CANCER CLINICAL TRIALS: PROACTIVE STRATEGIES

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CANCER CLINICAL TRIALS:

PROACTIVE STRATEGIES

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Cancer Treatment and Research

Steven T. Rosen, M.D., Series Editor

Sugarbaker, P. (ed): Peritoneal Carcinomarosis: Principles of Management. 1995. ISBN 0-7923-3727-1.

Dickson, R.B., Lippman, M.E. (eds): Mammary Tumor Cell Cycle, Differentiation and Metastasis.

1995. ISBN 0-7923-3905-3.

Freireich, E.J, Kantarjian, H. (4s): Molecular Genetics and Therapy of Leukemia. 1995. ISBN 0-7923-3912-6.

Cabanillas, F., Rodriguez, M.A. (eds): Advances in Lymphoma Research. 1996. ISBN 0-7923-3929-0.

Miller, A.B. (ed.): Advances in Cancer Screening. 1996. ISBN 0-7923-4019-1.

Hait, W.N. (ed.): Drug Resistance. 1996. ISBN 0-7923-4022-1.

Pienta, K.J. (ed.): Diagnosis and Treatment of Genitourinary Malignancies. 1996. ISBN 0-7923-4164-3.

Arnold, A.J. (4.): Endocrine Neoplasms. 1997. ISBN 0-7923-4354-9.

Pollock, R.E. (ed.): Surgical Oncology. 1997. ISBN 0-7923-9900-5.

Verweij, J., Pinedo, H.M., Suit, H.D. (eds): Soft Tissue Sarcomas: Present Achievements and Future Prospects. 1997. ISBN 0-7923-991 3-7.

Walterhouse, D.O., Cohn, S. L. (eds): Diagnostic and Therapeutic Advances in Pediatric Oncology.

1997. ISBN 0-7923-9978-1.

Mittal, B.B., Purdy, J.A., Ang, K.K. (eds): Radiation Therapy. 1998. ISBN 0-7923-9981-1.

Foon, K.A., Muss, H.B. (eds): Biological and Hormonal Therapies of Cancer. 1998. ISBN 0-7923-9997-8.

Ozols, R.F. (ed.): Gynecologic Oncology. 1998. ISBN 0-7923-8070-3.

Noskin, G. A. (ed.): Management of Infectious Complications in Cancer Patients. 1998. ISBN 0-7923-8150-5.

Bennett, C. L. (ed.): Cancer Policy. 1998. ISBN 0-7923-8203-X.

Benson, A. B. (4.): Gastrointestinal Oncology. 1998. ISBN 0-7923-8205-6.

Tallman, M.S., Gordon, L.I. (eds): Diagnostic and Therapeutic Advances in Hematologic Malignancies.

1998. ISBN 0-7923-8206-4.

von Gunten, C.F. (ed.): Palliative Care and Rehabilitation of Cancer Patients. 1999. ISBN 0-7923-8525-X Burt, R.K., Brush, M.M. (4s): Advances in Allogeneic Hematopoietic Stem Cell Transplantation. 1999.

ISBN 0-7923-7714-1.

Angelos, P. (ed.): Ethical Issues in Cancer Patient Care 2000. ISBN 0-7923-7726-5.

Gradishar, W.J., Wood, W.C. (eds): Advances in Breast Cancer Management. 2000. ISBN 0-7923-7890-3.

Sparano, J. A. (ed.): H N & HTLV-I Associated Malignancies. 2001. ISBN 0-7923-7220-4.

Ettinger, D. S. (ed.): Thoracic Oncology. 2001. ISBN 0-7923-7248-4.

Bergan, R. C. (ed.): Cancer Chemoprevention. 2001. ISBN 0-7923-7259-X.

Ram, A,, Mundle, S.D. (eds): Myelodysplastic Syndromes & Secondary Acute Myelogenous Leukemia 2001.

ISBN: 0-7923-7396.

Talamonti, M. S. (ed.): Liver Directed Therapy for Primary and Metastatic Liver Tumors. 2001.

ISBN 0-7923-7523-8.

Stack, M.S., Fishman, D.A. (eds): Ovarian Cancer. 2001. ISBN 0-7923-7530-0.

Bashey, A., Ball, E.D. (4s): Non-Myeloablative Allogeneic Transplantation. 2002. ISBN 0-7923-7646-3.

Leong, S. P.L. (ed.): Atlas of Selective Sentinel Lymphadenectomy for Melanoma, Breast Cancer and Colon Cancer. 2002. ISBN 1-4020-7013-6.

Andersson , B., Murray D. (4s): Clinically Relevant Resistance in Cancer Chemotherapy. 2002.

ISBN 1-4020-7200-7.

Beam, C. (ed.): Biostatistical Applications in Cancer Research. 2002. ISBN 1-4020-7226-0.

Brockstein, B., Masters, G. (eds): Head and Neck Cancer. 2003. ISBN 1-4020-7336-4.

Frank, D.A. (ed.): Signal Transduction in Cancer. 2003. ISBN 1-4020-7340-2.

Figlin, R. A. (ed.): Kidney Cancer. 2003. ISBN 1-4020-7457-3.

Kirsch, M.; Black, P. McL. (ed.): Angiogenesis in Brain Tumors. 2003. ISBN 1-4020-7704-1.

Keller, E.T., Chung, L.W.K. (eds): The Biology of Skeletal Metastases. 2004. ISBN 1-4020-7749-1.

Kumar, R. (4.): Molecular Targeting and Signal Transduction. 2004. ISBN 1-4020-7822-6.

Verweij, J., Pinedo, H.M. (eds): Targeting Treatment of Soft Tissue Sarcomas. 2004. ISBN 1-4020-7808-0.

Finn, W.G., Peterson, L.C. (eds.): Hematopathology in Oncology. 2004. ISBN 1-4020-7919-2.

Farid, N. (ed.): Molecular Basis of Thyroid Cancer. 2004. ISBN 1-4020-8106-5.

Khleif, S. (ed.): Tumor Immunology and Cancer Vaccines. 2004. ISBN 1-4020-81 19-7.

Balducci, L., Extermann, M. ( 4 s ) : Biological Basis of Geriatric Oncology. 2004. ISBN

Abrey, L.E., Chamberlain, M.C., Engelhard, H.H. (eds): Leptomeningeal Metastases. 2005. ISBN 0-387-24198-1 Platanias, L.C. (ed.): Cytokines and Cancer. 2005. ISBN 0-387-24360-7.

Leong, S. P.L., Kitagawa, Y., Kitajima, M. (eds): Selective Sentinel Lymphadenectomy for Human Solid Cancer. 2005. ISBN 0-387-23603-1.

Small, Jr. W., Woloschak, G. (4s): Radiation Toxicity: A Practical Guide. 2005. ISBN 1-4020-8053-0.

Haefner, B., Dalgleish, A. (eds): The Link Between Inflammation and Cancer. 2006. ISBN 0-387-26282-2.

Leonard, J.P., Coleman, M. (eds): Hodgkin's and Non-Hodgkin's Lymphoma. 2006. ISBN 0-387-29345.

Leong, S. P.L. (ed:) Cancer Clinical Trials: Proactive Strategies. 2006. ISBN 0-387-33224-3.

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CANCER CLINICAL TRIALS:

PROACTIVE STRATEGIES

edited by

STANLEY P. L. LEONG, MD, FACS

Professor and Director of Sentinel Lymph Node Program University of California Sun Francisco Medical Center

at Mount Zion Sun Francisco, CA, USA

a - ^springer

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Stanley P. L. Leong Department of Surgery University of California Medical Center at Mount Zion

1600 Divisadero Street San Francisco, CA 94143 leongs@surgery.ucsf.edu

CANCER CLINICAL TRIALS: PROACTIVE STRATEGIES

Library of Congress Control Number: 2006927192

ISBN-10: 0-387-33224-3 e-ISBN-10: 0-387-33225-1 ISBN-13: 978-0387-33224-6 e-ISBN-13: 978-0387-33225-3 Printed on acid-free paper.

All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.

The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made.

The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed in the United States of America.

9 8 7 6 5 4 3 2 1 springer.com

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CONTENTS

Contributors Foreword

Preface

Acknowledgement

Historical Perspective and Evolving Concerns for Human Research

Bernard Lo and Nesrin Garan

Cancer Trials and the Institutional Review Board (IRB) Scott Kurtzman and Zita Lazzarini

NCI's Cancer Therapy Evaluation Program:

A Commitment to Treatment Trials Jeffrey S. Abrams, Anthony Murgo and Michaele C. Christian

Practical Guide for Cancer Clinical Investigators Steven Hirschfeld

The Role of Cooperative Groups in Cancer Clinical Trials

Ann M. Mauer, Elizabeth S. Rich and Richard L. Schilsky The Advocate Role in Clinical Study Development and Partnering with Patient Advocates in Your Local Institution

Barbara Parker

The National Breast Cancer Coalition: Setting the Standard for Advocate Collaboration in Clinical Trials Fran Visco

The Role of the Principal Investigator in Cancer Clinical Trials

Stanley P. L. Leong

vii xiii xvii xix

1

11

3 1

5 1

11 1

131

143

157

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VI

9. The Audit Process and How to Ensure a Successful

Audit 179 Y. Nancy You, Lisa Jacobs, Elizabeth Martinez and

David M. Ota

10. The Privacy Rule (HIPAA) As It Relates To Clinical

Research 199 John M. Harrelson and John M. Falletta

11. The Commission on Cancer, American College of

Surgeons' Response to HIPAA 209 E. Greer Gay

12. Ethical and Legal Issues in the Conduct of Cancer

Clinical Trials 219 Gerianne J. Sands and Peggy A. Means

13. The Role of the Office of Research Integrity in Cancer

Clinical Trials 231 Peter Abbrecht, Nancy Davidian, Samuel Merrill and

Alan R. Price

14. Strategies for the Administration of a Clinical Trial

Infrastructure: Lessons from a Comprehensive Cancer 241 Center

Leonard A. Zwelling and Carleen A. Brunelli

15. The Clinical Research Process: Building a System in

Harmony with Its Users 275 Greg Koski

16. Cancer Research and CHnical Trial in Action: An

Important Exercise Before You Embark on Your Study 291 Stanley P.L. Leong, Larry Carbone and Scott Kurtzman

Index 311

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CONTRIBUTORS

Peter Abbrecht, MD, PhD Medical Expert

Office of Research Integrity

Department of Health and Human Services Rockville, Maryland

Jeffrey S. Abrams, MD NCI Project Officer

Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis National Cancer Institute

Bethesda, Maryland

Carleen A. Brunelli, PhD, MBA

Chief Research and Regulatory Affairs Officer Office of Research Administration

The University of Texas M.D. Anderson Cancer Center Houston, Texas

Larry Carbone, DVM, PhD Clinical Veterinarian

Department of Veterinary Medicine

University of California San Francisco Medical Center San Francisco, California

Michaele C. Christian, MD Associate Director

Cancer Therapy Evaluation Program Division of Cancer Treatment and Diagnosis National Cancer Institute

Bethesda, Maryland

Nancy Davidian, PhD Clinical Case Expert Office of Research Integrity

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V l l l

John M. Falletta, MD

IRB Chairman Institutional Review Board Professor of Pediatrics

Duke University Health System Durham, North Carolina

Nesrin Garan

Program in Medical Ethics Department of Medicine

University of California San Francisco San Francisco, California

Greer Gay, RN, PhD, MPH

Manager, Research Unit National Cancer Data Base Division of Research and Optimal Care

American College of Surgeons Chicago, Illinois

John M. Harrelson, MD

Associate Professor Pathology/Orthopedic Surgery Director Musculoskeletal Oncology Division Director Diabetic Foot Clinic

Duke University Health System Durham, North Carolina

Steven Hirschfeld, MD, PhD CAPT USPHS

Office of Cellular, Tissue and Gene Therapy Center for Biologies Evaluation and Research Food and Drug Administration

Rockville, Maryland

Lisa Jacobs, MD

Assistant Professor of Surgery Department of Surgery Johns Hopkins University Baltimore, Maryland

Greg Koski, MD, PhD

Associate Professor of Anesthesia Senior Scientist

Institute for Health Policy Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

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IX

Scott Kurtzman, MD, FACS Director of Surgery

Waterbury Hospital Waterbury, Connecticut Department of Surgery

University of Connecticut School of Medicine Farmington, Connecticut

Zita Lazzarini, JD

Division Director and Associate Professor Department of Surgery

University of Connecticut School of Medicine Farmington, Connecticut

Stanley P. L. Leong, MD, FACS

Professor and Director, Sentinel Lymph Node Program Department of Surgery

University of California San Francisco Medical Center at Mount Zion Member, UCSF Comprehensive Cancer Center, San Francisco, California

Bernard Lo, MD Professor

Program in Medical Ethics Department of Medicine

University of California San Francisco San Francisco, California

Elizabeth Martinez, LPN, BS Lead Auditor

American College of Surgeons Oncology Group Durham, North Carolina

Ann M. Mauer, MD

Assistant Professor of Medicine Cancer and Leukemia Group B Central Office of the Chairman Chicago, Illinois

Peggy A. Means Consultant

Fred Hutchinson Cancer Research Center Seattle, Washington

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Samuel Merrill, PhD Scientist-Investigator Office of Research Integrity

Anthony Murgo, MD

Acting Chief Investigational Drug Branch

Associate Chief for Developmental Chemotherapy Evaluation Program Cancer Therapy Evaluation Program

Division of Cancer Treatment and Diagnosis National Cancer Institute

Bethesda, Maryland

David M. Ota, MD Department of Surgery

Duke University Medical Center Durham, North Carolina

Barbara Parker

Breast Cancer SPORE and

American College of Surgeons Oncology Group Duke University Medical Center

Durham, North Carolina

Alan R. Price, PhD

Associate Director for Investigative Oversight Office of Research Integrity

Rockville, Maryland

Elizabeth S. Rich, MD, PhD Assistant Professor of Medicine Cancer and Leukemia Group B Central Office of the Chairman Chicago, Illinois

Gerianne J. Sands Associate General Counsel

Fred Hutchinson Cancer Research Center Seattle, Washington

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XI

Richard L. Schilsky, MD Professor of Medicine

Cancer and Leukemia Group B Central Office of the Chairman Chicago, Illinois

Fran Visco President

National Breast Cancer Coalition Washington, DC

Y. Nancy You, MD Surgical Research Fellow

Leonard A. Zwelling, MD, MBA Vice President for Research Administration Office of Research Administration

The University of Texas M.D. Anderson Cancer Center Houston, Texas

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FOREWORD

Samuel A. Wells, Jr., MD Professor of Surgery Duke University Medical Center

Durham, North Carolina

The formal organization of a clinical trial program for the treatment of patients with malignant diseases began in this country over 50 years ago and resulted in a large part from the availability of promising therapeutic agents for the treatment of leukemia, and subsequently solid tumors. The National Cancer Institute (NCI) initiated this effort, which has gradually expanded to include twelve cooperative clinical trial groups involving 1700 institutions in Canada, Europe and the United States. The cooperative groups, administered by the Cancer Therapy Evaluation Program of the NCI, enter over 22,000 patients on clinical studies each year. The groups are large and complex organizations that include a number of specialists, such as: clinical oncologists, statisticians, other medical specialists, basic scientists, nurses, epidemiologists, health services researchers, data managers, information technologists, auditors, data and safety monitoring committee members, and patient advocates. Additional cancer clinical trials are supported by investigator-initiated grants or by the NO1 contract mechanism. The individual groups have conducted highly important clinical trials, which have substantially improved the treatment of patients with cancer. To appreciate the contributions of the cooperative group program, one need only review the accomplishments of the National Surgical Adjuvant Breast Project, which greatly improved the management of patients with carcinoma of the breast, or the role of the Children's Cancer Group and the Pediatric Oncology Group (now combined as the Children's Oncology Group), which reduced the mortality of childhood cancer (Figure IA) despite an increasing incidence (Figure 1B). The pediatric clinical trial groups have had a remarkable impact on the survival of children with cancer, due in a large part to their ability to accrue over half of children with cancer in the U.S. and Canada to their clinical trials, a rate more than ten times that achieved by the adult cooperative groups.

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XIV

Dr. Leong has edited and authored an important book on Cancer Clinical Trials: Proactive Strategies. There are contributions from a series of international experts on clinical trials. This book provides an important historical context and thoroughly addresses the broad operational aspects of cancer clinical trials. Substantial personal effort and resources are required to develop a cancer clinical research program, whether in the academic or the private practice setting. The institutional review board, regulatory personnel, and ethicists are essential to the efficient and safe performance of clinical research. Furthermore, the role of a dedicated principal investigator, skilled in the theory and practice of clinical research, is critical to a successful clinical trial program. Above all the patients are the key element of successful clinical trials, as it is they who serve as both the participants and the direct beneficiaries of the clinical research process.

This book is especially timely, as we are entering one of the most important eras of cancer research and treatment, characterized by the development of targeted therapeutics. These novel compounds, a direct result of the human genomic project, have already shown great promise in the treatment of patients with leukemia and malignant solid tumors. We are also into an era of financial constraint in the government-supported clinical research. A well-organized, economically efficient, clinical research infrastructure, in part supported by the federal government, is essential for the critical evaluation of these new compounds, either alone or in combination with existing therapies. It is important that there be a close communication and interaction among the NCI, the Food and Drug Administration, the pharmaceutical and biotechnology industries, basic scientists, and clinical investigators with their institutions if these new therapeutics are to be evaluated in a timely manner.

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Annual National Cancer Mortality Rate Among U.S. Children <15 Years of Age

2 4 6 8

1950 1960 1970 1980 1990 2000

0

Mortality per 100,000, Age-Adjusted CHILDRENS CANCER GROUP

PEDIATRIC ONCOLOGY GROUP IRSG

NWTSG

CALGB PEDIATRIC DIVISION SWOG PEDIATRIC DIVISION

U.S. Cancer Mortality Rate among Children <15 Years

2 4 6 8

Rate per 100,000, Age Adjusted

0

1950 1960 1970 1980 1990 2000

10 12 14 16

U.S. SEER Cancer Incidence among Children <15 Years

Continued decline in Continued decline in mortality rate despite mortality rate despite increase in incidence increase in incidence Mortality Rate vs. Incidence

xv

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PREFACE

According to the American Cancer Society, about 1 million persons in the United States will be diagnosed with solid cancer every year. About 50% of them will be potentially cured by surgery. The other half of the population may develop metastatic cancer. To date, there is no systemic treatment available to cure metastatic cancer.

Therefore, cancer clinical trials are critical to evaluate reliable treatment modalities against metastatic cancer. Likewise, adjuvant trials are needed to prevent high risk patients from developing recurrence following definitive surgical resection of their cancer. Only about 3-5% of the cancer patients are enrolled in clinical trials.

Multiple barriers exist to block patients from entering into clinical protocols. The ever-changing regulations for clinical trials and the ethical dilemma of treating cancer patients as subjects have made it ever so difficult for the principal investigators to conduct clinical research, especially when they are often ill-informed of the complex nature of the regulations. Therefore, cancer clinical trials are at a critical junction. The objective of this book is to bring the issues of cancer clinical trials into focus so that proactive strategies may be developed to make such trials more user-friendly. Ultimately, the cancer patients will be benefited.

Stanley P. L. Leong, M.D.

Professor of Surgery UCSF

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ACKNOWLEDGEMENT

We would like to thank Jorge Arteaga and Regina Hopkins of the Department of Surgery, UCSF for the preparation of this book.

We are grateful to Laura Walsh and Maureen Tobin of Springer for their advice and expertise in making this book a reality.