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

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington D.C.
www.nap.edu



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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 government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in pro - viding services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the 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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