INFANT FORMULA

EVALUATING THE SAFETY OF NEW INGREDIENTS

Committee on the Evaluation of the Addition of Ingredients New to Infant Formula

Food and Nutrition Board

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

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



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INFANT FORMULA EVALUATING THE SAFETY OF NEW INGREDIENTS Committee on the Evaluation of the Addition of Ingredients New to Infant Formula Food and Nutrition Board INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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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 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 No. 223-01-2460, TO4, and Contract No. 4500033271 be- tween the National Academy of Sciences and the Food and Drug Administration, U.S. Department of Health and Human Services, and Health Canada. Any opinions, findings, conclusions, or recommen- dations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.). Committee on the Evaluation of the Addition of Ingredients New to Infant Formula. Infant formula : evaluating the safety of new ingredients / Committee on the Evaluation of the Addition of Ingredients New to Infant Formula, Food and Nutrition Board. p. ; cm. Includes bibliographical references. ISBN 0-309-09150-0 (pbk.) 1. Infant formulas—Standards—United States. 2. Infant formulas—Law and legislation—United States. [DNLM: 1. Infant Formula—standards. 2. Evaluation Studies. 3. Food Analysis—methods. 4. Food Contamination—prevention & control. 5. Infant Formula—legislation & jurisprudence. 6. Infant Nutrition. WS 120 I59 2004] I. Title. RJ216.I538 2004 613.2′083′2—dc22 2004008412 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 and the Food and Nutrition Board, visit the IOM and FNB home pages at www.iom.edu and www.iom/fnb.edu. Copyright 2004 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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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 spon- sors 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 pertain- ing 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 associ- ate the broad community of science and technology with the Academy’s purposes of furthering knowl- edge 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 chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON THE EVALUATION OF THE ADDITION OF INGREDIENTS NEW TO INFANT FORMULA RICHARD J. DECKELBAUM (Chair), Institute of Human Nutrition and Pediatric Gastroenterology and Nutrition, Columbia University, New York, New York LINDA ADAIR, Department of Nutrition, Schools of Public Health and Medicine, University of North Carolina at Chapel Hill MARK APPELBAUM, Department of Psychology, University of California, San Diego GEORGE L. BAKER, Snowmass Village, Colorado SUSAN S. BAKER, Department of Pediatrics, State University of New York at Buffalo CHESTON M. BERLIN, Department of Pediatrics, Pennsylvania State University, Hershey WILLIAM C. FRANKE, Center for Advanced Food Technology, Rutgers, State University of New Jersey, New Brunswick MICHAEL K. GEORGIEFF, Department of Pediatrics, University of Minnesota, Minneapolis JAMES M. NTAMBI, Department of Biochemistry, University of Wisconsin, Madison THEODORE D. WACHS, Department of Psychological Science, Purdue University, West Lafayette, Indiana Consultants CARMI ZVI MARGOLIS, University Center for Health Sciences, Ben-Gurion University of the Negev, Israel PEARAY OGRA, State University of New York at Buffalo ODED SUSSKIND, Brookline, Massachusetts Editor SARAH CARROLL, Minnetonka, Minnesota Staff MARIA ORIA, Study Director (from June 2003) PAULA TRUMBO, Study Director (September 2002–June 2003) SANDRA SCHLICKER, Study Director (until September 2002) LESLIE J. VOGELSANG, Research Assistant SANDRA AMAMOO-KAKRA, Senior Project Assistant (from September 2002) HARLEEN K. SETHI, Senior Project Assistant (until September 2002) v

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FOOD AND NUTRITION BOARD CATHERINE E. WOTEKI (Chair), College of Agriculture, Iowa State University, Ames ROBERT M. RUSSELL (Vice Chair), Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts LARRY R. BEUCHAT, Center for Food Safety, University of Georgia, Griffin SUSAN A. FERENC, SAF*RISK, LC, Madison, Wisconsin NANCY F. KREBS, Department of Pediatrics, University of Colorado Health Sciences Center, Denver SHIRIKI KUMANYIKA, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia REYNALDO MARTORELL, Department of International Health, Emory University, Atlanta, Georgia LYNN PARKER, 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 Staff LINDA D. MEYERS, Director GAIL E. SPEARS, Staff Editor GERALDINE KENNEDO, Administrative Assistant ELISABETH RIMAUD, Financial Associate vi

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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 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 deliberative process. We wish to thank the follow- ing individuals for their review of this report: M. Tom Clandinin, MTI MetaTech, Inc.; Susan Ferenc, SAF*RISK, LC; Kenneth Fisher, KD Consultants; Cutberto Garza, Cornell University; William C. Heird, Baylor College of Medicine; Charlie Homer, National Initiative for Children’s Healthcare Quality; Nancy F. Krebs, University of Colorado Health Sciences Center; Mary F. Locniskar, Hill’s Pet Nutri- tion, Inc.; Michael Posner, University of Oregon; Catharine Ross, Pennsylvania State Uni- versity; Steve L. Taylor, University of Nebraska, Lincoln; John E. Vanderveen, San Antonio, Texas. 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 Dennis M. Bier, USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accor- dance with institutional procedures and that all review comments were carefully consid- ered. Responsibility for the final content of this report rests entirely with the authoring committees and the institution. vii

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Preface Infant formulas are unique because they are the only source of nutrition for many infants during the first 4 to 6 months of life. They are critical to infant health because they must safely support growth and development during a period when the consequences of inadequate nutrition are most severe. The safety standard for an ingredient added to infant formula is defined as a “reasonable certainty of no harm.” In recent years infant formula manufacturers have proposed ingredients (e.g., long-chain polyunsaturated fatty acids [LC- PUFAs], probiotics) that have created new scientific challenges that existing regulations may not address. Meanwhile the Food and Drug Administration (FDA) has been working to revise several aspects of its infant formula regulations, including requirements for quality factors and current good manufacturing practices. In 2002 FDA and Health Canada asked the Institute of Medicine’s Food and Nutrition Board (FNB) to formulate an expert committee to review and identify gaps in methods currently used to assess the safety of ingredients new to infant formulas. The committee was asked to identify tools to evaluate the safety of these ingredients under intended conditions of use in term infants. This charge included determining the data needed to demonstrate the safety of a component already present in human milk, that is, the effect of the matrix, and the utilization of preclinical and clinical studies and postmarket monitoring in the safety assessment process. FDA also asked the committee to apply its recommenda- tions to the recent addition of LC-PUFAs as new ingredients in infant formulas, and others as appropriate. A 10-member committee was appointed with expertise in the areas of pediatric nutri- tion, pediatric gastroenterology, epidemiology and public health, statistics, food technology, food regulatory processes, pediatric neurology, biochemistry, and infant formula manufac- turing. Members brought a diversity of experience from research laboratories, industry, and hospital and clinic settings. Many of the committee members had never met, yet the group developed a cohesion that allowed them to work through and agree upon several difficult issues over the 18-month project. The committee sought additional expertise and background from several consultants. ix

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x PREFACE Two medical education consultants worked with the committee to develop several decision- making tools (algorithms) that emerged as important components of the committee’s recom- mendations. An editorial consultant helped the committee bridge the gap from rough draft to final report to ensure uniformity of style and maximum readability for all possible users. Another consultant provided targeted guidance in the areas of immunology and endocrinol- ogy. In addition, the committee held two open sessions to learn more about updated systems and information that was relevant to its charge. In one open session, the committee reviewed differences that might apply to safety of foods as compared with drugs. In the other open session, one specialist discussed the use of growth charts and another from FDA’s Center for Food Safety and Applied Nutrition discussed the Adverse Event Reporting System. The committee held six meetings and utilized frequent conference calls to develop this report. The committee decided at an early stage that as a general approach, it would first review current (and past) approaches to establishing the safety of ingredients new to infant formulas. Next, gaps or limits of the current systems were to be identified, and then recom- mendations were to be proposed to improve current approaches. Realizing that detailed recommendations for every possible new ingredient would be impossible to achieve within the framework of the committee’s work, generic templates were designed to be utilized (and modified) to fit a large range of potentially new ingredients with varying characteristics and different levels of safety concern. The committee proposes the use of a hierarchical approach to assess the safety of ingredients new to infant formulas. These hierarchies, which often utilize algorithms, assist decision-making through a step-by-step process that places priority on commonly used assessments (e.g., screening) and progresses to more specific assessments (e.g., neuroimaging) when early indicators suggest safety concerns. The primary benefit of using algorithms is that they provide an appropriate balance of information and flexibility to navigate through a decision-making process without being prescriptive. This is especially useful given the wide diversity in possible new ingredients. On behalf of the committee, I am grateful to FNB’s staff for their support and contribu- tions. This report was guided by three study directors: Sandra Schlicker laid the initial foundation for the committee’s work, Paula Trumbo provided input through the middle stages of deliberation, and Maria Oria assisted the committee in bringing the report to its conclusion. The committee is grateful to Leslie Vogelsang, research assistant, and Sandra Amamoo-Kakra, senior project assistant, for their support and dedication. The committee would also like to thank Linda Meyers, director of FNB, for her objective insights and invaluable expertise that informed committee deliberations and conclusions and Allison Yates for her leadership during the early stages of the project. This report would not have been possible without the leadership and dedication of the FNB staff. Finally, I wish to thank each member of the committee for his or her unique contribu- tions and unfailing dedication to a report that has the potential to improve the safety of infant formulas for a new generation. Richard J. Deckelbaum, Chair Committee on the Evaluation of the Addition of Ingredients New to Infant Formula

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Contents EXECUTIVE SUMMARY 1 1 INTRODUCTION AND BACKGROUND 17 Infant Formula Regulations and Guidelines, 18 Charge to the Committee, 20 The Committee’s Approach, 22 Organization of the Report, 27 Summary, 27 References, 27 2 DEFINING SAFETY FOR INFANTS 29 Abstract, 29 Introduction, 30 U.S. Regulatory Agencies, 30 Fundamental Concepts of Safety Regulations, 30 Statistical Considerations in Food Safety Determination, 31 Models of Safety Assessment, 33 Special Considerations for Infant Formulas, 36 Summary, 39 References, 40 3 COMPARING INFANT FORMULAS WITH HUMAN MILK 41 Abstract, 41 Background, 42 History of the Development of Infant Formulas, 42 Challenges of Matching Human-Milk Composition and Breastfeeding Performance, 44 Performance Advantages of Breastfeeding, 46 Risks of Breastfeeding, 50 xi

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xii CONTENTS Summary, 51 References, 52 4 STRENGTHENING THE CURRENT PROCESS TO EVALUATE NEW INGREDIENTS FOR INFANT FORMULAS 55 Abstract, 55 Introduction, 56 The Current U.S. Regulatory System, 56 Proposed Safety Assessment Process, 61 Summary, 69 References, 69 5 TESTING INGREDIENTS WITH PRECLINICAL STUDIES 70 Abstract, 70 Introduction, 71 The Importance of Appropriate Preclinical Studies, 71 Current Regulatory Guidelines for Preclinical Studies, 72 Overview of Recommended Levels of Assessment, 73 Conducting Preanimal Tests, 73 Conducting Animal Toxicity Studies, 77 Conducting Neurological Tests, 87 Summary, 94 References, 94 6 GOING BEYOND CURRENT CLINICAL STUDIES 98 Abstract, 98 Introduction, 99 The Importance of Clinical Studies, 99 Current Regulatory Guidelines for Clinical Studies, 100 General Approach to Conducting Clinical Studies, 101 Overview of Recommended Levels of Assessment, 105 Growth, 105 Specific Organ Systems, 113 Developmental-Behavioral Outcomes, 124 Summary, 144 References, 150 7 SELECTING AN IN-MARKET SURVEILLANCE PLAN 160 Abstract, 160 Background, 161 Overview of Recommended Levels of Assessment, 165 Criteria and Methods for In-Market Surveillance, 166 Summary, 172 References, 172

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xiii CONTENTS APPENDIXES A Acronyms and Glossary 175 B Composition of Infant Formulas and Human Milk for Feeding Term Infants in the United States 179 C Redbook Table of Contents 183 D Applying the Recommended Approaches 186 E Biographical Sketches of Committee Members 204

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