A FRAMEWORK FOR EVALUATING SAFETY
THE NATIONAL ACADEMIES
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 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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was supported by Contract Number 223-00-2458 between the National Academy of Sciences and the Food and Drug Administration. Additional support came from Institute of Medicine internal funds. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project.
Library of Congress Cataloging-in-Publication Data
Dietary supplements : a framework for evaluating safety / Committee on the Framework for Evaluating the Safety of Dietary Supplements, Food and Nutrition Board [and] Board on Life Sciences.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-309-09110-1 (hardcover)
1. Dietary supplements—Evaluation. 2. Dietary supplements—Toxicology.
[DNLM: 1. United States. Food and Drug Administration. 2. Dietary Supplements—standards—United States. 3. Safety—United States. 4. Government Regulation—United States. 5. Product Surveillance, Postmarketing—methods—United States. QU 145.5 D5639 2004] I. Committee on the Framework for Evaluating the Safety of Dietary Supplements.
Additional copies of this report are available from the
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Copyright 2005 by the National Academy of Sciences. All rights reserved.
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Cover photo of red ginger taken by Dr. Aniko Solyom, University of Arizona.
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. Bruce M. Alberts is president of the National Academy of Sciences.
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COMMITTEE ON THE FRAMEWORK FOR EVALUATING THE SAFETY OF DIETARY SUPPLEMENTS
BARBARA O. SCHNEEMAN (Chair),
Departments of Nutrition and Food Science, Division of Clinical Nutrition and Metabolism, and Office of University Outreach, University of California, Davis
DANIEL L. AZARNOFF,
D.L. Azarnoff Associates and Clinical/ Regulatory Affairs, Cellegy Pharmaceuticals, South San Francisco, California
CINDY LYNN CHRISTIANSEN,
Center for Health Quality, Outcomes, and Economic Research, Bedford V.A. Hospital, and Boston University School of Public Health, Massachusetts
ALICE M. CLARK,
Office of Research and Sponsored Programs, University of Mississippi, Oxford
NORMAN R. FARNSWORTH,
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
Medical Information Strategy, American Cancer Society, Atlanta, Georgia
JAMES E. GIBSON,
Department of Pharmacology and Toxicology, The Brody School of Medicine at East Carolina University, North Carolina
STEPHEN A. GOLDMAN,
Stephen A. Goldman Consulting Services, LLC, Morris Plains, New Jersey
PHILIP S. GUZELIAN,
Department of Medicine, University of Colorado Health Sciences Center, Denver
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign
LOREN D. KOLLER,
Loren Koller and Associates, LLC, Corvallis, Oregon
Institute for Clinical Research and Health Policy Studies, Tufts New England Medical Center, Boston, Massachusetts
RUSSELL J. MOLYNEUX,
USDA Western Regional Research Center, Albany, California
SUSAN S. PERCIVAL,
Department of Food Science and Human Nutrition, University of Florida, Gainesville
CHERYL L. ROCK,
Department of Family and Preventive Medicine, University of California, San Diego, La Jolla
JERROLD M. WARD,
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
LEWIS A. GROSSMAN,
Washington College of Law, American University, Washington, D.C.
ENVIRON International, Arlington, Virginia
ALLISON A. YATES, Study Director
MARILEE SHELTON-DAVENPORT, Program Officer
JANICE OKITA, Program Officer
CRYSTAL RASNAKE, Research Assistant
SANAIT TESFAGIORGIS, Senior Project Assistant
CYNTHIA K. ARON,
University of Massachusetts Memorial Medical Center, Worcester
Pharmacognosy Consulting Services, San Carlos, California
CARL K. WINTER,
Department of Food Science and Technology, University of California, Davis
Chromium Picolinate Consultants
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire
Department of Environmental Medicine, New York University Medical School, New York City
JIM K. LIU,
College of Pharmacy, University of New Mexico, Albuquerque
STEVEN R. PATIERNO,
Department of Pharmacology, George Washington University School of Medicine, Washington, D.C.
STEVEN R. SMITH,
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge
Department of Nutritional Sciences, Oklahoma State University, Stillwater
H.B. “SKIP” MATTHEWS, Consultant,
Hertford, North Carolina
TIMOTHY EDWARD McALINDON,
Boston University School of Medicine, Massachusetts
DONALD ALLAN McCLAIN,
Division of Endocrinology and Metabolism, University of Utah School of Medicine, Salt Lake City
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
STANLEY T. OMAYE,
Department of Nutrition, University of Nevada, Reno
PHYLLIS C. ZEE,
Neurobiology and Physiology, Northwestern University Institute for Neuroscience, Chicago, Illinois
Saw Palmetto Consultants
Ben May Institute, University of Chicago, Chicago, Illinois
LEONARD S. MARKS,
Urological Sciences Research Foundation, Culver City, California
STEPHEN H. SAFE,
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station
Shark Cartilage Consultants
SAMUEL M. COHEN,
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
SUSAN E. CRAWFORD,
Department of Pathology, Northwestern University Medical School, Chicago, Illinois
JOSEPH A. SCIMECA,
General Mills, Inc., St. Louis Park, Minnesota
College of Science and Mathematics, California State University, Fresno
FOOD AND NUTRITION BOARD
CATHERINE E. WOTEKI (Chair),
College of Agriculture, Iowa State University, Ames
ROBERT M. RUSSELL (Vice Chair),
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
LARRY R. BEUCHAT,
Center for Food Safety, University of Georgia, Griffin
SAF*Risk, LC, Madison, Wisconsin
NANCY F. KREBS,
Department of Pediatrics, University of Colorado Health Sciences Center, Denver
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia
Rollins School of Public Health, Emory University, Atlanta, Georgia
Child Nutrition Programs and Nutrition Policy, Food Research and Action Center, Washington, D.C.
BARBARA O. SCHNEEMAN,
Department of Nutrition, University of California, Davis
NICHOLAS J. SCHORK,
Polymorphism Research Laboratory, University of California, San Diego
JOHN W. SUTTIE,
Department of Biochemistry, University of Wisconsin, Madison
STEVE L. TAYLOR,
Department of Food Science and Technology and Food Processing Center, University of Nebraska, Lincoln
BARRY L. ZOUMAS,
Department of Agricultural Economics and Rural Sociology, Pennsylvania State University, University Park
LINDA D. MEYERS, Director starting October 2003
ALLISON A. YATES, Director through September 2003
GERALDINE KENNEDO, Administrative Assistant
GAIL SPEARS, Staff Editor
ELISABETH RIMAUD, Financial Associate
BOARD ON LIFE SCIENCES
COREY S. GOODMAN (Chair),
Department of Molecular and Cell Biology, University of California, Berkeley
Rollins School of Public Health, Emory University, Atlanta, Georgia
R. ALTA CHARO,
Law and Medical Ethics, University of Wisconsin, Madison
The Salk Institute for Biological Studies, La Jolla, California
JEFFREY L. DANGL,
Department of Biology, University of North Carolina, Chapel Hill
Department of Biological Sciences, Stanford University, Palo Alto, California
JAMES M. GENTILE,
Natural Science Division, Hope College, Holland, Michigan
LINDA E. GREER,
Natural Resources Defense Council, Washington, D.C.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
Institute for Cellular and Molecular Biology, University of Texas, Austin
KENNETH F. KELLER,
Humphrey Institute of Public Affairs, University of Minnesota, Minneapolis
Institute for Defense Analyses, Alexandria, Virginia
ROBERT T. PAINE,
Department of Zoology, University of Washington, Seattle
GREGORY A. PETSKO,
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts
STUART L. PIMM,
Nicholas School of Environmental and Earth Sciences, Duke University, Durham, North Carolina
BARBARA A. SCHAAL,
Department of Biology, Washington University, St. Louis, Missouri
Center for Microbial Ecology, Michigan State University, East Lansing
Department of Cellular and Molecular Pharmacology, University of California, San Francisco
FRANCES SHARPLES, Director
MARILEE SHELTON-DAVENPORT, Program Officer
The Committee on the Framework for Evaluating the Safety of Dietary Supplements was asked to develop a framework for use by the Food and Drug Administration (FDA) to evaluate the safety of dietary supplement ingredients (see Appendix B for scope of work). It was to include, from a science-based perspective, a system for prioritizing review of dietary supplement ingredients that could be extended to new ingredients as notifications regarding intent to market are submitted by manufacturers. Although evaluation of data regarding the efficacy of such ingredients to maintain health is of interest to many, a review of these data was specifically not included in the charge to the committee.
Once a proposed framework was constructed, FDA requested that it be made available to the dietary supplement industry and other stakeholders for review and comment. In addition, it requested that six prototype safety monographs be developed using the proposed framework. In July 2002, the proposed framework was released for comment, along with the list and a brief rationale for which six dietary supplement ingredients were to undergo a safety review and development of a prototype safety monograph. The committee valued the input received regarding the workability and utility of the proposed framework (see summary in Appendix B). Subsequently, new members with expertise in toxicology, natural product chemistry, pharmacokinetics, and pharmacoepidemiology were added to the committee and several aspects of the proposed framework were revised.
Included in the proposed framework released in July 2002 was a requirement that, prior to the completion of a monograph, there would be a sharing of information obtained to date on the dietary supplement ingredi-
ent under review and a request for additional information regarding its safety. Thus during the fall and early spring of 2002–2003, comments were received on the six prototype monographs as well as on the framework itself.
What follows in this report is a framework for prioritizing and evaluating the safety of dietary supplements based on existing information available to FDA and others. This framework, the primary work of the committee, was developed in the context of the current law regulating dietary supplements, the Dietary Supplement Health and Education Act of 1994 (DSHEA). It has been nearly 10 years since Congress passed DSHEA, and considerable experience has been gained in attempting to protect public health under its provisions. Consequently, in the process of completing our task, the committee identified several ways that the law could be more effective in meeting the goal of protecting public health, and these findings and recommendations are included in this report. Although some might consider such recommendations to be outside the scope of the task, the committee felt it had gained valuable insight into this challenging task through its work on the framework and felt it was important to convey this information to policy-makers.
Although this study is under the primary management of the staff of the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM), it has been conducted as a collaborative project within the National Academies by the FNB and the Board on Life Sciences (BLS) of the Division of Earth and Life Studies of the National Research Council (NRC).
The committee was assisted in its task by the invaluable contributions of a number of individuals. Christine Lewis Taylor, Ph.D., Director of FDA’s Office of Nutritional Products, Dietary Supplements, and Labeling and the FDA’s Project Officer for this project; Susan Walker, M.D., Director of the Division of Dietary Supplement Programs; and Elizabeth Yetley, Ph.D., Lead Scientist for Nutrition, all from the Center for Food Safety and Applied Nutrition of FDA, met with the committee in open session at almost every meeting to respond to questions and provide insight into what would be useful to the agency in developing the framework. We appreciated their clear presentations about the committee’s task.
The committee also recognizes the significant contributions made by two former members of the committee, Lars Noah of the University of Florida and Adriane Fugh-Berman of George Washington University, who resigned during the development of the initial report released for comment in 2002; their insights were very valuable to the initial thinking of the proposed process. We also gratefully acknowledge the significant assistance of the four consultants: Dr. Kenneth Fisher, now with the Office of Dietary Supplements at the National Institutes of Health, who assisted in the early development of the proposed framework report; Dr. Edward Bortnichak,
Sanofi-Synthelabo, who was also involved in the early phases; Mr. Lewis Grossman, American University, who came into the project to assist after Mr. Noah resigned and guided us through the areas of food and drug law; and Dr. Joseph Rodricks of Environ International, who provided significant assistance in how risk assessment and toxicology are applied to chemicals and other substances. We also gratefully appreciate the assistance of Stephen F. McNamara of Hyman, Phelps, and McNamara, for his early technical review of Chapter 1.
During the development of the prototype monographs, we were fortunate to have outstanding experts as consultants who participated in the working groups on the ingredients reviewed. Their input was invaluable for the monograph development which also helped the committee rethink aspects of the framework. These experts are listed in the front of this report, and we do appreciate their assistance.
The committee was greatly assisted by the very able work of Dr. Marilee Shelton-Davenport, program officer for BLS, who has provided major and critical assistance in the management and conceptual development of the framework; her efforts to move the project forward have been key to the process. Dr. Janice Rice Okita, who served as the monographer for the project, provided the resources, knowledge, and organizational skills to help the working groups complete their tasks in a timely manner. Throughout all aspects of the project Dr. Allison A. Yates, Study Director, has provided valuable insight and input for accomplishing the task of the committee. We also greatly appreciate the able and dedicated assistance of FNB research associates Alice Vorosmarti and Vivica Kraak, as well as senior project assistant Sybil Boggis, who assisted in the early phases with the proposed framework, and most recently the significant dedication and assistance of Crystal Rasnake, research assistant for the second phase of the study and for the monograph documentation. Thanks also go to Sanait Tesfagiorgis, senior project assistant, who assisted with the completion of this final report; Gail Spears for her editorial assistance; Gary Walker and Elisabeth Rimaud for financial management; and members of IOM’s Office of Reports and Communication for assistance in the production and dissemination of the report.
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 NRC’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 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 delibera-
tive process. We wish to thank the following individuals for their review of this report:
Neal L. Benowitz, University of California, San Francisco; Joseph M. Betz, National Institutes of Health; Steven Dentali, Dentali Associates; John Edgar, Honorary Fellow, CSIRO Livestock Industries; Kenneth D. Fisher, KD Consultants; Freddie Ann Hoffman, HeteroGeneity, LLC; Marvin M. Lipman, Consumers Union of U.S., Inc.; Richard A. Merrill, The University of Virginia and Covington & Burling; Robert M. Russell, Tufts University; Meir Stampfer, Harvard University; Brian L. Strom, University of Pennsylvania; and Roy Upton, American Herbal Pharmacopoeia.
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Sanford A. Miller, Virginia Polytechnic Institute and State University, coordinator, appointed by the IOM, and Ronald Estabrook, The University of Texas Southwestern Medical Center at Dallas, monitor, appointed by the NRC’s Report Review Committee. The coordinator and monitor were 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 authoring committee and the institution.
As a final note, I extend the appreciation and respect of the committee to our Study Director, Dr. Allison Yates, as she completes her position of director of the Food and Nutrition Board and wish her the best in future endeavors. I personally am grateful to my fellow committee members for their commitment to the work of the committee under a rather demanding time schedule. Their quick and constructive responses to the many drafts of the report, their respect for each other’s opinion and willingness to find common ground, has made the task possible. It has been a pleasure to work with this entire group.
Barbara O. Schneeman
Consideration of Frameworks for Evaluating the Safety of Other Substances,
Annex 3-1. Applying the Safety Framework to Required Nutrients,