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FACILITATING
COLLABORATIONS TO
DEVELOP COMBINATION
INVESTIGATIONAL
CANCER THERAPIES
WORKSHOP SUMMARY
Margie Patlak, Erin Balogh, and Sharyl J. Nass, Rapporteurs
National Cancer Policy Forum
Board on Health Care Services
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Gov-
erning Board of the National Research Council, whose members are drawn from
the councils of the National Academy of Sciences, the National Academy of Engi -
neering, and the Institute of Medicine.
This study was supported by Contract Nos. HHSN261200900003C and 200-2005-
13434 TO #1 between the National Academy of Sciences and the National Cancer
Institute and the Centers for Disease Control and Prevention, respectively. In addi-
tion, the National Cancer Policy Forum is also supported by the American Asso -
ciation for Cancer Research, the American Cancer Society, the American Society
of Clinical Oncology, the Association of American Cancer Institutes, Bristol-Myers
Squibb, C-Change, the CEO Roundtable on Cancer, Novartis Oncology, and the
Oncology Nursing Society. Any opinions, findings, conclusions, or recommenda -
tions expressed in this publication are those of the author(s) and do not neces -
sarily reflect the view of the organizations or agencies that provided support for
this project.
International Standard Book Number-13: 978-0-309-22064-4
International Standard Book Number-10: 0-309-22064-5
Additional copies of this report are available from the National Academies Press,
500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202)
334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page
at: www.iom.edu.
Copyright 2012 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
The serpent has been a symbol of long life, healing, and knowledge among almost
all cultures and religions since the beginning of recorded history. The serpent
adopted as a logotype by the Institute of Medicine is a relief carving from ancient
Greece, now held by the Staatliche Museen in Berlin.
Suggested citation: IOM (Institute of Medicine). 2012. Facilitating collaborations to
develop combination investigational cancer therapies: Workshop summary. Washington,
DC: The National Academies Press.
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“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
— Goethe
Advising the Nation. Improving Health.
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The National Academy of Sciences is a private, nonprofit, self-perpetuating
society of distinguished scholars engaged in scientific and engineering research,
dedicated to the furtherance of science and technology and to their use for the
general welfare. Upon the authority of the charter granted to it by the Congress
in 1863, the Academy has a mandate that requires it to advise the federal govern -
ment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the
National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter
of the National Academy of Sciences, as a parallel organization of outstanding
engineers. It is autonomous in its administration and in the selection of its mem -
bers, sharing with the National Academy of Sciences the responsibility for advis -
ing the federal government. The National Academy of Engineering also sponsors
engineering programs aimed at meeting national needs, encourages education
and research, and recognizes the superior achievements of engineers. Dr. Charles
M. Vest is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of
Sciences to secure the services of eminent members of appropriate professions
in the examination of policy matters pertaining to the health of the public. The
Institute acts under the responsibility given to the National Academy of Sciences
by its congressional charter to be an adviser to the federal government and, upon
its own initiative, to identify issues of medical care, research, and education.
Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of
Sciences in 1916 to associate the broad community of science and technology
with the Academy’s purposes of furthering knowledge and advising the federal
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Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and
vice chair, respectively, of the National Research Council.
www.national-academies.org
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WORKSHOP PLANNING COMMITTEE1
JOHN HOHNEKER (Chair), Senior Vice President and Head, Global
Development, Integrated Hospital Care, Novartis Pharma AG,
Basel, Switzerland
RENZO CANETTA, Vice President, Oncology Global Clinical Research,
Bristol-Myers Squibb, Wallingford, CT
MICHAELE CHAMBLEE CHRISTIAN, Retired, Washington, DC
ROY S. HERBST, Chief of Medical Oncology, Yale Cancer Center, New
Haven, CT
PATRICIA LoRUSSO, Professor of Medicine and Director, Center
for Experimental Therapeutics, Barbara Ann Karmanos Cancer
Institute, Detroit, MI
FRANK McCORMICK, Director, University of California, San
Francisco (UCSF) Helen Diller Family Comprehensive Cancer
Center, and Associate Dean, UCSF School of Medicine
RICHARD PAZDUR, Director, Office of Oncology Drug Products, Food
and Drug Administration, Silver Spring, MD
PHILIP D. PORTER, Partner, Hogan Lovells, McLean, VA
ELLEN SIGAL, Chairperson and Founder, Friends of Cancer Research,
Washington, DC
JOHN A. WAGNER, Vice President, Clinical Pharmacology, Merck and
Company, Inc., Rahway, NJ
JAMES A. ZWIEBEL, Chief, Investigational Drug Branch, Cancer
Therapy Evaluation Program, Division of Cancer Treatment and
Diagnosis, National Cancer Institute, Rockville, MD
Project Staff
ERIN BALOGH, Study Director
MICHAEL PARK, Senior Program Assistant
SHARYL J. NASS, Director, National Cancer Policy Forum
ROGER HERDMAN, Director, Board on Health Care Services
1 The Institute of Medicine planning committee was solely responsible for organizing the
meeting, identifying topics, and choosing speakers. The responsibility for the published
summary rests with the rapporteurs and the institution.
v
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NATIONAL CANCER POLICY FORUM1
JOHN MENDELSOHN (Chair), President, MD Anderson Cancer Center,
Houston, TX
PATRICIA A. GANZ (Vice Chair), Professor, University of California at
Los Angeles (UCLA) School of Medicine & Public Health, Division
of Cancer Prevention & Control Research, Jonsson Comprehensive
Cancer Center, Los Angeles, CA
AMY ABERNETHY, Associate Professor of Medicine, Duke University
School of Medicine, and Director, Duke Cancer Care Research
Program, Durham, NC
FRED APPELBAUM, Director, Clinical Research Division, Fred
Hutchinson Cancer Research Center, Seattle, WA
PETER B. BACH, Attending Physician, Memorial Sloan-Kettering
Cancer Center, New York
EDWARD BENZ, JR., President, Dana-Farber Cancer Institute and
Director, Harvard Cancer Center, Harvard School of Medicine,
Boston, MA
MONICA BERTAGNOLLI, Professor of Surgery, Harvard University
Medical School, Boston, MA
OTIS W. BRAWLEY, Chief Medical Officer, American Cancer Society,
Atlanta, GA
MICHAEL A. CALIGIURI, Director, Ohio State Comprehensive Cancer
Center, Columbus, OH, and President, Association of American
Cancer Institutes
RENZO CANETTA, Vice President, Oncology Global Clinical Research,
Bristol-Myers Squibb, Wallingford, CT
MICHAELE CHAMBLEE CHRISTIAN, Retired, Washington, DC
WILLIAM DALTON, President, CEO, and Center Director, Moffitt
Cancer Center, Tampa, FL, and Chair, AACR Committee on Science
Policy and Legislative Affairs
WENDY DEMARK-WAHNEFRIED, Associate Director for Cancer
Prevention and Control, University of Alabama at Birmingham
Comprehensive Cancer Center, Birmingham, AL
ROBERT ERWIN, President, Marti Nelson Cancer Foundation,
Davis, CA
ROY S. HERBST, Chief of Medical Oncology, Yale Cancer Center,
New Haven, CT
1Institute of Medicine forums and roundtables do not issue, review, or approve individual
documents. The responsibility for the published meeting summary rests with the rappor-
teurs and the institution.
vi
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JOHN HOHNEKER, Senior Vice President and Head, Global
Development, Integrated Hospital Care, Novartis Pharma AG,
Basel, Switzerland
THOMAS J. KEAN, President and Chief Executive Officer, C-Change,
Washington, DC
DOUGLAS R. LOWY, Deputy Director, National Cancer Institute,
Bethesda, MD
DANIEL R. MASYS, Affiliate Professor, Biomedical and Health
Informatics, University of Washington School of Medicine,
Seattle, WA
MARTIN J. MURPHY, Chief Executive Officer, CEO Roundtable on
Cancer, Durham, NC
BRENDA NEVIDJON, Clinical Professor and Specialty Director,
Nursing & Healthcare Leadership, Duke University School of
Nursing, Durham, NC, and Past President, Oncology Nursing
Society
STEVEN PIANTADOSI, Director, Samuel Oschin Comprehensive
Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
LISA C. RICHARDSON, Associate Director for Science, Division of
Cancer Prevention and Control, Centers for Disease Control and
Prevention, Atlanta, GA
YA-CHEN TINA SHIH, Director, Program in the Economics of Cancer,
University of Chicago, Chicago, IL
ELLEN SIGAL, Chairperson and Founder, Friends of Cancer Research,
Washington, DC
JOHN A. WAGNER, Vice President, Clinical Pharmacology, Merck and
Company, Inc., Rahway, NJ
RALPH R. WEICHSELBAUM, Chair, Radiation and Cellular Oncology,
and Director, Ludwig Center for Metastasis Research, The
University of Chicago Medical Center, Chicago, IL
JANET WOODCOCK, Director, Center for Drug Evaluation and
Research, Food and Drug Administration, Rockville, MD
National Cancer Policy Forum Staff
SHARYL J. NASS, Director, National Cancer Policy Forum
LAURA LEVIT, Program Officer
CHRISTINE MICHEEL, Program Officer
ERIN BALOGH, Associate Program Officer
MICHAEL PARK, Senior Program Assistant
PATRICK BURKE, Financial Associate
SHARON B. MURPHY, Scholar in Residence
ROGER HERDMAN, Director, Board on Health Care Services
vii
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Reviewers
This report has been reviewed in draft form by individuals chosen
for their diverse perspectives and technical expertise, in accordance with
procedures approved by the National Research Council’s Report Review
Committee. The purpose of this independent review is to provide candid
and critical comments that will assist the institution in making its pub-
lished report as sound as possible and to ensure that the report meets
institutional standards for objectivity, evidence, and responsiveness to
the study charge. The review comments and draft manuscript remain
confidential to protect the integrity of the deliberative process. We wish
to thank the following individuals for their review of this report:
Ramzi Dagher, Vice President, Worldwide Regulatory Strategy and
Regulatory Head, Oncology Business Unit, Pfizer, Inc., New
London, CT
Beloo Mirakhur, Senior Director, R&D/Medical Affairs, Oncology
N.A., GlaxoSmithKline, Collegeville, PA
Jane Perlmutter, Founder, Gemini Group, Ann Arbor, MI
Jeffrey Sosman, Professor of Medicine and Director, Melanoma &
Tumor Immunotherapy Program, Vanderbilt-Ingram Cancer
Center, Nashville, TN
Although the reviewers listed above have provided many construc-
tive comments and suggestions, they were not asked to endorse the final
draft of this report. The review of this report was overseen by Melvin
ix
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x REVIEWERS
Worth. Appointed by the Institute of Medicine, he was responsible for
making certain that an independent examination of this report was car-
ried out in accordance with institutional procedures and that all review
comments were carefully considered. Responsibility for the final con -
tent of this report rests entirely with the authoring committee and the
institution.
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Contents
1 INTRODUCTION 1
2 WHY COMBINATIONS AND COLLABORATIONS ARE
NECESSARY 3
3 SCIENTIFIC CHALLENGES IN DEVELOPING
INVESTIGATIONAL COMBINATION THERAPIES 11
Improving Preclinical Development of Investigational
Combination Therapies, 11
Prioritizing Combinations to Test, 19
Building on the Basic Knowledge Base, 23
Improving Clinical Trials for Combination Therapies, 24
4 OVERCOMING CULTURAL CHALLENGES TO
COLLABORATIONS 37
Competitiveness, 38
Sharing Resources, 39
Resistance to Innovation, 41
5 LEGAL ISSUES IN COLLABORATIONS 43
Indemnification, 44
Intellectual Property, 44
Antitrust Legislation, 49
xi
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xii CONTENTS
6 FINANCIAL CHALLENGES 53
7 REGULATORY ISSUES 55
FDA Draft Guidance, 56
Showing the Contribution of Each Drug in a Combination, 57
Effect of Combined Toxicity on Single-Agent Approval, 58
Multiple INDs?, 59
Labeling Combination Therapies, 59
Coordination of Diagnostic and Therapeutic Regulation, 60
FDA Versus European Regulation, 61
8 CODEVELOPMENT OF THERAPIES FOR
HIV AS A MODEL 63
The Importance of Surrogate Markers, 64
Vaccines in Combination Therapies, 66
The Key Role of Patient Advocates, 66
9 EXAMPLES OF COLLABORATIONS RELEVANT TO CANCER 69
10 WRAPPING UP 73
APPENDIXES
A Examples of Collaborations 77
B Workshop Agenda 91
REFERENCES 97
ACRONYMS 101
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Table, Box, and Figures
TABLE
4-1 Rankings of Immunotherapy Agents with High Potential for Use in
Treating Cancer, 40
BOX
5-1 Department of Justice/Federal Trade Commission Collaboration
Guidelines: Safety Zone for R&D Competition Analyzed in Terms of
Innovation Markets, 50
FIGURES
2-1 Growth factor receptor signal transduction pathways, 5
2-2 Adoptive cellular therapy, 7
2-3 Clonal evolution of human neoplasia, 9
3-1 An example of an adaptive trial design that includes several
treatment arms at the start of the trial, 28
3-2 Design features of an I-SPY-like trial, 29
8-1 Instantaneous inhibitory potential (IIP) of antiretroviral drugs, 65
A-1 The BATTLE 2 trial protocol, 83
A-2 The BATTLE 2 clinical trial preparation steps, 84
xiii
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