FOR COMMENT

Proposed Framework for Evaluating the Safety of Dietary Supplements

Committee on the Framework for Evaluating the Safety of Dietary Supplements

Food and Nutrition Board

Board on Life Sciences

INSTITUTE OF MEDICINE

NATIONAL RESEARCH COUNCIL

NATIONAL ACADEMY PRESS
Washington, D.C.



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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements FOR COMMENT Proposed Framework for Evaluating the Safety of Dietary Supplements Committee on the Framework for Evaluating the Safety of Dietary Supplements Food and Nutrition Board Board on Life Sciences INSTITUTE OF MEDICINE NATIONAL RESEARCH COUNCIL NATIONAL ACADEMY PRESS Washington, D.C.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 20418 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. Support for this project was provided by Food and Drug Administration under contract number 223-00-2458. The views presented in this report are those of the Institute of Medicine Committee on the Framework for Evaluating the Safety of Dietary Supplements and are not necessarily those of the funding agencies. This report is available for downloading as a pdf file at www.nap.edu and at www.iom.edu/fnb. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2002 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.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements Knowing is not enough; we must apply. Willing is not enough; we must do. —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. 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 members, sharing with the National Academy of Sciences the responsibility for advising 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. Wm.A.Wulf 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 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. Bruce M.Alberts and Dr. Wm.A.Wulf are chairman and vice chairman, respectively, of the National Research Council.

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements 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 ADRIANE FUGH-BERMAN, Department of Health Care Sciences, George Washington University School of Medicine, Washington, D.C. (until April 2002). TED GANSLER, Medical Information Strategy, American Cancer Society, Atlanta, Georgia PHILIP S.GUZELIAN, Department of Medicine, University of Colorado Health Sciences Center, Denver ELIZABETH JEFFERY, Department of Food Science and Human Nutrition, University of Illinois at Urbana JOSEPH LAU, Division of Clinical Care Research, New England Medical Center, Boston, Massachusetts LARS NOAH, University of Florida College of Law, Gainesville (until January 2002) 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 Consultants EDWARD A.BORTNICHAK, Strategic Value Assessment, Sanofi-Synthelabo, New York, New York KENNETH FISHER, Washington, D.C. LEWIS A.GROSSMAN, Washington College of Law, American University, Washington, D.C. Staff ALLISON A.YATES, Study Director MARILEE K.SHELTON, Program Officer ALICE VOROSMARTI, Research Associate VIVICA KRAAK, Research Associate SYBIL BOGGIS, Senior Project Assistant

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements FOOD AND NUTRITION BOARD CUTBERTO GARZA (chair), Division of Nutritional Science, Cornell University, Ithaca, New York ROBERT M.RUSSELL (vice chair), Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts VIRGINIA A.STALLINGS (vice chair), Division of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia, Pennsylvania LARRY R.BEUCHAT, Center for Food Safety and Quality Enhancement, University of Georgia, Griffin BENJAMIN CABALLERO, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland ROBERT J.COUSINS, Center for Nutritional Sciences, University of Florida, Gainesville SHIRIKI KUMANYIKA, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia LYNN PARKER, Child Nutrition Programs and Nutrition Policy, Food Research and Action Center, Washington, D.C. ROSS L.PRENTICE, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington A.CATHARINE ROSS, Department of Nutrition, The Pennsylvania State University, University Park BARBARA O.SCHNEEMAN, Departments of Nutrition and Food Science, Division of Clinical Nutrition and Metabolism, and Office of University Outreach, University of California, Davis ROBERT E.SMITH, R.E.Smith Consulting, Inc., Newport, Vermont STEVE L.TAYLOR, Department of Food Science Technology, University of Nebraska-Lincoln CATHERINE E.WOTEKI, College of Agriculture, Iowa State University, Ames BARRY L.ZOUMAS, Department of Agricultural Economics and Rural Sociology, The Pennsylvania State University, University Park Staff ALLISON A.YATES, Director LINDA D.MEYERS, Deputy Director GERALDINE KENNEDO, Administrative Assistant GAIL SPEARS, Staff Editor GARY WALKER, Financial Associate

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements BOARD ON LIFE SCIENCES COREY S.GOODMAN (chair), Department of Molecular and Cell Biology, University of California, Berkeley R.ALTA CHARO, Law and Medical Ethics, University of Wisconsin at Madison JOANNE CHORY, The Salk Institute for Biological Studies, La Jolla, California DAVID J.GALAS, Keck Graduate Institute of Applied Life Sciences, Claremont, California BARBARA GASTEL, Department of Journalism, Texas A&M University, College Station JAMES M.GENTILE, Natural Science Division, Hope College, Holland, Michigan LINDA E.GREER, Natural Resources Defense Council, Washington, DC ED HARLOW, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts ELLIOTT MEYEROWITZ, Division of Biology, California Institute of Technology, Pasadena 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, Center for Environmental Research and Conservation, Columbia University, New York JOAN B.ROSE, Department of Marine Science, University of South Florida, St. Petersburg GERALD M.RUBIN, Howard Hughes Medical Institute, Chevy Chase, Maryland BARBARA A.SCHAAL, Department of Biology, Washington University, St. Louis, Missouri RAYMOND L.WHITE, DNA Sciences, Inc., Fremont, California Staff FRANCES SHARPLES, Director MARILEE K.SHELTON, Program Officer

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements Foreword The Committee on the Evaluation of the Safety of Dietary Supplement Ingredients was asked to develop a framework for use by the U.S. Food and Drug Administration (FDA) to evaluate the safety of dietary supplement ingredients. It should 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 were 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. Thus, what follows in this report is a proposed framework for prioritizing and evaluating the safety of dietary supplements based on existing information available to FDA and others. The committee is now in the process of evaluating six dietary supplement ingredients in a mock evaluation following the process outlined in this report. Our expectations is that by (1) the experience of applying the proposed framework to develop prototype monographs on these ingredients, albeit within the constraints of an outside organization, and (2) the review of comments solicited from various stakeholders regarding the proposed framework, the committee will be able to revise and further elaborate the proposed system, resulting in a final, fully developed framework to provide to FDA. 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 is being conducted as a collaborative project within The National Academies by FNB and the Board on Life Sciences (BLS) of the Division of Earth and Life Studies. The committee was assisted in this challenging first task by the invaluable contributions of a number of individuals. Christine Lewis Taylor, FDA’s Project Officer, met with the committee early in its deliberations. We appreciated her clear presentation about the committee’s task. The committee also recognizes the significant contributions made by two members of the committee who resigned during the development of the report, Lars Noah and Adrianne Fugh-Berman; their insights were very valuable to the development of the proposed process. We also acknowledge the real loss experienced by the committee and its progress in the untimely death of committee member Dr. Norman Gillis last year as the committee was just beginning this process. Finally, we gratefully appreciate the assistance of Stephen F.McNamara, of Hyman, Phelps, and

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements McNamara, for his technical review of Chapter 1, and of Janice Rice Okita, a new FNB program officer working on the monograph development phase of this project, for her assistance with the toxicology section in Chapter 4, Key Factors. The committee was greatly assisted by the very able work of Marilee Shelton, program officer for BLS, who has provided significant assistance to the management and conceptual development of the framework; her efforts to the move the project forward have been key to the process. In addition, Allison 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 Alice Vorosmarti, research associate; Vivica Kraak, research associate, who joined the project as Alice Vorosmarti went on leave; and Sybil Boggis, senior project assistant. We thank Gail Spears for her editorial advice, Gary Walker for financial management, and members of IOM’s Office of Reports and Communication for assistance in the production and dissemination of the report. Finally, we would like to thank the FNB and BLS reviewers, Robert W.Russell, Tufts University; Robert J.Cousins, University of Florida; and Linda E.Greer, Natural Resources Defense Council for their comments on the clarity 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 National Research Council’s (NRC) 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 deliberative process. We wish to thank the following individuals for their review of this report: Joseph Betz, National Institutes of Health Joseph Borzelleca, Virginia Commonwealth University D.Craig Brater, Indiana University School of Medicine Steven Dentali, Dentali Associates Sanford A.Miller, Virginia Polytechnic Institute and State University R.William Soller, Consumer Healthcare Products Association Meir Stampfer, Harvard University 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 Bernadette Marriott, Burroughs Wellcome Fund, appointed by the Institute of Medicine, and Catherine Woteki, Iowa State University, appointed by the National Research Council’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 chair of the committee, I want to thank 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 made meeting the deadline possible. Barbara O.Schneeman, Committee Chair

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements Contents     EXECUTIVE SUMMARY   1 1   INTRODUCTION AND BACKGROUND   13 2   APPROACHES USED BY OTHERS TO CONSIDER DIETARY SUPPLEMENT SAFETY AND OTHER EXISTING SAFETY FRAMEWORKS   29 3   OUTLINE OF THE OVERALL PROCESS FOR EVALUATION OF DIETARY SUPPLEMENT INGREDIENTS   39 4   FACTORS CONSIDERED IN SCREENING, SETTING PRIORITIES, AND SAFETY EVALUATION   47 5   FRAMEWORK STEPS ONE AND TWO: SCREENING/FLAGGING AND PRIORITY SETTING   77 6   FRAMEWORK STEP 3: CRITICAL SAFETY EVALUATION OF DIETARY SUPPLEMENT INGREDIENTS   91 7   ATTRIBUTES AND LIMITATIONS OF THE PROPOSED FRAMEWORK   99 8   DIETARY SUPPLEMENT INGREDIENTS SELECTED FOR PROTOTYPE SAFETY MONOGRAPHS   103

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For Comment: Proposed Framework for Evaluating the Safety of Dietary Supplements     APPENDIXES     A   Other Approaches to Considering the Safety of Dietary Supplements,   106 B   Existing Frameworks or Systems for Evaluating the Safety of Other Substances,   116 C   Possible Combinations of Scores,   124 D   Table of Food and Drug Administration Actions on Dietary Supplements,   138 E   Presenters at the Open Sessions of the Project on the Framework for Evaluating the Safety of Dietary Supplements,   140 F   Biographical Sketches of Committee Members,   141