Policy Issues in the
Development and Adoption of
Biomarkers for Molecularly
Targeted Cancer Therapies

WORKSHOP SUMMARY

Sharyl J. Nass, Jonathan Phillips, and Margie Patlak, 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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NOTICE: The workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.

This project was supported by Contract No. HHSN261200900003C and Contract No. HHSN263201200074I (Task Order No. HHSN26300052) between the National Academy of Sciences and 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, the American Cancer Society, the American Society for Radiation Oncology, the American Society of Clinical Oncology, the American Society of Hematology, the Association of American Cancer Institutes, AstraZeneca, Bristol-Myers Squibb, the Cancer Support Community, C-Change, the CEO Roundtable on Cancer, EMD Serono, Helsinn Healthcare SA, the LIVESTRONG Foundation, the National Comprehensive Cancer Network, Novartis Oncology, the Oncology Nursing Society, and Sanofi Oncology. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity.

International Standard Book Number-13: 978-0-309-36857-5
International Standard Book Number-10: 0-309-36857-X

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Suggested citation: IOM (Institute of Medicine). 2015. Policy issues in the development and adoption of biomarkers for molecularly targeted cancer therapies: Workshop summary. Washington, DC: The National Academies Press.

“Knowing is not enough; we must apply.
Willing is not enough; we must do.”      

                                                —Goethe

INSTITUTE OF MEDICINE
              OF THE NATIONAL ACADEMIES

Advising the Nation. Improving Health.

THE NATIONAL ACADEMIES

Advisers to the Nation on Science, Engineering, and Medicine

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 government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.

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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. Victor J. Dzau 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 providing 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. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.

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WORKSHOP PLANNING COMMITTEE¹

ADRIAN SENDEROWICZ (Chair), President, Oncology Drug Development, LLC

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

MICHAEL A. CALIGIURI, CEO, James Cancer Hospital & Solove Research Institute, Director, Ohio State University Cancer Center

BARBARA CONLEY, Associate Director, Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute

CAROL A. HAHN, Associate Professor of Radiation Oncology, Duke University Medical Center, Medical Director of Radiation Oncology, Duke Raleigh Hospital, Clinical Affairs and Quality Council Chair, American Society for Radiation Oncology

ROY HERBST, Professor of Medicine & Chief, Section of Medical Oncology, Yale Cancer Center

SAMIR N. KHLEIF, Director, Georgia Health Sciences University Cancer Center, Georgia Regents University Cancer Center

ROBERT McDONOUGH, Head of Clinical Policy Research & Development, Aetna, Inc.

LISA McSHANE, Mathematical Statistician, Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute

RICHARD PAZDUR, Office of Oncology and Hematology Products, Food and Drug Administration

RICHARD SCHILSKY, Chief Medical Officer, American Society of Clinical Oncology

_______________

¹ Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution.

Project Staff

SHARYL J. NASS, Forum Director and Director, Board on Health Care Services

JONATHAN PHILLIPS, Research Associate

SARA THARAKAN, Research Assistant

HANNAH DURING, Senior Program Assistant

PATRICK ROSS, Senior Program Assistant

NATIONAL CANCER POLICY FORUM¹

MICHAEL A. CALIGIURI (Chair), CEO, James Cancer Hospital & Solove Research Institute, Director, Ohio State University Comprehensive Cancer Center

PATRICIA A. GANZ (Vice Chair), Professor, University of California, Los Angeles, School of Medicine & Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center

AMY P. ABERNETHY, Associate Professor of Medicine, Duke University School of Medicine, and Director, Duke Cancer Care Research Program

LUCILE ADAMS-CAMPBELL, Professor of Oncology, Associate Director for Minority Health and Health Disparities Research, Georgetown University Lombardi Cancer Center

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

LOYCE PACE BASS, Health Policy Director, LIVESTRONG Foundation

MONICA BERTAGNOLLI, Professor of Surgery, Harvard University Medical School

OTIS BRAWLEY, Chief Medical Officer and Executive Vice President, American Cancer Society

CARLTON BROWN, Director of Professional Services, Oregon Nurses Association, and Past President, Oncology Nursing Society

SERGIO CANTOREGGI, Chief Scientific Officer and Global Head of Research and Development, The Helsinn Group

ROBERT W. CARLSON, CEO, National Comprehensive Cancer Network

GREGORY CURT, U.S. Medical Science Lead, AstraZeneca

_______________

¹ Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution.

WILLIAM S. DALTON, CEO, M2Gen Personalized Medicine Institute, Moffitt Cancer Center, and Chair, American Association for Cancer Research Science Policy & Legislative Affairs Committee

GWEN DARIEN, Executive Vice President, Programs and Services, Cancer Policy Institute, Cancer Support Community

WENDY DEMARK-WAHNEFRIED, Associate Director for Cancer Prevention and Control, University of Alabama at Birmingham Comprehensive Cancer Center

JAMES DOROSHOW, Deputy Director, National Cancer Institute

CAROL A. HAHN, Associate Professor of Radiation Oncology, Duke University Medical Center, Medical Director of Radiation Oncology, Duke Raleigh Hospital, Clinical Affairs and Quality Council Chair, American Society for Radiation Oncology

LORI HOFFMAN HOGG, Veterans Health Administration National Oncology Clinical Advisor, Office of Nursing Services and Cancer Program Director, Albany Stratton VA Medical Center

CHARLES HUGH-JONES, Chief Medical Officer, Sanofi North America

SAMIR N. KHLEIF, Director, Georgia Health Sciences University Cancer Center, Georgia Regents University Cancer Center

RICHARD A. LARSON, Hematology/Oncology Director, University of Chicago

MICHELLE M. LE BEAU, Arthur and Marian Edelstein Professor of Medicine, Director, Comprehensive Cancer Center, University of Chicago

JOSEPH LEVEQUE, Vice President, Head U.S. Medical–Oncology, Bristol-Myers Squibb

SHARI LING, Deputy Chief Medical Officer, Center for Clinical Standards and Quality, Centers for Medicare & Medicaid Services

GRETA MASSETTI, Associate Director for Science, Division of Cancer Prevention and Control, Centers for Disease Control and Prevention

DANIEL R. MASYS, Affiliate Professor, Biomedical Informatics, University of Washington

MARTIN J. MURPHY, CEO, CEO Roundtable on Cancer

RICHARD PAZDUR, Director, Office of Oncology and Hematology Products, Food and Drug Administration

STEVEN PIANTADOSI, Phase One Foundation Endowed Chair and Director, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center

JENNIFER A. PIETENPOL, Director, Vanderbilt-Ingraham Cancer Center, Benjamin F. Byrd, Jr., Professor of Oncology, Professor of Biochemistry, Vanderbilt University

ANDREW SCHIERMEIER, Senior Vice President, Head of Global Oncology, Merck Serono

RICHARD SCHILSKY, Chief Medical Officer, American Society of Clinical Oncology

DEBORAH SCHRAG, Chief, Division of Population Sciences, Professor of Medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School

YA-CHEN TINA SHIH, Professor of Health Economics, Chief, Section of Cancer Economics and Policy, Department of Health Services Research, University of Texas MD Anderson Cancer Center

ELLEN V. SIGAL, Chair and Founder, Friends of Cancer Research

ELIZABETH THOMPSON, President and CEO, C-Change

RALPH WEICHSELBAUM, Daniel K. Ludwig Professor and Chair, Department of Radiation Oncology, Director, Ludwig Center for Metastasis Research, The University of Chicago Medical Center

GEORGE J. WEINER, Director, Holden Comprehensive Cancer Center, University of Iowa, President, Association of American Cancer Institutes

National Cancer Policy Forum Staff

SHARYL J. NASS, Forum Director and Director, Board on Health Care Services

JONATHAN PHILLIPS, Research Associate

SARA THARAKAN, Research Assistant

HANNAH DURING, Senior Program Assistant

PATRICK ROSS, Senior Program Assistant

PATRICK BURKE, Financial Associate

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Reviewers

This workshop summary 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 published workshop summary as sound as possible and to ensure that the workshop summary 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 process. We wish to thank the following individuals for their review of this workshop summary:

Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop

summary before its release. The review of this report was overseen by Eli Y. Adashi, Warren Alpert Medical School at Brown University. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the rapporteurs and the institution.

Acknowledgments

Support from the many annual sponsors of the Institute of Medicine’s National Cancer Policy Forum is crucial to the work of the Forum. Current sponsors include the Centers for Disease Control and Prevention, the National Cancer Institute/National Institutes of Health, the American Association for Cancer Research, the American Cancer Society, the American Society for Radiation Oncology, the American Society of Clinical Oncology, the American Society of Hematology, the Association of American Cancer Institutes, AstraZeneca, Bristol-Myers Squibb, the Cancer Support Community, C-Change, the CEO Roundtable on Cancer, EMD Serono, Helsinn Healthcare SA, the LIVESTRONG Foundation, the National Comprehensive Cancer Network, Novartis Oncology, the Oncology Nursing Society, and Sanofi Oncology.

The Forum wishes to express its gratitude to the expert speakers whose presentations helped define the current challenges and opportunities in the development and adoption of biomarkers for molecularly targeted cancer therapies. The Forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda.

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Contents

ACRONYMS

INTRODUCTION

MOLECULAR BIOLOGY REVOLUTION IN CANCER DIAGNOSIS AND TREATMENT

Lessons Learned from Single Analyte Tests

Next-Generation Sequencing

RNA Sequencing Tests

Tests for Circulating Tumor DNA

Business Climate for Developing Diagnostic Tests

CHALLENGES IN BIOMARKER TEST DEVELOPMENT

Setting Standards

Assessing Analytical Validity, Clinical Validity, and Clinical Utility

Sharing Data

REGULATORY OVERSIGHT CHALLENGES

Evolving Regulation of Laboratory-Developed Tests

Companion Diagnostics

CLINICAL IMPLEMENTATION CHALLENGES

Insufficient or Inadequate Specimens

Tsunami of Information

Choosing the Best Test

Time Delays

Lack of Resources

Reporting Test Results

Incidental Findings

REIMBURSEMENT CHALLENGES

Lack of Evidence

Investigational and Off-Label Uses

Incidental Findings

Greater Expense, But Not Necessarily Greater Value

GATHERING THE EVIDENCE: INNOVATIVE CLINICAL TRIALS

Basket Trials

Lung-MAP Umbrella Trial

Challenges with Basket and Umbrella Trials

GATHERING THE EVIDENCE: COVERAGE DECISIONS

Coverage with Evidence Development

The MolDx Approach to Test Reimbursement

Green Park Collaborative Recommendations

GATHERING THE EVIDENCE: DATABASES AND REGISTRIES

My Cancer Genome

ClinGen

Targeted Agent and Molecular Profiling Utilization Registry

Challenges in Using Databases

EDUCATION AND CLINICAL DECISION SUPPORT NEEDS

Guidelines

Treatment Pathways

RESEARCH NEEDS

CLOSING REMARKS

REFERENCES

APPENDIX: Workshop Statement of Task and Agenda

Boxes, Figures, and Tables

BOXES

1 Suggestions Made by Individual Workshop Participants

2 Actionable Genome Consortium

3 Steps to Validating a Next-Generation Sequencing Assay System for Use in a Clinical Trial

4 Root-Cause Analysis

5 Proposed Definition of Clinically Actionable Variants and Criteria for Drug Selection for the Targeted Agent and Molecular Profiling Utilization Registry

FIGURES

1 Genotyping time line for non-small-cell lung cancer

2 High-level strategy for drug and test co-development

3 Neratinib basket study schema

4 NCI-MATCH study schema

5 Lung-MAP study schema

6 Proposed collaborative multipharma network to advance multibiomarker diagnostics

7 MolDx: Algorithm for expedited review

TABLES

1 Clinical and Functional Translation of CFTR (CFTR2) Database

2 List of FDA Approved Companion Diagnostic Devices for Oncology

3 Selected International Trials to Match Patients Based on Molecular Profile

4 Lung-MAP Drug Selection Committee Nomination

Acronyms