselves [that] we have a good enough postapproval
system to do it.” He added that although FDA has a postmarketing surveil-
lance system, “it does not work well for cancer as an outcome, but it can
be done.”
Several workshop participants also discussed when randomized trials are
necessary and when single-arm studies are sufficient for drug approval, par-
ticularly in cancers for which there are no effective treatments. B lumenthal
noted that there has been a long track record of accelerated and sometimes
even full approval of cancer drugs based on response rate and duration of
response in single-arm trials. He noted that FDA is often blamed for not
approving a drug without a randomized clinical trial, but he argued that the
agency often takes an activist role in ensuring flexibility and will even, on
occasion, directly and proactively ask sponsors if randomization is necessary.
Joffe suggested doing randomization unless early clinical data suggest
a very large effect size, “because if we do not randomize, I think we are
going to find ourselves making some very flawed decisions.” Redman sug-
gested, “We should randomize when it is the best way to answer a question.
Expediting drug development is not necessarily done by completing s tudies
faster, but by designing trials that consider all possible outcomes, both posi-
tive and negative, of a trial, and the value of information provided in that
trial.” Schilsky added, “Acceleration per se is not what we need, but rather to
get the right information at the right time in the drug development process
in order to optimize the process.” There are substantial risks from going
too fast, not only to patients, but to the drug development process itself,
Schilsky said. “If you do not get the dose and formulation right, you can
ultimately derail your whole drug development process and then at the end
of the day, you do not have a product that can help people,” Schilsky said.
But he added that there is also a risk to going too slowly, in terms of losing
a competitive position. Blumenthal noted that sometimes payers also want
to see overall survival data before providing the reimbursement that enables
adoption of new drugs in clinical care.
Leveraging Real-World Evidence from Clinical Practice

Several workshop participants noted the potential for the growing
volume of clinical practice data—collected in EHRs, laboratory informa-
tion, claims data, and other sources—to provide real-world evidence on the

benefits and risks to patients of new oncology therapies. Woodcock noted

that the field of oncology is leading the way in using real-world evidence,
with several groups integrating laboratory results, EHRs, and claims data
to generate evidence on how therapies are being used, treatment outcomes,
adverse events, and transitions to subsequent therapies. “To various extents
[researchers] are curating these data so that they have greater reliability
than the raw data from these [clinical] experiences,” Woodcock said. “We
can learn rapidly many things about the outcomes in actual practice of
using these drugs and how patients fare. Within a year or two we will learn
things that may enable us to modify drug labels for subsequent indications
in subgroups. So we are seeing progress in the use of real-world evidence in
oncology,” she added. Ultimately, such use of real-world data may enable
the “merging of the practice setting with the trial setting so that barriers
to data collection are minimized, and for cancer particularly, so that more
patients in the U.S. can participate in trials intended to optimize disease
outcomes,” Woodcock said. Real-world evidence may take longer than
anticipated to yield significant benefits, she added, but it represents “a real
opportunity.”
Although many participants noted the potential value in using real-
world data, some also highlighted potential issues to consider. For example,
Rockhold pointed out the importance of using real-world data appropri-
ately. “You run clinical trials to answer some questions and you look at
real-world data to answer others. One does not necessarily substitute for
the other, and people get seduced by the supposed ease and size of the data,
but that is a problem. Real-world data are quite useful to answer real-world
questions. They may not be useful to answer every clinical question, and
studies using them are not necessarily less expensive, depending on what
you want to do.” Brown agreed, noting, “It is very hard to use the data well,
particularly these data that are collected for another purpose. You could
prove all sorts of things that are both absolutely precise and completely
wrong if you do not know what you are doing, so we have to be careful.”
He added that data reliability is also a potential concern because the current
practice of having nurses verify the data manually is cost intensive.
Koehler and Amy Abernethy, chief medical officer, chief scientific offi-
cer, and senior vice president of oncology at Flatiron Health, outlined some
types of real-world data and the circumstances in which they are appropriate
to use in drug development. Koehler defined real-world data as health care
data that are not collected through randomized controlled clinical trials and
used for decision-making purposes (Annemans et al., 2007; Garrison et al.,

2007). Such health care data include registries, EHRs, claims data, data
gathered from health apps and social media, and large patient databases.
Registries are usually designed for research on a single disease, are
expensive, lack direct access to data, and tend to have smaller, biased sam-
ples, said Koehler. In contrast, claims data are large datasets that can indicate
treatment patterns and costs, and can also enable follow-up across health
care settings. However, there is usually a 6-month lag between when the
data are accrued and when they are reported in claims databases. In addi-
tion, claims data provide information on what interventions were provided
to patients, but these data do not provide any clinical information about
the patient. Because of this limitation, Koehler said that ongoing research
focuses on how to use newer sources of data, such as EHRs and health apps.
“These types of data could and should be incorporated in the drug label if
we only knew how to do that.”
Abernethy stressed that real-world evidence may not come solely from
EHRs or other databases, but rather from the production of “big data,” or
the amalgamation of different datasets (including EHRs, administrative
claims databases, registries, as well as patient-generated health data) that
is intended to complement clinical trials by providing more generalizable
knowledge. “Big data more clearly complete the picture of what is hap-
pening to patients in the real world in routine clinical practice,” she said.
Big data involve rapidly accumulating, high-volume datasets with different
types of data that should be verified and improved over time, according to
Abernethy. She stressed that big data should not be viewed as amorphous,
but rather as an organizing framework that can be applied to research
questions in a competent, consistent, and reliable way. “Real-world data
analyzed in a consistent manner can generate clinically meaningful and
generalizable evidence,” she said.
For researchers to be able to use real-world data in a study, the data
have to be accurate, of high quality, complete, longitudinal, reproducible,
and traceable back to their source, Abernethy said. There also needs to be
patient-level data linkages when appropriate for the research question, and
endpoints and outcomes need to be embedded in the datasets. The study
analysis approach needs to include objectives and strict analysis plans that
are reproducible and credible, Abernethy stressed, adding, “We cannot
cherry pick but need to be systematic in our cohort selection.” In addition,
real-world data can be used retrospectively to identify patients with rare
diseases who can be followed longitudinally over time, to observe outcomes

in patients who receive off-label medications, or to follow clinical outcomes

of patients who have participated in clinical trials in the past.
Pragmatic Trials
Koehler said that a pragmatic trial is a study that uses real-world data
and usually answers practical questions about risk, benefit, and cost of one
intervention versus competing interventions. In contrast, an explanatory
trial determines how well a drug works and how safe the drug is when it
is evaluated under ideal conditions in a clinical trial setting (Roland and
Torgerson, 1998). Randomization and placebo controls are often critical
for explanatory studies to maximize the chance of revealing true biological
effects of new treatments, Koehler noted. Because pragmatic trials compare
multiple treatments used in clinical practice, they typically do not use
control arms. Pragmatic trials are randomized, but this could include ran-
domization in which outcomes in an entire group of patients is compared
with those of another similar group of patients. Although blinding is usually
required in an explanatory study, it is usually not possible in a pragmatic
trial, she added.
Koehler emphasized that pragmatic trials should have strict require-
ments aimed at reducing many types of bias in the study. These include set-
ting randomization requirements to address selection bias, defining similar
conditions to study arms to address performance bias, and ensuring that the
groups being compared have the same performance standards for collecting
data on patients who drop out of the studies and conducting intention-to-
treat analyses to address attrition bias.
Explanatory trials are conducted in a carefully controlled population
of patients, who tend to be relatively homogeneous, lack concomitant ill-
nesses, and often have less ethnic diversity (Roland and Torgerson, 1998).
By contrast, pragmatic trials are conducted in more heterogeneous patient
populations in a variety of clinical settings, Koehler said. Compared to
explanatory trials, pragmatic trials tend to be simpler and can potentially be
less expensive to run, she said. Koehler stressed that pragmatic trials tend to
answer questions that patients and payers care about, such as how a treat-
ment affects symptoms, patient quality of life, and costs, in addition to the
mortality and morbidity usually assessed in explanatory studies. She also
described nine dimensions to characterize the level of pragmatism of a trial
(see Figure 8). For example, she said that a study comparing self-supervised
tuberculosis treatment with directly observed treatment is considered highly

FIGURE 8 The Pragmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2)

wheel.
NOTE: In order to assess whether a study design matches its intended purpose, these
nine domains can be evaluated on a 5-point scale, with 1 = very explanatory (clinical
trial–like conditions) to 5 = very pragmatic (usual care conditions).
SOURCES: Koehler presentation, December 12, 2016; Reproduced from British
Medical Journal, Loudon, K., S. Treweek, F. Sullivan, P. Donnan, K. E. Thorpe, and M.
Zwarenstein, 350, 1-11, © 2015 with permission from BMJ Publishing Group Ltd.
pragmatic in all factors assessed by a Pragmatic-Explanatory Continuum

Indicator Summary (PRECIS) and closely resembles usual clinical care. In
contrast, a study evaluating surgery for treatment of carotid artery blockage
(the North American Symptomatic Carotid Endarterectomy Trial) is closer
to the center of the PRECIS wheel and much more closely resembles an
explanatory trial, she said.
Using EHR Data in Studies

Abernethy suggested using EHRs as the organizing framework for clini-
cal data given that more than 90 percent of oncologists use EHRs, these

data are linkable, and they can be used to document and improve quality.
Abernethy outlined several key steps undertaken at Flatiron Health to
gather evidence from EHRs to derive usable real-world evidence:
• Aggregate data across different care settings or across the country.

• Standardize and harmonize the information in EHRs so data com-
ing from multiple sources use the same terminology and units of
measure.
• Abstract the information gathered from various reports and make
sure key information is entered, such as biomarker data from labora-
tory tests, findings in radiology and pathology reports, or clinicians’
notes.
• Have quality assurance for each item of data entered. This includes
having all abstracted data processed in accordance with approved
procedures, quality control and auditing of abstracted informa-
tion, audit trails and documentation, and traceability of abstracted
information.
• Match the data in EHRs to a variety of other key datasets, such as
mortality data, genomics, patient-reported outcomes, and claims
data.
• Incorporate endpoints and outcomes that enable interrelating the
intervention to documented differences in individual patients or
patient groups.
• Organize the data for analysis and prepare an analytic plan.
Using this approach, Abernethy discussed an evaluation of the appro-

priateness of the black box warning on the breast cancer drug Kadcyla that
she and her colleagues conducted. This warning specifies that clinicians
should not use the drug to treat breast cancer patients with suboptimal
heart pumping ability, specifically with heart ejection fractions of less
than or equal to 50 percent. Kadcyla is composed of two anticancer drugs,
emtansine and trastuzumab. Because trastuzumab had been shown to
cause heart damage, patients with less than optimal ejection fraction were
excluded from clinical trials. Consequently, it was not truly known how
patients with the lower ejection fraction would fare with this combination
drug. Despite the black box warning, many of these patients have received
Kadcyla. Abernethy is conducting a retrospective study to assess the rate
and severity of cardiac events in patients treated with Kadcyla using data
derived from the EHRs of approximately 8,000 women with breast cancer,

1,000 of whom had been treated with Kadcyla. Sixty-six of these women
had ejection fractions of 50 or less prior to being treated with Kadcyla.
These patients are now being followed to assess treatment outcomes.
“We now are starting to understand what happens to these women both
in terms of their ejection fraction over time as well as their breast cancer
outcomes,” Abernethy said.
When to Use Real-World Evidence

Woodcock noted at the workshop that FDA had just published an article
defining real-world evidence and how it can be used (Sherman et al., 2016).
This article is both forward thinking and cautionary, she said, noting that
FDA has already approved drugs for rare diseases based on such patient care
data. Woodcock noted that such data will become more useful when studies
can be randomized within the care setting. “That will be very helpful when it
happens, but we are not there yet,” she said, adding, “The bottom line is that
we are open to real-world evidence.” She pointed out studies on standard of
care that “got answers rather quickly” from doing cluster or block randomiza-
tion analyses of real-world data. Such studies may compare the standard of
care of patients in one setting compared to another, for example.
Woodcock reiterated that once oncology drugs enter the market, many
questions about them remain unanswered, and “what we hope is that in
the future, evidence from care can help inform and answer some of those
additional questions we have about the use of the drug.” Koehler suggested
that real-world evidence could be used to further evaluate drugs that enter
the market via accelerated approval, which requires less preapproval testing,
and could also support evidence generation for subsequent indications, label
updates, and drug combinations within an approved indication.
Koehler suggested that pragmatic trials could play a larger role in
answering regulatory questions, such as formulating drug labels. She
emphasized that “the most useful source of knowledge will come from ran-
domization in the context of clinical practice . . . therefore, the best thing
to do is to potentially consider real-world outcomes for regulatory review
as soon as possible.” She provided the Salford Lung Study as an example of
a real-world evidence trial, which was conducted in the United Kingdom
for patients with chronic obstructive pulmonary disease before the drug
entered the market and used randomized and controlled real-world data to
assess the drug’s effectiveness (Vestbo et al., 2016). In this study, patients
were randomized as to whether they received the investigational drug from

their clinicians or the standard of care. Koehler noted that it was one of the
first times that data were used from community clinician practices to sup-
port regulatory approval of an investigational drug (Vestbo et al., 2016).
Koehler is currently conducting a study assessing whether patient outcomes
using EHR data is similar to patient outcomes observed in a clinical trial
(with a similar patient population) for women with metastatic breast cancer
receiving the drug letrozole.
Koehler emphasized that although evidence on the safety and efficacy
of a drug is gathered as it goes through preapproval clinical trials, the evi-
dence generated is from a much smaller and more homogeneous patient
population than in the real-world setting once the drug enters the market.
Because the drug’s use in patients in the general population outpaces the
collection of evidence on how it will affect them, there is an evidence gap
that could be addressed by real-world data (see Figure 9).
Redman noted that real-world data can help in an iterative fashion
to expand findings from clinical trials. She suggested using real-world
FIGURE 9 Utilization of cancer drugs outpaces trial evidence contributing to the

evidence gap.
NOTE: OTC = over the counter.
SOURCES: Koehler presentation, December 12, 2016; Cziraky and Pollock, 2015, used
with permission from HealthCore.

data to evaluate the eligibility criteria used in clinical trials and potentially
modify a clinical trial design in the future that expands eligibility. Brown
agreed that real-world data can be useful when determining the eligibility
criteria of clinical trials. Abernethy concurred, adding that researchers are
using the data when designing their clinical trials because “you have a lot
of the key features that will help you pressure test, for example, eligibility
criteria and how to better design your studies.” Sridhara added, “You can use
all of these data to learn more about a disease, which will help us in future
clinical trials to determine what we should be targeting or how we can run
these studies and what should be the control.” Ratain said that such data
also enable detection of adverse drug reactions.
Sridhara noted that prospective observational studies using real-world
data could affect drug labeling. Studies may also randomize the clinicians
rather than the patients. However, she raised the issue of determining end-
points in pragmatic oncology studies. “We cannot really use progression-
free survival or tumor response rate because RECIST criteria are used
by specialists and that is not going to be available in every community
hospital,” she said. Although it is possible to follow patients over time, she
added that in general, the formal recordkeeping and follow-up observed in
traditional clinical trials are not possible with pragmatic trials because the
records of patients are not often carried over when they switch from one
provider to another.
Ratain noted that real-world evidence has been used to establish proof
of concept at Vanderbilt University (Denny et al., 2013). This institution
has a large patient database20 that includes genomic data and diagnostic
coding data on tens of thousands of patients. Researchers have used the
database to discover and validate genetic differences linked to various dis-
orders. “The area where real-world data may be most useful is to discover
and validate patient response biomarkers,” he said. Abernethy agreed, not-
ing that some institutions have processed their EHR data so they can act
as clinical annotation for biospecimens in their biorepositories. “This helps
biologic discovery and understanding and identifying biomarkers,” she said.
Brown stressed that “there is no single data source that is going to
answer all your questions, so thinking about how to match your question
to the data and method you need is critically important. You cannot answer
everything with the data sources we have, but you can usually get pretty far.”
20 See https://medschool.vanderbilt.edu/dbmi/synthetic-derivative (accessed May 18,
2017).

Rockhold added, “It is easy to get seduced by the size of real-world

data, but an approximate answer to a good question is better than a precise
answer to the wrong one. So do not just go somewhere because there is a
lot of information if that information does not have the content that can
answer your question.”
Standardization
Several speakers described the need to ensure that real-world data are
accurate and of high quality. Data need to be reproducible, said Abernethy:
“One of the biggest problems with real-world evidence and the reason why
it is so easily dismissed is because we are so worried about the quality of the
data. So we need to be transparent about the current quality and how we
are going to improve it over time.” Monica Bertagnolli, chief of the Divi-
sion of Surgical Oncology at Dana-Farber/Brigham and Women’s Cancer
Center, added, “We are deluged by data and sometimes the data gathering
that is done is very accurate and other times it is very inaccurate. How do we
understand it and make sense of it, especially since in oncology, the stakes
are so incredibly high?”
Rubin noted that information technology efforts are under way to stan-
dardize and harmonize data, and make them easily transferrable from one
platform to another. He described the efforts of the South Texas Accelerated
Research Therapeutics (START), which uses a high-quality and innovative
information technology infrastructure to ensure accurate and rapid clinical
trials of novel anticancer agents (START, 2017). Bernard Munos, senior
fellow at FasterCures, suggested using a model that constantly merges and
extracts knowledge from raw data without the need for a common template,
which is done by entities such as Google and the National Security Agency,
to find answers to clinical questions. Abernethy said that she has taken an
approach of starting with a parsimonious model that has flexibility to add
new data points as needed over time, such as heart failure data in breast
cancer patients. She pointed out that “there is great excitement about artifi-
cial intelligence and machine learning” that can curate and harmonize data,
but she suggested caution in how those technologies are applied until their
effectiveness for clinical applications is better understood.
Ronald Kline, medical officer of the Patient Care Models Group at the
Centers for Medicare & Medicaid Services’ (CMS’s) Center for M edicare
& Medicaid Innovation, noted that with the Oncology Care Model, par-
ticipating physicians are required to use a data registry that collects ana-

tomical staging information, relevant molecular mutations, and histology

(CMS, 2017). The cancer registry of the Centers for Disease Control and
Prevention is used as the basic format; EHRs are exported to the registry
in an automated fashion when possible, with the remainder of data entered
manually where fields are missing or do not align. He added that EHR com-
panies do not use a common standard for reporting oncology or other dis-
ease data, so CMS set its own data standards for the Oncology Care Model
for the field to use. Rockhold added that unless an agency such as CMS
requires it, standardization of real-world clinical data is unlikely to occur.
Guidance on Standardizing and Using Real-World Evidence

Abernethy commented on the need to clarify the role of real-world
evidence in oncology drug development. She suggested that FDA guidance
on real-world evidence would be helpful, including a delineation of drug
development scenarios to which real-world evidence is most applicable, data
quality requirements, data management and dataset production require-
ments, optimal analytic approaches, and how real-world evidence would
be represented in a drug label. Abernethy added that a transparent multi-
stakeholder process to develop an approach to using real-world endpoints
would be beneficial.
Howard Burris, chief medical officer and president of clinical opera-
tions at the Sarah Cannon Research Institute, noted that many community
oncologists are confounded by the plethora of genetic information that is
often reported for patients and how to interpret it. “In practice you get your
radiology and pathology report back and it is three pages long, but you read
the three lines that are the assessment and conclusion, which is really what
you want when you are busily seeing patients during the day,” he said. He sug-
gested that similar synopses and clinical implications be provided for patient’s
genetic profiling information, perhaps by analytic software built into EHRs.
Finally, Bertagnolli suggested that real-world evidence could be used
to assess not only the impact of a specific drug or therapy, but also the
impact that new treatments have on the use and impact of other treat-
ment modalities, such as surgery and radiation therapy. She noted that
her sarcoma surgery program was radically transformed by the advent of
imatinib to treat gastrointestinal stromal tumors, and she wanted to study
the impact of surgery on metastatic disease now that it can often be well
controlled with targeted treatments.

Patient Privacy
Piantadosi asked if using real-world clinical data in research will neces-
sitate changes to the Privacy Rule that was promulgated under HIPAA.
Brown noted that the HIPAA Privacy Rule is unclear about what types
of data sharing is acceptable, and therefore leads to many inefficiencies in
data management and analysis. “We are so horrified of doing the wrong
thing, and there is plenty of work we could do that we just do not because
it involves linking information; there is no single source of information
good enough. But linking it requires identifiers, and then it becomes a big
mess,” Brown said.
Pentz added that “we have to be careful about how we protect patient
data because there is no privacy if you are on the grid,” but “in the medical
field we have these artificial [regulations] that make it almost impossible for
us to do good things.” She said that we have to modify these regulations so
they are more realistic and provide real abilities to prevent the wrong people
from misusing patients’ medical information while facilitating access by
clinicians and researchers who might actually cure diseases and help people.
Pentz pointed out that some of the patient privacy concerns regarding the
use of real-world data, particularly for prospective pragmatic studies, could
be addressed by a broad consent process, similar to that used for performing
future research on biospecimens.
Expanding Clinical Trial Eligibility

Currently only about 3 to 5 percent of adults with cancer enroll in a
clinical trial in the United States, said Gwynn Ison, clinical reviewer in
FDA’s OHOP. Ison pointed out that one of the goals of clinical trials is
to facilitate the ability to generalize study findings and apply them to all
patients with the disease. “To that end, eligibility criteria are a key compo-
nent of the design of a clinical trial,” she said. These criteria define patients
who are appropriate to receive the investigational treatment, and exclude
patients who might be at greater risk of being harmed by the agent. How-
ever, excessive or overly rigid eligibility criteria may hamper patient accruals
to trials and limit the generalizability of their findings, Ison noted, adding
that this can result in drug labels without adequate guidance for clinicians
on how to deliver the therapy to a more heterogeneous population.
There have been recent attempts to modernize eligibility criteria,
including a multiyear project led by Edward Kim (Kim et al., 2015), Ison

reported. Furthermore, one of the goals of the Cancer Moonshot is to

modernize eligibility requirements. Additionally, Ison noted that at a work-
shop21 held in May 2016, multiple stakeholders, including ASCO, FDA,
NCI, clinical investigators, industry representatives, and patient advocacy
groups, addressed specifically which eligibility criteria potentially could be
relaxed or eliminated within clinical trial protocols. This workshop focused
on the exclusion of patients with HIV, brain metastases, or organ dysfunc-
tion, such as those with kidney, liver, or heart disease; patients with prior
malignancies; and pediatric patients. Working groups presenting at the
workshop recommended major revisions in eligibility requirements in all
these patient groups. These working groups recommended including
• patients with treated or stable brain metastases in all phases of

clinical trials unless there is a compelling safety reason for exclu-
sion. Patients with newly diagnosed active and/or progressive brain
metastases may be included in some trials based on factors related
to the specific cancer and agent under investigation.
• HIV patients in all phases of trials unless there is reason to believe
the drug under investigation may interfere with the control of the
HIV infection. Patients with stable HIV disease—based on their
blood cell counts, history of opportunistic infections, and the status
of their HIV treatment—should be treated with the same standards
as patients without HIV.
• pediatric patients in initial dose-finding trials, especially when there
is a scientific rationale for including them. Pediatric patients ages 12
and older should also be included in late-phase trials for diseases,
such as sarcomas, that span across adult and pediatric populations.
• patients with prior malignancies, depending on the type and time
since cancer treatment, with more liberal time frames than are
currently used to exclude patients with malignancies from trials.
Patients with current non-threatening malignancies, such as non-
melanoma skin cancer, should also be included in clinical trials.
In addition, the working groups recommended using liberal criteria for

creatinine clearance when excluding patients because of suboptimal kidney
function, especially if the agent being tested is not thought to be excreted
21 See https://am.asco.org/daily-news/eligibility-criteria-project-seeks-benefit-patients

primarily by the kidneys. Serum creatinine levels should not be used as an

eligibility determinant. No changes were recommended for the current
criteria for liver or cardiac functioning of eligible patients, although investi-
gators were encouraged to include geriatric patients in clinical trials, as well
as to include specific cohorts of these patients in their studies.
The working group is publishing their recommendations and plans to
promote standardized and inclusive eligibility criteria that can be adopted
by protocols, and to encourage sponsors to follow the recommendations.
FDA also plans to develop metrics to determine whether the recommenda-
tions are being implemented, and will address practical issues and barriers
to implementation when they arise. Finally, the working group plans to
explore more possibilities for expanding eligibility, including revisions to
criteria related to drug washout periods, concomitant medications, and
other factors that may lead to exclusion of elderly patients, Ison reported.
Ison noted that the TAPUR (Targeted Agent Profiling Utilization Reg-
istry) study is unique because it has very broad patient eligibility criteria
(see Box 8).
Kline encouraged the inclusion of more pediatric patients in trials. He
noted that there are no ethical problems with including children in trials,
as this is done all the time for studies of pediatric cancers. “I have two kids
and they mean more to me than my own life, and I think most of us feel
the same way. So how, as an oncology community, do we completely ignore
pediatrics in developing new drugs?” he said.
Keegan added that the recommendation to loosen the eligibility criteria
to include children 12 years and older is based on the understanding that
children in this age group metabolize drugs very similarly to adults, so there
is no reason to exclude them based on their exposure to the drug. She added
that FDA also asks sponsors to consider pediatric use of a cancer drug when
it is near approval,22 and consults with pediatric oncologists both to ensure
that the rights of the children are protected, and to identify areas where a
drug might specifically benefit children with cancer.
Rothenberg added that as more basket and other trials have been devel-
oped that can test an intervention in multiple subgroups, pediatric patients
could be another subgroup added. “This would be a nice way of addressing
that new drugs do not get tested in children early enough, so therefore, any
benefit to them is also delayed. With the vast majority of new drugs that
22 See https://www.fda.gov/drugs/resourcesforyou/consumers/ucm143565.htm (accessed
May 25, 2017).

BOX 8
Targeted Agent Profiling Utilization Registry Study
The Targeted Agent Profiling Utilization Registry (TAPUR)

study is an ongoing Phase II study conducted by the American
Society of Clinical Oncology (ASCO), reported Gwynn Ison, clini-
cal reviewer in the Office of Hematology and Oncology Products
at the Food and Drug Administration (FDA). This study is a non-
randomized clinical trial that is evaluating FDA-approved cancer
drugs in the treatment of patients with advanced cancer whose
tumors have a genomic variant that is known to be a drug target
or to predict sensitivity to a drug. The goal of the trial is to evaluate
the efficacy and safety of various targeted therapies in cancers for
which drugs are currently not FDA approved.
Ison noted that the trial protocol has very broad eligibility cri-
teria. There are no exclusions for patients with prior malignancies,
and patients with HIV are generally included unless an individual
clinician sees a reason for exclusion. Likewise, patients with a per-
formance status scorea of 2 are generally accepted. Patients with
brain metastases will also be eligible to enroll in the trial, as long as
they are not progressing or receiving treatment for the metastases;
they have not experienced a seizure or had a significant change in
their neurological status within 3 months; and they have not used
steroids for at least 1 month.
a The Eastern Cooperative Oncology Group performance score helps clinicians to

assess patients’ performance status and guide treatment decisions. A performance
status score of 2 indicates patients are “ambulatory and capable of all self care but
unable to carry out any work activities; up and about more than 50 percent of waking
hours.” See https://www.ncbi.nlm.nih.gov/pubmed/7165009 (accessed May 22, 2017).
SOURCES: Ison presentation, December 13, 2016; ASCO, 2017.
come along, children are able to tolerate higher doses corrected for body
surface area than adults, so this is something that is very much in our aware-
ness and we are going to try and make that happen,” he said.
Sridhara agreed that subgroup analyses are a way to make trial popula-
tions more heterogeneous. “There is nothing written in the study designs
that say you cannot include, for example, patients with a performance status

score23 of 2, or pediatric or geriatric patients. These are often excluded and

you can always put them in the studies,” she said.
Elad Sharon, medical officer and senior investigator at the NCI, noted
that the NCI has already been encouraging inclusion of HIV-positive
patients in clinical trials for pembrolizumab, as it did with most of its
nivolumab and atezolizumab trials. However, the NCI often finds that
sponsors and investigators resist including patients with HIV, and suggested
that when that happens, FDA should ask sponsors to provide justification.
Ison clarified that although FDA endorses the recommendations to expand
eligibility and can suggest these revised criteria to sponsors, it has no legal
mandate to enforce the criteria.
Pentz commented that there also are other major barriers to clinical
trial participation, including the cost or difficulty of transportation, or tak-
ing time off work, which many low-income patients cannot afford to do.
Collaboration
Several speakers stated that the new drug development paradigm
requires greater collaboration among companies and other stakeholders,
and provided several examples of how companies are sharing their data, and
in some cases, participating in the same clinical trials. Sigal stressed that due
to the growing complexity of cancer diagnostics and treatments, there also is
a growing need for collaboration in the testing of these agents. “Everybody
used to do their own thing individually, but the complexity of the science
and the new models that emerged started to show us we better start to do
this together because if we do not, everybody pays for it,” she said.
Blumenthal noted several collaborative data-sharing efforts to improve
the development of drugs and diagnostics:
• Project Data Sphere LLC, an independent, not-for-profit initiative

of the CEO Roundtable on Cancer’s Life Sciences Consortium,
operates the Project Data Sphere platform. It is a free digital library-
laboratory that provides one place where the research community
23 The Eastern Cooperative Oncology Group performance score helps clinicians to assess
patients’ performance status and guide treatment decisions. A performance status score of
2 indicates patients are “ambulatory and capable of all self care but unable to carry out any
work activities; up and about more than 50 percent of waking hours.” See https://www.ncbi.
nlm.nih.gov/pubmed/7165009 (accessed May 22, 2017).

can broadly share, integrate, and analyze historical, patient-level

data from academic and industry Phase III cancer clinical trials.
It is open to researchers that apply for, and are granted, status as
an authorized user (Project Data Sphere LLC, 2017). “There are
lots of inferences that can be made from very old legacy datasets,”
Blumenthal said.
• The FNIH Volumetric CT for Precision Analysis of Clinical Trial
results (VolPACT), which seeks to analyze volumetric CT imag-
ing trial data contributed “in-kind” from completed Phase II solid
tumor trials to improve quantitative prediction of Phase III results,
including metrics of response to therapies (FNIH, 2017).
• Immune-related Response Evaluation Criteria In Solid Tumors
(irRECIST), which was developed by the Cancer Immunotherapy
Consortium, formerly the Cancer Vaccine Consortium, in col-
laboration with the International Society of Biological Therapy of
Cancer (Wolchok et al., 2009).
• The Blood Profiling Atlas in Cancer is composed of representatives
from government, academia, pharmaceutical, and diagnostic com-
panies and aims to “accelerate the development of safe and effective
blood profiling diagnostic technologies for patient benefit.” The
group will launch a Blood Profiling Atlas in Cancer pilot to aggre-
gate, harmonize, and make freely available raw datasets derived
from circulating tumor cells, circulating tumor DNA, and exosome
assays, as well as relevant clinical data and sample preparation and
handling protocols from 13 studies (Bhan, 2017; BloodPAC, 2017).
Public–private partnerships that engage in collaboration with drug

companies are valuable and constitute “a different way of doing business,”
Sigal said. “It is a partnership and that means behavior has to change on
all sides, and it has to be patient driven.” She gave the example of the
Lung-MAP study, where there was a compelling need to test a variety of
treatments in rare subsets of patients. What made this trial particularly
attractive to sponsors was that FDA approved it as a registration trial. The
NCI was a catalyst, but the Cooperative Groups of the NCI Clinical Trials
Network, patient groups, and the companies all collaborated for this trial.
“Collaboration among all sectors is very important and it is a way to get
us there faster. Necessity drives us to collaborate because we need all hands
on deck,” she said. Scott Fogarty, diagnostics partner at Thermo Fisher

Scientific, suggested that it would be valuable to have participation by the

diagnostic industry in these collaborations as well.
Schilsky remarked that “one of the challenges we consistently face is
aligning the culture of drug development with the science of drug develop-
ment. The science is typically far out ahead of the cultural change that is
necessary. The things that seem to drive changes to the culture ultimately
come down to: what is the medical and business opportunity, what is the
competition, what is the risk tolerance of the sponsor, how willing are
people to fail at various points of the process, and what are the consequences
of doing so?”
Rubin noted that “data sharing and cooperation for industry particu-
larly is important because we have lots of data and in general we do not like
to share.” However, he noted that there is extensive data sharing occurring
among industry to develop alternatives to RECIST, including protocols
for assessing a drug’s impact on a tumor. “Everyone mentions this need for
an alternative to RECIST, but they all do it slightly differently so everyone
shared their protocols and there was a consensus gathering around how
protocols should be written to do this,” he said. The guidelines developed
from this work have now been published (Seymour et al., 2017).
Another major sharing endeavor undertaken by industry is the devel-
opment of a standardized PD-L1 diagnostic test that can be used to assess
which patients might be eligible for certain cancer immunotherapy drugs.
FDA recognized that companies developing anti-PD-L1 drugs were also
developing assays for the ligand, and that each assay was different. “The
concern was that there would be a lot of confusion around how pathologists
would handle” these different diagnostic tests, Rubin said. Consequently,
ASCO, FDA, and the American Association for Cancer Research con-
vened a workshop to address this issue, at which an industry workgroup
volunteered to develop a blueprint proposal of potential solutions using
non-small cell lung cancer as the first test case (FDA, 2017a). This resulted
in the Blueprint Programmed Death Ligand 1 Immunohistochemistry
Assay Comparison Project, in which 39 lung cancer specimens were stained
and analyzed with each assay developed by different companies (Hirsch
et al., 2017). Rubin said this study “will be helpful to the community in
understanding the [level of ] concordance across the various assays,” adding
that “it is another example of where industry is sharing. It may take some
effort but it can happen.” Such sharing has to be done voluntarily, McKee
noted, as FDA is prohibited by law from sharing any company’s proprietary
information.

In addition to duplication of efforts in PD-L1 diagnostic tests, there

is also a redundancy of 22 different PD-L1 inhibitors sponsored by differ-
ent companies, Redman noted. Rothenberg said PD-L1 inhibitors were
showing such extraordinary promise in early tests that every drug company
wanted one in their portfolio, especially because a combination therapy
with PD-L1 inhibitors was thought to be likely in the future. However,
there was also recognition that the market could not support so many
inhibitors: for example, Rothenberg noted that there are only four or five
drugs on the market to treat high cholesterol, which is much more common
than the cancers that PD-L1 inhibitors target. “You could ask me to design
the most efficient trial, but it will not be efficient if it is being repeated
22 times,” he said. Driven by projections of market demand and a desire to
share their expertise, Pfizer and Merck KGaA collaborated to develop the
PD-L1 inhibitor avelumab, said Rothenberg. Sigal added that FDA is also
concerned about this redundancy because there are not enough patients to
test all of the inhibitors, and suggested a master protocol in which mul-
tiple treatments from multiple companies could be tested simultaneously.
However, she said that industry was reticent to use such a model, probably
because some companies were further along the development path with
their inhibitors than others.
Blumenthal said companies have less incentive to share safety data than
efficacy data, and suggested engaging in partnerships to identify and study
biomarkers that could potentially predict rare but serious toxicities. Sigal
noted that such sharing of information is especially critical with cancer
immunotherapies, in order to discern important safety signals earlier. A
number of workshop participants discussed barriers that discourage such
sharing. For example, Rubin cited a lack of resources devoted to sharing
data: “We have to convince people to carve out some internal resources to
work on this data-sharing piece, because it is the right thing to do,” he said.
An additional barrier, raised by Rubin and Blumenthal, is the possibility
of finding a different, conflicting result when efficacy data are reanalyzed.
Some participants thought the barriers could be addressed, however, and
Blumenthal cited the Blood Profiling Atlas in Cancer as an encouraging
initiative in support of data sharing.
Blumenthal agreed, adding that for “hot data” such as immunotherapy
data, “there probably is some consternation that if they share all their data,
someone will misinterpret and reanalyze it and come up with some other
[incorrect] answer.” He noted that barriers to sharing may arise within the
legal departments of companies and research institutions. But with the

Blood Profiling Atlas in Cancer, he said he has been encouraged by the

degree of sharing, and how those roadblocks have been overcome.
POTENTIAL POLICY OPPORTUNITIES

Several workshop participants discussed recent policy changes and
new opportunities to improve cancer drug development, including
innovations at CMS, FDA’s Oncology Center of Excellence (OCE) and
Expanded Access Program, and the Cancer Moonshot. A number of
workshop participants also considered other potential policy strategies,
such as some of the recommendations made by the Blue Ribbon Panel of
the Cancer Moonshot.
Innovations at CMS
Kline outlined the newly instituted parallel review process of FDA
and CMS for medical devices.24 Such parallel reviews should alleviate the
lag time between FDA marketing approval for a device or diagnostic and
a national coverage determination by CMS, enabling reimbursement for
clinical use concomitant with market approval. “It is a CMS–FDA col-
laboration to move things forward on a more timely basis,” Kline said.
As previously mentioned, CMS has also developed an Oncology Care
Model, which is an episode-based payment model25 for 6 months of care,
and includes performance-based payments when clinicians achieve various
quality measures (CMS, 2017). “This provides incentives to use high-value
drugs and we are hoping to push the field toward value-based reimburse-
ment,” Kline said.
FDA Oncology Center of Excellence

Woodcock and Sigal reported on FDA’s OCE, which is expected to
avert regulatory delays by fostering connections among three separate divi-
sions in the agency (FDA, 2017c,d). OCE will support integrated evalua-
24 See https://www.federalregister.gov/documents/2016/10/24/2016-25659/program-for-
parallel-review-of-medical-devices (accessed May 18, 2017).

25 Episode-based payment is when “reimbursement for medical services delivered during
defined episodes of care is bundled together.” See http://www.nejm.org/doi/full/10.1056/

NEJMp1105963#t=article (accessed May 18, 2017).

tion of new treatments by coordinating the agency’s expertise in regulatory

science, small molecules, biologics, devices, and diagnostics. The OCE will
make oncology the first disease area to have a coordinated clinical review of
drugs, biologics, and devices across the agency’s three medical product cen-
ters, and it is expected to make regulatory review more seamless, particularly
for combination treatment regimens, said Woodcock.
Woodcock underscored the benefits of integrated regulatory evaluation
in an increasingly sophisticated and complex drug development environ-
ment. She also noted that in order to facilitate understanding of novel
research and to incorporate the views and priorities of a variety of stakehold-
ers, OCE is also expected to have intensive interaction with the scientific,
medical, and patient communities.
Expanded Access
Steven Lemery, lead medical officer in the Division of Oncology
roducts 2 at FDA’s OHOP, provided a summary of FDA’s Expanded
P
Access Program. This program enables patients to receive investigational
agents if they have a serious or immediately life-threatening disease or con-
dition and meet all of the following conditions26:
• There is no comparable or satisfactory alternative therapy.

• The potential benefit of the new agent justifies the risks.
• Providing access will not interfere with clinical investigations that
could support marketing approval of the agent.
Expanded access is intended to provide compassionate use of an inves-

tigational therapeutic agent for a patient with no other treatment options,
Lemery stressed. Most requests are single-patient requests made by clini-
cal investigators who have a letter of cross-reference from the commercial
sponsor allowing access for a single patient. FDA also has provisions for
an intermediate-sized population to receive expanded access, usually at the
end of the drug development process. Expanded access protocols can also
be submitted by commercial sponsors as part of their ongoing IND testing.
In order for expanded access to be granted, patients, their clinicians, and
the drug’s sponsor must all be willing to participate, and the clinician must
26 See https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=
312.305 (accessed May 22, 2017).

submit a form to FDA (Jarow et al., 2017). Expanded access also requires
IRB consent except in emergency cases.
Of 1,332 single-patient expanded access requests made to FDA for
oncology drugs between 2014 and 2016, only 1 request was declined by
the agency, and 4 were withdrawn prior to an FDA decision. About two-
thirds were for drugs that subsequently were approved for market (Lemery
et al., 2016).
Although most expanded access requests are not intended to support
drug development or provide information about drug performance, in some
instances data from expanded access cases could be used to support approval
of a drug, according to Lemery. He noted that FDA’s OHOP approved
four drugs for oncology indications based in part on data from the use of
these drugs in its expanded access program. Two drugs were to provide a
treatment alternative for patients who had to discontinue the standard che-
motherapy because of toxicity, and two others were used to treat pediatric
patients, with one drug already approved for adults. These drug approvals
depended in part on safety, survival, or pharmacodynamics data collected
from patients who were granted expanded access to the drugs, Lemery
reported. He said the expanded access program could be useful in other
cases as well, such as for patients with rare cancers or who have rare genetic
mutations targeted by the drug. Lemery noted that often it is not feasible
to enroll patients with rare cancer mutations into a clinical trial because
they do not live in a location where the trial is offered, “so expanded access
might be a good way to obtain information about the use of your drug in
these rare populations. You could maybe get data on patients who do not
meet eligibility criteria, but can give you some real-world experience. You
may not be getting all the data you would get in a clinical trial, but you can
at least get scans and demographic information,” he said. Theoret agreed,
noting that expanded access could be useful once an investigational new
drug has Breakthrough Therapy designation, for those patients who would
like to receive the drug, but are unable to enroll in a clinical trial testing it.
“As development programs receive their Breakthrough Therapy Designa-
tion, it is often very early in the discussions that we should start thinking
about what their expanded access program is going to look like,” he said.
The expanded access program has not posed undue risks for drug
development, according to a study of the program over a 10-year period.
This study found that with more than 10,000 expanded access requests,
only two commercial development programs involving more than 1,000
patients were placed on hold or partial hold due to a serious adverse event

observed in a patient who received the drug via expanded access. One hold
was removed months later and the other, a partial hold limited to a specific
patient population, was eventually removed as well (Jarow et al., 2017).
Another study of failed oncology trials found that none of these studies
failed in clinical development due to data collected from expanded access
cases (Khozin et al., 2015).
Ison noted that many informed consents are based on the side effect
profiles in populations being studied and are not always applicable to those
subjects who are applying for expanded access. Therefore, she cautioned
that patients and clinicians be accurately informed of the benefits and risks
of an experimental intervention and suggested that clinicians be proactive
about informed consent.
Cancer Moonshot
Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University, presented the recommenda-
tions of the Cancer Moonshot’s Blue Ribbon Panel related to improving
cancer drug development. She noted that the Cancer Moonshot was initi-
ated based on the recognition that there has been unprecedented progress
in cancer research recently, but that there is insufficient coordination, data
sharing, and funding to reap the benefits of this progress. “The science is
ripe, but the progress made in getting it to benefit patients is too slow and
lacks efficient coordination,” Jaffee stressed.
The overarching goals of the Cancer Moonshot are to accelerate prog-
ress in cancer research; encourage greater cooperation and collaboration
among academia, government, and the private sector; and enhance sharing
of data (The White House, 2016). To carry out its goals, a federal task force
was convened to determine policy measures to pursue, and a Blue Ribbon
Panel was convened to delineate research goals.
The federal task force delineated several policy goals, including the
following:
• Support greater access to new research, data, and computational

capabilities.
• Improve patient access to clinical trials and standard of care.
• Identify and address any unnecessary regulatory barriers to drug
development and approvals and consider ways to expedite adminis-
trative reforms.

• Explore opportunities to develop public–private partnerships and

increase coordination of the federal government’s interactions with
the private sector with regard to drug development, treatment
access, and information systems.
More specific strategic goals are to expand use of mobile devices and
create tracking systems for patients to unleash the power of data, deter-
mine best practices for consent, develop a seamless data environment with
open platforms, and develop the necessary workforce. The task force also
recommended bringing new therapies to patients faster by modernizing
eligibility criteria for clinical trials, and developing trials for patients with
specific genetic defects rather than tissue-specific types of cancer, such as
the NCI-MATCH trial, and using real-world evidence.
The Working Groups of the Blue Ribbon Panel made several recom-
mendations focused on research that also have policy implications in drug
development (Cancer Moonshot Blue Ribbon Panel, 2016):
• Enlist patients in a federated network that includes patient tumor

profiling data, and “preregister” patients for clinical trials in which
their biopsy tissues are analyzed to learn which features predict
outcomes.
• Organize a network to discover and evaluate novel immune-based
approaches for adult and pediatric cancers, and eventually develop
vaccines for prevention.
• Create an ecosystem to collect, share, and interconnect datasets.
• Support research to accelerate development of guidelines for man-
agement of patient-reported symptoms to improve quality of life
and adherence to treatment regimens.
• Create a human tumor atlas that catalogs genetic lesions and inter-
actions among tumor cells, immune cells, and other cells in the
tumor microenvironment.
• Develop new enabling technologies, such as liquid biopsies and
multiplex analyses of the tumor microenvironment, to accelerate
testing of therapies and tumor characterization.
Blue Ribbon Panel working groups also recommended demonstration

projects, including a national pediatric immunotherapy translational sci-
ence network to facilitate testing of new immunotherapies in childhood
cancers, and a tumor pharmacotyping demonstration project to help

discern biomarkers that reveal the most effective therapeutic agents for
individual patients.
Jaffee also described current ongoing Cancer Moonshot programs,
including the following components (NCI, 2017b):
• NCI Drug Formulary that will leverage lessons learned from the
NCI-MATCH trial to forge relationships with 20 to 30 public–
private partners to expedite researcher access to investigational
agents and approved drugs for combination trials. One goal is to
reduce negotiation time for collaborations.
• Application Programming Interface, an endeavor in which several
third-party innovators, including Smart Patients, Synapse, Cure
Forward, and Antidote, are participating to build applications, inte-
grations, search tools, and digital platforms to disseminate clinical
information to the community.
• Strategic Computing Partnership between the Department of
Energy (DOE) and the NCI to accelerate precision oncology, that
is, getting the right treatments to the right patients. There are three
new pilots to apply the most advanced supercomputing capabilities
to analyze data from preclinical models of molecular interaction data.
• Open-access resource for sharing cancer data via the Genomic Data
Commons. Foundation Medicine is participating in this endeavor
and hopes to double the total number of patients who provide
information to this database. This will provide a mechanism for
broad sharing and partnerships among government agencies,
academia, and industry that will be complemented by the NCI’s
Genomics Cloud Pilots, which will provide imaging, proteomics,
and immunotherapeutics datasets.
• Public–private Partnership for Accelerating Cancer Therapies
that involves collaborations of 12 biopharmaceutical companies,
research foundations, philanthropies and the FNIH. This partner-
ship will fund precompetitive cancer research and share broadly
all data generated for further research, with initial focus areas
that include identifying and validating biomarkers for treatment
response and resistance to cancer therapies, clinical trial platforms
for combination therapies, and predictive modeling approaches and
therapies for rare cancers.
• Applied Proteogenomics Organizational Learning Outcomes,
which is a partnership between DOE, the NCI, and the Depart-

ment of Veterans Affairs to use new technologies to rapidly identify

new targets and pathways for detection and intervention. This
initiative plans to develop a national biospecimens bank on which
researchers can conduct proteomic analyses over time as patients
respond to or become resistant to treatments.
Future planned initiatives from the Cancer Moonshot include the

development of predictive computer algorithms to rapidly develop, test,
and validate preclinical models predicting drug response via a partnership
between the NCI and DOE. Another initiative will build computational
collaborative relationships, beginning with a partnership among the Uni-
versity of California, Intel, IBM, and GE to create a virtual data ecosystem.
The Blue Ribbon Panel also identified several current policy barriers
to drug development that were not covered in its scope, but will need to
be addressed in order to advance its recommendations (Cancer Moonshot
Blue Ribbon Panel, 2016):
• coverage of the costs of routine care and clinical trials for patients
with cancer
• uniform patient consent forms and patient access to data
• use of a central IRB, data sharing among federal agencies, and
adequate clinical trial site evaluation processes
• improved delivery of cancer care in communities through reducing
economic burden of clinical trial enrollment on patients and prac-
titioners, sharing EHR data, and releasing best practices for state
vaccine registries
• incentives for development of pediatric cancer drugs, especially
molecularly targeted therapies
• data-sharing mechanisms, including standardization and harmoni-
zation of data, licensing, and sharing among the private sector
EXAMPLES OF INNOVATIONS IN
CANCER DRUG DEVELOPMENT
A number of workshop speakers discussed examples of drug develop-
ment pathways and clinical trial designs reflective of the move toward a
new drug development paradigm for oncology. These examples included
the development of

• crizotinib,
• avelumab,
• pembrolizumab,
• vemurafenib, and
• EGFR T790M inhibitors.
Development of Crizotinib
Rothenberg said that the development of crizotinib serves as a good
example of how new scientific information led to an amendment in the
clinical trial protocol. The strong signal seen in first-in-human tests, com-
bined with the understanding of its molecular mechanism of action, led to
crizotinib’s rapid approval, Rothenberg added.
Crizotinib targets c-MET, a molecular signaling pathway that is
thought to be mutated and activated in a large proportion of patients who
became resistant to targeted therapies. Thus, Rothenberg said that “there
was a good preclinical rationale for this drug.” In a Phase I test, 3 out of 37
patients responded to crizotinib, which was not considered a strong signal.
However, it was later discovered, because of preclinical research from an
unrelated group, that all three responders overexpressed a fusion mutation
of anaplastic lymphoma kinase (ALK).27 Therefore, it became apparent that
in addition to targeting c-MET, crizotinib inhibits ALK.
This information led Pfizer to work with FDA to develop a reliable
companion diagnostic for crizotinib to detect the ALK mutation. In addi-
tion, Pfizer expanded the cohort of patients expressing the ALK fusion in
the Phase I study, and a Phase II trial was opened to test the drug in lung
cancer patients with the ALK mutation (Malik et al., 2014). Then Pfizer
opened two Phase III trials simultaneously: One to test crizotinib as a
second-line treatment for lung cancer patients versus single-agent chemo-
therapy (Shaw et al., 2013); the other was to test it as a first-line treatment
in lung cancer patients versus combination chemotherapy (Solomon et al.,
2014).
While the Phase III trials were opening, it was discovered that mutated
versions of the ROS1 gene, another tyrosine kinase closely related to ALK,
also were prevalent in patients with lung cancer. So Pfizer amended the
Phase I trial to include lung cancer patients with this mutation. Accrual
27 This triggers a molecular signaling pathway that fosters the growth and survival of tumor
cells (Genentech USA Inc., 2017).

FIGURE 10 The crizotinib drug development timeline from 2006 to 2011.
NOTE: ALK = anaplastic lymphoma kinase; CDx = companion diagnostic; FDA = Food
and Drug Administration; NSCLC = non-small cell lung cancer; RP2D = recommended
Phase II dose.
SOURCE: Rothenberg presentation, December 12, 2016.
to the Phase I, II, and III trials occurred simultaneously, as can be seen in
Figure 10, and was completed in 2011.
In August 2011, FDA approved crizotinib for the treatment of patients
with locally advanced or metastatic non-small cell lung cancer that is ALK-
positive, about 6 years after it was first tested in patients (FDA, 2011). FDA
additionally approved crizotinib for ROS1-positive mutations in 2016 on
the basis of the Phase I and Phase II data.28
Rothenberg said a number of lessons can be learned from the crizotinib
drug development experience, including how strong signals of activity can
be seen in Phase I studies and that expansion cohorts in Phase I trials can
provide an opportunity to rapidly and efficiently test a clinical hypothesis
when there is a good scientific understanding of the disease and the drug.
Rothenberg also emphasized that Phase I, II, and III trials of the same inves-
28 See https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm490329.htm

tigational agent can be run simultaneously when strong signals of efficacy

are detected and confirmed. This can result in an agent with truly trans-
formational levels of activity reaching the market years ahead of schedule,
particularly if the data are sufficiently rigorous to earn regulatory approval
before Phase III trials are initiated, he said.
Development of Avelumab
Rothenberg also reported on the development of avelumab, which is
an immunotherapy checkpoint inhibitor of PD-L1. He noted that prior
to avelumab entering clinical testing in 2013, the populations and diseases
most likely to respond to this type of treatment were known from clinical
studies of similar checkpoint inhibitors. This led Merck-Serono to test it
in a Phase I study that had multiple cohorts of likely responders, with the
assumption that the cohorts showing the most response would be expanded.
Currently, there is an expansive international clinical trial program explor-
ing the use of PD-L1 inhibition with avelumab to treat multiple types of
cancer, such as solid tumors, gastric cancer, Merkel cell carcinoma,29 and
non-small cell lung cancer (Pfizer, 2015). Multiple actions were then taken
for different indications following this Phase I study:
• The strong signal seen in Phase I studies in the absence of major

safety issues led the sponsor to skip Phase II and III trials and to
directly seek approval of the drug for Merkel cell carcinoma, a dis-
ease for which there is an unmet medical need.
• A Phase IB study was undertaken combining avelumab with the
tyrosine kinase inhibitor axitinib for metastatic kidney cancer
(NIH, 2017b). Because each of these drugs had been tested previ-
ously in a large number of patients, there was abundant evidence
of efficacy and safety, and low probability of overlapping toxicities
that would cause major safety issues, according to Rothenberg. In
addition, there was a strong scientific rationale for the combination
to have synergistic efficacy. Positive results in this Phase IB trial are
expected to lead directly to a Phase III trial of the combination,
he said.
29 On March 23, 2017, FDA granted accelerated approval to avelumab for the treatment of
patients 12 years and older with metastatic Merkel cell carcinoma. See https://www.fda.gov/
Drugs/InformationOnDrugs/ApprovedDrugs/ucm547965.htm (accessed May 18, 2017).

• A Phase IB study was also undertaken combining avelumab with

another immunotherapy to test the combination therapy for over-
lapping side effects (NIH, 2017a). This Phase IB study could prog-
ress to Phase II and then Phase III studies or proceed directly to a
Phase III study, depending on the results from the Phase IB study.
The development of avelumab demonstrates that multiple paths may

be pursued following a Phase I expanded cohort study. However, signifi-
cant resources must be committed for long periods of time for this type
of development, Rothenberg noted, making it unsuitable for most novel
agents about which little is known. In addition, FDA has taken steps to
limit the size of expansion cohorts and to require specific hypotheses to be
tested in them. Despite those caveats, he noted that “successful application
of this strategy can shorten clinical development substantially and speed
new medicines to the marketplace.”
Development of Pembrolizumab
Rubin described the development of the PD-L1 targeted immuno
therapy pembrolizumab. This drug is an example of how a single-arm Phase I
dose-expansion trial involving patients with different types of solid tumors
led to FDA approval. The Phase I protocol prespecified expansion of the
cohort of patients with melanoma if high response rates were demonstrated.
Initial striking responses in melanoma patients led to the expansion of that
cohort, including patients who had previously not responded to ipilimumab,
another cancer immunotherapy, as well as lung cancer patients.
Additional patients were added after an analysis of the melanoma
patients in the Phase I study found that those who had progressed on
ipilimumab might respond to pembrolizumab. A further expansion tested
the appropriate dose in both melanoma and lung cancer patients. Finally,
after initial analyses demonstrated that most patients who responded to
pembrolizumab had high PD-L1 expression levels, Merck KGaA began
developing a companion diagnostic, which involved adding more patients
within the Phase I study. While the Phase I trials were ongoing, FDA
granted pembrolizumab Breakthrough status.
Rubin noted that “we were moving so fast that we did not have the
results back from the randomized dosing study when we had to take cohorts
into our Phase III studies so those were also tested for dose and schedule.”
Ultimately, nine amendments were made to the Phase I protocol and FDA

ultimately awarded three approvals: an accelerated approval for patients

with ipilimumab-refractory melanoma; an accelerated approval for
patients with previously treated non-small cell lung cancer whose tumors
that had high expression of PD-L1; and approval of the first companion
diagnostic test for cancer immunotherapy (FDA, 2014b, 2016; Merck,
2015). Although FDA required confirmatory studies, p embrolizumab
was approved just 3 years after it was initially tested in humans. While the
study was considered adequate for initial approval in the United States,
Canada, and Australia, it was not deemed sufficient in the European
Union, where the European Medicines Agency (EMA) wanted to see data
from a randomized controlled trial.
Rubin noted several challenges with adaptive trial design that were
encountered in the development of pembrolizumab. It created operational
burden due to rapid accrual in multiple cohorts and increased manufac-
turing demands. Multiple amendments also generated complexity, and
required experts in multiple cancer fields to collaborate. “There is complex-
ity in bringing together separate groups in a single site to work together
on a single protocol,” Rubin said. Finally, data analyses for simultaneous
hypotheses and data curation from multiple sites presented challenges.
Despite the challenges, Rubin stated that an adaptive, multiple expan-
sion cohort design, as used to test pembrolizumab, can efficiently enable
testing of multiple hypotheses about dose, biomarker, and patient popu-
lation, and can be performed with sufficient rigor to support regulatory
filings. Most importantly, it can accelerate development and approval for
transformative drugs with strong efficacy signals by avoiding delays in ini-
tiating separate trials for each cohort and hypothesis.
He concluded that single-arm Phase I trials may be especially benefi-
cial for quickly evaluating new cancer immunotherapies that are expected
to be effective for multiple tumor types, and thus require methods “where
one could have an efficient path to approval rather than requiring large,
randomized studies for every single tumor type.” He added that “when
you are seeing tremendous efficacy in a single cohort, it can then be very
difficult to randomize patients against a standard of care, particularly when
the standard of care is not very effective.”
Development of Vemurafenib
Flaherty reported on the development of vemurafenib, which illus-
trates the advantages of conducting serial biopsies on patients to determine

whether the drug is acting on its intended target, and to molecularly define
resistance when it develops. Vemurafenib targets the BRAF protein, which
is mutated in 60 percent of melanoma patients, as well as in some colon
and other cancer patients. In vitro studies suggested no plateau in the
dose–response relationship, so in the first Phase II dosing studies, Flaherty
examined not only efficacy, but also biomarker status to verify drug activity
and determine effectiveness at lower doses. Melanoma patients had variable
responses to the drug, but because it was so efficacious in a subset of patients
and there was great unmet medical need for an advanced melanoma treat-
ment, FDA agreed to a single-arm Phase II study in melanoma patients,
rather than randomizing patients to receive standard of care (Sosman et al.,
2012). In August 2011, after conducting a Phase III trial, FDA approved
vemurafenib for the treatment of patients with unresectable or metastatic
melanoma with the BRAF V600E mutation (NCI, 2013). At the time,
there was some debate about whether the randomized Phase III trial was
necessary or ethical, Flaherty noted (Hey and Truog, 2015).
Unfortunately, the responses melanoma patients had to v emurafenib
were often transient. To assess how patients were responding to
vemurafenib, the investigators conducted biopsies before and during their
treatment, as well as when their tumors progressed. These biopsies showed
that the drug consistently blocked its intended target, despite variability
in patients’ durability of responses to it, and that only patients receiving
high doses of the drug responded. “The serial tumor biopsy data were
quite informative because they showed there was a fairly homogeneous
molecular effect on the target pathway that was lost over time when we
did biopsies at the time of relapse,” Flaherty stated.
His analysis of the biopsies suggested that tumors in the relapsed
patients had activated MEK. The analyses therefore suggested a com-
bination therapy for future trials. Accordingly, Flaherty began treating
melanoma patients in 2010 with BRAF-MEK combination therapy in a
Phase I study. Phase II and III trials of a MEK inhibitor in combination
with vemurafenib subsequently demonstrated improved overall survival of
melanoma patients (Ugurel et al., 2016).
Three randomized Phase III trials have now demonstrated that the
combination of a BRAF inhibitor (vemurafenib or dabrafenib) with a MEK
inhibitor is better than BRAF inhibitor therapy alone. Flaherty summed
up his presentation on BRAF inhibitors by stressing, “Interrogating what
happens in patients’ tumors, until the day comes that we can do it purely in
blood, is important and impactful in driving forward benefit in the field.”

The BRAF-MEK combination therapy shows durable responses in patients,

with 3-year overall survival rates of as high as 44 percent (Flaherty et al.,
2016). This approach suggested a biologically relevant and effective combi-
nation therapy that may otherwise have not been discovered.
T790M EGFR Inhibitors

Most patients with non-small cell lung cancer that is resistant to treat-
ment with EGFR inhibitors have a single mutation called EGFR T790M
(Kobayashi et al., 2005; Yun et al., 2008), reported Pasi Jänne, director of
the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Insti-
tute. Osimertinib targets this mutation and was developed quickly and effi-
ciently due to solid understanding of the underlying mechanism of action,
and to innovative trial design combined with the Breakthrough Designation
by FDA. He discussed the development pathway for osimertinib with that
of rociletinib, an EGFR T790M inhibitor whose clinical development was
stopped (see Box 9).
He pointed out that in the Phase I/Phase II study of osimertinib, small
groups of patients whose tumors were resistant to EGFR inhibitors were
tested with escalating doses of drug as they would be in a typical Phase I
clinical trial. However, the protocol stipulated that if any groups showed
response to osimertinib, these cohorts would be expanded and patients
would be tested for the presence or absence of T790M (Jänne et al., 2015).
“This allowed in a very rapid and expeditious manner to both identify effec-
tive doses, and secondarily to evaluate the efficacy of the agent,” Jänne said.
The T790M-positive patients were shown to have high response
rates, with about half of them responding to the drug. This led to an FDA
Fast-Track Designation, followed by a Breakthrough Therapy Designa-
tion. Randomized Phase III studies of osimertinib showed the same high
response rates as seen in previous studies (Mok et al., 2017). Furthermore, a
Phase I study in patients with treatment-naïve lung cancer also showed high
response rates of 77 percent, leading investigators to conduct a Phase III
trial that randomized patients to receive osimertinib or two other EGFR
inhibitors. Results are expected to be published in 2017. Finally, patients
treated with osimertinib also showed significant neurologic improvement in
the central nervous system, which is important given that lung cancer often
metastasizes to the brain, Jänne noted (Yang et al., 2016).
Because of a well-defined biological underpinning; innovative, flexible
trial design; and clear biomarkers to identify patients most likely to benefit

BOX 9
A Contrasting Development Story of Rociletinib,
a T790M EGFR Inhibitor
In contrast to osimertinib, the development of another EGFR

T790M inhibitor, rociletinib, was discontinued. Pasi Jänne, direc-
tor of the Lowe Center for Thoracic Oncology at the Dana-Farber
Cancer Institute, said that a good summary of the clinical develop-
ment pathway of rociletinib is presented in the April 2016 Oncologic
Drugs Advisory Committee Meeting.a Clinical trials evaluating
rociletinib were initiated in 2011, approximately 15 months prior to
those for osimertinib. Rociletinib was initially predicted to have an
activity similar to that later seen with osimertinib, and enthusiasm
for the treatment and the promising results of initial clinical testing
led to publication in the New England Journal of Medicine (Sequist
et al., 2015).
However, it later became clear that the results for rociletinib
were calculated using unconfirmed partial response rates, rather
than confirmed response rates (Sequist et al., 2016). Rociletinib
also entered clinical trials before the drug’s structure and formula-
tion were optimized, which made it difficult to predict the pharma-
cokinetics and its effects on patients. In addition, doses tested in
clinical trials showed significant toxicity, including arrhythmias and
hyperglycemia. The short half-life of the drug required patients to
receive more treatments to maintain concentration of the drug in
a patient’s system and increased the likelihood of toxicities. Later,
data demonstrated that the hyperglycemia and other side effects
were due to a genetic polymorphism found in 40–60 percent of
U.S. African Americans, Caucasians, and Hispanics that leads to a
decreased ability to breakdown a toxic rociletinib metabolite.
a See https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/OncologicDrugsAdvisoryCommittee/ucm486395.htm (accessed May 26, 2017).
from the drug, osimertinib was very quickly brought to market and made
available to patients. FDA granted accelerated approval for osimertinib
in 2015,30 just 4 years after it was first synthesized, and 2 years after the
30 See https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm472525.htm

FIGURE 11 Key milestones in the (A) discovery and (B) development of osimertinib.
NOTES: The first patient was treated in March 2013 and the first approval was Novem-
ber 2015. AURA = trial of AZD9291; AZ = AstraZeneca; CE-IVD = Conformité
Européene in Vitro Diagnostic; ctDNA = circulating tumor DNA; EGFR = epidermal
growth factor receptor; EU = European Union; FDA = Food and Drug Administration;
PMA = premarket approval; PMDA = Pharmaceutical and Medical Devices Agency in
Japan.
SOURCES: Jänne presentation, December 12, 2016; Yver, A., Osimertinib
(AZD9291)—a science-driven, collaborative approach to rapid drug design and
development, Annals of Oncology, 2016, 27(6):1165-1170, by permission of Oxford
University Press.
first clinical tests of the drug (see Figure 11). “This was one of the fastest
oncology drug approvals ever,”31 Jänne stated.
31 On March 30, 2017, FDA granted regular approval to osimertinib. See https://www.
fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm549683.htm (accessed May 22,

2017).

WORKSHOP WRAP-UP
Schilsky said that improving the drug development paradigm in oncol-
ogy is critical, given that cancer will soon become the leading cause of death
in the United States. “There are more cancer cases than ever before despite
our progress in treating cancer because of the ag[ing] of the population and
the increasing prevalence of the disease,” Schilsky said. He said rapid prog-
ress in cancer research has led to a better biological understanding of cancer
that has fostered the identification of new drug targets, including genetic
aberrations that stimulate tumor growth, and those involved in the immune
system’s response to tumors. New classes of cancer drugs often have a wider
range of doses that are both more effective and less toxic than previous
chemotherapies. There also has been rapid development of biomarker tests
to stratify and characterize patient populations with differential prognoses
and sensitivities to treatment. In addition, there are new sources of data,
and although they may lack the precision and accuracy of clinical trial data,
Schilsky noted that this challenge could be overcome through methodologi-
cal tactics. Therefore, he said, “We should not make more of the distinction
than we need to between real-world data and clinical trial data.”
FDA recognizes the novel strategies being used in oncology drug devel-
opment and supports improvements aimed at making the process more effi-
cient and expedient, Schilsky noted. FDA also has broader authority than
it did in the past with passage of the 21st Century Cures Act, and despite
some concerns voiced that this Act might make FDA too permissive at the
sacrifice of patient safety, Schilsky stressed that “I do not expect FDA would
suddenly abandon all of its standards for regulatory approval.”
Given all the recent changes in cancer drug development and its regula-
tion, much of the discussion in the workshop focused on potential ways to
capitalize on all of these changes to improve the drug development process.
Schilsky pointed out several recurring themes at the workshop, the first
and foremost being to put patients at the center of the drug development
paradigm. “At the end of the day, the reason we do what we do and try to
advance new drugs into the clinical workplace is to help improve outcomes
for patients. So let us continue to think about this as patient-centered
drug development and not product-centered drug development,” Schilsky
stressed. To that end, there needs to be a focus on clinically meaningful out-
comes and endpoints in clinical trials, including patient-reported outcomes.
Another recurrent topic of discussion at the workshop was that bio-
marker or diagnostic test development tends to lag behind therapeutic

development. “This seems to me to be something that should be fairly easy

to address,” Schilsky said.
He noted that although the workshop began by focusing on speeding
up the drug development process, many of the discussions had also high-
lighted the value of efficiency. In characterizing possible ways to achieve
efficiency, he stated that “It is important to avoid waste, and there are many
sources of waste in the whole process, including the very costly ones result-
ing from failing late.” In addition, although companies may wish to have a
unique version of a popular efficacious drug class in their portfolio, such as
the PD-L1 inhibitors, “at some point there is going to be saturation, and we
ought to encourage drug developers to begin to focus on new targets and
continuing areas of unmet medical need,” Schilsky said. Finally, he added
that in aiming for efficient development, there are risks in both moving too
fast and moving too slow. “If you move too slowly, you risk competitive
disadvantage, but if you move too fast, you risk not really understanding
your drug well enough or the way it should be used with the population in
whom it will achieve maximal effectiveness.”
He added that “in our zeal to move product development quickly, we
cannot lose sight of the first principles of drug development.” Those prin-
ciples are to improve understanding of the underlying biology of the disease
and target, and of the drug. The basic understanding of the pharmacology of
the drug should include whether it is the right chemical entity, the optimal
formulation, dosing, pharmacodynamics, and pharmacokinetics.
Schilsky referred to Brown’s notion that data gathered to support drug
approvals or labeling should be fit for purpose. “We need to use the right
study design at the right time with the right data sources to address the
question that is being posed. We also need to ensure appropriate design and
timing of confirmatory studies, and to balance rigor in the study design with
flexibility to adapt to new information,” he stressed. And, more emphasis
needs to be put on data standardization and data quality, he said.
Another consistent theme in the workshop was the need for improved
collaboration and information sharing among all parties. “When incentives
are aligned and there are common needs and goals, sharing even among
commercial entities that have strong proprietary interests can be accom-
plished and hopefully can lead to improvements in the way we collectively
develop drugs,” Schilsky said. However, aligning the culture of industry
with the developing science in drug development can be challenging, even
within a single entity, much less across a partnership. Disconnects occur
between early and late development teams, and expert academic advisors

who have been involved in drug development plans at certain points in the
process can end up being excluded from key decisions later, Schilsky said.
Many workshop discussions focused on the information needed to
confidently advance investigational agents in the drug development process,
Schilsky noted. “We have numerous endpoints in oncology, none of which
are perfect and each of which has its own challenges. We have to be able
to integrate our assessment of a drug using as much information as we can
glean from all the endpoints available to us at any particular point in time,”
he said. A related point made repetitively throughout the workshop was the
need to learn throughout the drug development process and beyond FDA
approval, not just from individual trials or individual cohorts, Schilsky said.
With rapid clinical testing, many drugs are entering the market with
less learning behind them, Schilsky said. Some of that learning about new
drugs could come with postmarketing studies, but such research is difficult
to conduct in the United States. “Once that drug is on the market, it can
be prescribed and if it gets paid for, it is a huge disincentive for either the
doctor or the patient to participate in a postmarketing research study, which
is one of the reasons why so many of these studies take so long to complete
or in some cases, are never completed,” he said.
He summarized several potential strategies for improving drug develop-
ment (see Box 10). “It all comes down to clearly articulating the question
we want to answer and the best approach to answering that question among
an entire range of clinical trial designs and data sources available to us.” He
added that the Cancer Moonshot offers many opportunities for improving
drug development. “It is incumbent on us all to take advantage of them
and try to use the new funding and infrastructures that will be available to
continue to address some of these issues.”
“Drug development is inherently risky and the drug development
paradigm is essentially about managing uncertainty in the context of unmet
medical need and business opportunity,” Schilsky concluded. “The more
that we, as a community, can get comfortable with how to manage that
uncertainty and make key decisions about regulatory approval, clinical use,
and reimbursement in the face of that uncertainty and then continue to
develop the information to reduce that uncertainty, then the better off we
will be and the better off our patients will be.”

BOX 10
Potential Strategies to Improve the
Drug Development Paradigm in Oncology
Summarized by Richard Schilsky
1. Enhancing flexibility, communication, and ability to respond

quickly to striking signals of efficacy.
2. Identifying incentives for investigators and sponsors to put
more focus on preclinical and early clinical research.
3. Using modeling to help identify appropriate doses and drug
combinations.
4. Using new imaging approaches for in vivo assessment to
determine whether a drug is hitting its intended target, to tar-
get treatments simultaneously with imaging, and to clinically
assess antitumor effects.
5. Broadening eligibility for clinical trials.
6. Learning from expanded access programs.
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Appendix A
Statement of Task
An ad hoc committee will plan and host a 1.5-day public workshop to

examine the drug development paradigm for cancer therapy. The workshop
will feature invited presentations and panel discussion on topics that may
include
• Challenges with the traditional phased drug development paradigm

in the age of targeted therapies and opportunities for using new
approaches to cancer therapy development and regulatory review.
• Best practices for cancer drug development and review (e.g., trial
design, statistical approaches, ethical considerations and informed
consent, industry–Food and Drug Administration interactions).
• Lessons learned from recent expedited drug approval processes.
• Evidence requirements for cancer therapies before and after regula-
tory approval, and the mechanisms needed to generate this knowl-
edge (e.g., clinical trials, “real-world” experiential data, combination
approaches).
• Examples of international regulatory approaches.
The committee will develop the agenda for the workshop sessions, select
and invite speakers and discussants, and moderate the discussions. A sum-
mary of the presentations and discussions at the workshop will be prepared
by a designated rapporteur in accordance with institutional guidelines.
115


Appendix B
Workshop Agenda
December 12, 2016

7:30 am Registration
8:00 am Welcome and Overview of the Workshop

Richard L. Schilsky, American Society of Clinical Oncology
Planning Committee Chair
8:10 am Session 1: Vision for a Seamless Cancer Drug Development

Paradigm
Moderator: Richard L. Schilsky, American Society of Clinical
Oncology
• Mark Ratain, The University of Chicago

• Mace Rothenberg, Pfizer Inc.
• Janet Woodcock, Food and Drug Administration
• Ellen Sigal, Friends of Cancer Research
Panel Discussion
10:00 am Break
117

10:15 am Session 2: Case Studies and Lessons Learned from Recent

Experiences
Moderator: Suzanne Topalian, Johns Hopkins University
Anti-PD-1 Immunotherapy
• Eric Rubin, Merck
BRAF Pathway Inhibitors

• Keith Flaherty, Massachusetts General Hospital
T790M EGFR Inhibitors

• Pasi Jänne, Dana-Farber Cancer Institute
Challenges Resulting from Rapid Regulatory Approvals

• Donald Harvey, Emory University
Panel Discussion – Session speakers and

• Gideon Blumenthal, Food and Drug Administration
12:15 pm Lunch
1:00 pm Session 3: Flexible Drug Development and Decision

Making: Accommodating New Insights
Moderator: Mace Rothenberg, Pfizer Inc.
Understanding Biological Activity to Inform Drug

Development
• Kenneth Anderson, Dana-Farber Cancer Institute
• Wolfgang Weber, Memorial Sloan Kettering Cancer Center
Assessing Early Signals of Efficacy to Guide Clinical

Development
• David Feltquate, Bristol-Myers Squibb
• Richard Finn, University of California, Los Angeles,
Jonsson Comprehensive Cancer Center
Dose-Finding Considerations and Strategies for Novel

Combination Development
• Steven Piantadosi, Cedars-Sinai Medical Center

APPENDIX B 119

• Patricia Keegan, Food and Drug Administration
• Hedvig Hricak, Memorial Sloan Kettering Cancer Center
3:15 pm Break
3:30 pm Session 4: Continuous Evidence Generation Across the

Cancer Therapy Life Cycle
Moderator: Monica Bertagnolli, Dana-Farber Cancer Institute
Clinical Trial Designs to Expedite Drug Development

• Mary Redman, Fred Hutchinson Cancer Research Center
• Rajeshwari Sridhara, Food and Drug Administration
The Use of Real-World Evidence in Drug Development

• Maria Koehler, Pfizer Inc.
• Amy Abernethy, Flatiron Health

• Jeffrey Brown, Harvard Pilgrim Health Care Institute
5:30 pm Wrap-Up of Day 1

December 13, 2016

7:30 am Registration
8:00 am The National Cancer Moonshot Initiative and Seamless

Drug Development
Moderator: Richard L. Schilsky, American Society of Clinical
Oncology
Blue Ribbon Panel Recommendations

• Elizabeth Jaffee, Johns Hopkins University
Q&A

8:30 am Session 5: Managing Benefit and Risk in Seamless Cancer

Drug Development
Moderator: Rebecca Pentz, Emory University School of
Medicine
Food and Drug Administration Perspectives on Seamless

Drug Development
• Marc Theoret, Food and Drug Administration
Expanding Eligibility Criteria and Access to Experimental

Therapies
American Society of Clinical Oncology, Friends of Cancer
Research, and the Food and Drug Administration Working
Group to Expand Eligibility Criteria
• Gwynn Ison, Food and Drug Administration
Expanded Access Programs

• Steven Lemery, Food and Drug Administration
Patient Protections and Ethical Considerations

• Steven Joffe, University of Pennsylvania
Data Monitoring Approaches in a Seamless Drug

Development Paradigm
• Frank Rockhold, Duke Clinical Research Institute
Benefit–Risk Analysis of Decision Making in Oncology

• G. K. Raju, Massachusetts Institute of Technology
Panel Discussion
11:15 am Break
11:30 am Session 6: Stakeholder Perspectives: Goals of the New

Paradigm and Priorities for the Path Forward
Moderator: Steven Piantadosi, Cedars-Sinai Medical Center
• Howard A. Burris, III, Sarah Cannon Research Institute

• Elizabeth Jaffee, Johns Hopkins University

APPENDIX B 121
• Lynn M. Matrisian, Pancreatic Cancer Action Network

• Eric Rubin, Merck
• Amy McKee, Food and Drug Administration
• Jeffrey Brown, Harvard Pilgrim Health Care Institute
• Rebecca Pentz, Emory University School of Medicine
• Ronald Kline, Centers for Medicare & Medicaid Services
12:45 pm Wrap-Up of the Workshop

Planning Committee Chair
1:00 pm Adjourn


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Amanda Wagner Gee, Erin Balogh, Margie Patlak, and

National Cancer Policy Forum

Board on Health Care Services

Health and Medicine Division

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International Standard Book Number-13: 978-0-309-45794-1

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.

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The National Academy of Sciences was established in 1863 by an Act of

The National Academy of Engineering was established in 1964 under

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The three Academies work together as the National Academies of Sciences,

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Proceedings published by the National Academies of Sciences, Engineering,

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WORKSHOP PLANNING COMMITTEE1

RICHARD L. SCHILSKY (Chair), Senior Vice President and Chief

1 The National Academies of Sciences, Engineering, and Medicine’s planning committees

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DANIEL J. SARGENT, Professor of Biostatistics and Oncology,

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NATIONAL CANCER POLICY FORUM1

EDWARD J. BENZ, JR. (Chair), President and Chief Executive Officer

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ROGER D. DANSEY, Senior Vice President, Clinical Research—Late

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MICHELLE M. LE BEAU, Arthur and Marian Edelstein Professor of

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WENDY A. WOODWARD, Associate Professor and Service Chief,

National Cancer Policy Forum Staff

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This Proceedings of a Workshop was reviewed in draft form by indi-

JESSE BERLIN, Johnson & Johnson

Although the reviewers listed above provided many constructive com-

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dent examination of this proceedings was carried out in accordance with

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This Proceedings of a Workshop is dedicated to Dr. Daniel J. Sargent,

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Support from the many annual sponsors of the National Academies

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ACRONYMS AND ABBREVIATIONS xxi

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APPENDIX A: STATEMENT OF TASK 115

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Boxes, Figures, and Tables

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xx BOXES, FIGURES, AND TABLES

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Acronyms and Abbreviations

ALK amplastic lymphoma kinase

• Improve standardized criteria for imaging interpretation to guide

• se postmarketing surveillance to update drug labels, espe-

drug approvals: regular and accelerated approvals. Regular and a ccelerated