Consensus Study Report

NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

This activity was supported by a contract between the National Academy of Sciences and the U.S. Food and Drug Administration Contract No. 75F40122D00002. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-73521-6
International Standard Book Number-10: 0-309-73521-1
Digital Object Identifier: https://doi.org/10.17226/29065
Library of Congress Control Number: 2025938255

This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242; http://www.nap.edu.

Copyright 2025 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved.

Printed in the United States of America.

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2025. Protein quality and growth monitoring studies: Quality factor requirements for infant formula. Washington, DC: National Academies Press. https://doi.org/10.17226/29065.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president.

The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president.

The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president.

The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine.

Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task.

Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies.

Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release.

For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

COMMITTEE ON PROTEIN QUALITY AND GROWTH MONITORING STUDIES TO SATISFY QUALITY FACTOR REQUIREMENTS FOR INFANT FORMULA

STEPHANIE A. ATKINSON (Chair), McMaster University

STEVEN A. ABRAMS, University of Texas at Austin

TERESA A. DAVIS, Baylor College of Medicine

RAJAVEL ELANGO, University of British Columbia

SHIBANI GHOSH, Tufts University

JAMES D. HOUSE,¹ University of Manitoba

DANIEL ROTH, The Hospital for Sick Children and University of Toronto

JOHN C. WALLINGFORD, Nutrispectives

XIAOBIN WANG, Johns Hopkins Bloomberg School of Public Health

Study Staff

ANN L. YAKTINE, Food and Nutrition Board Director

SARAH PONCET LANDOLT, Research Associate

JENNIFER K. STEPHENSON, Research Associate

MELANIE ARTHUR, Research Assistant

ALICE VOROSMARTI, Associate Program Officer

KATHERINE M. DELANEY, Program Officer (October 2024–December 2024)

ANDI REISER, Senior Program Assistant (November 2023–January 2025)

Consultants

HILDEGARD PRZYREMBEL, BfR Institute, Berlin, Germany (retired)

MELISSA MAITIN-SHEPARD, Science Writer, MMS Health Strategies, LLC

___________________

¹ James D. House passed away during completion of the study.

This page intentionally left blank.

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, 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 thank the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by PATRICK STOVER, Texas A&M University, and CATHERINE E. WOTEKI, Iowa State University. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

DEDICATION
to Dr. James Duncan House

We dedicate this report to committee member Dr. James (Jim) Duncan House, who contributed to the project on a weekly basis with scientific rigor and enthusiasm until his passing on September 10, 2024. Jim’s outstanding expertise in the fields of food science, particularly protein foods and protein quality, nutritional regulation of sulfur amino acids and sustainable egg protein contributed significantly to the development of Chapter 3 on protein quality. Jim’s leadership in nutrition and food science in Canada is marked by his position as professor and Manitoba Strategic Research Chair in Sustainable Protein, Department of Food and Human Nutritional Sciences, University of Manitoba, and his service as president of the Canadian Nutrition Society, which honoured him with the Earl Willard McHenry Award and designation as Fellow. Jim is remembered by the committee as a thoughtful, warm, and generous colleague.

This page intentionally left blank.

Contents

PREFACE

ACRONYMS AND ABBREVIATIONS

SUMMARY

The Committee’s Approach

Protein Quality

Normal Physical Growth

Future Research on Quality Factors

1 INTRODUCTION AND BACKGROUND

Rationale for the Study

Congressional Request

The Committee’s Task and Approach

Organization of the Report

Reference

2 METHODOLOGY

Introduction

Committee’s Interpretation of the Task

Committee’s Approach and Methods

References

3 QUALITY FACTORS FOR INFANT FORMULA: PROTEIN QUALITY

Evaluation of the Protein Efficiency Ratio

Alternative Methods for Demonstrating Protein Quality of Infant Formulas

Summary of Methodology to Assess Protein Quality

References

4 QUALITY FACTORS FOR INFANT FORMULA: NORMAL PHYSICAL GROWTH

Historical Perspective on Growth Monitoring Study Regulations

Current Regulatory Requirements

Alternative Approaches

References

5 FUTURE RESEARCH ON QUALITY FACTORS

Protein Quality

Growth Monitoring Studies

References

APPENDIXES

A Committee Member Biographies

B Disclosure of Unavoidable Conflict of Interest

C Open Meeting Agendas

D Protein Quality in Infant Formula: A Scoping Review

E Modification of Infant Formula and Growth: A Scoping Review

Boxes, Figures, and Tables

BOXES

S-1 Statement of Task

S-2 Committee-Developed Questions for the Scoping Review

1-1 Statement of Task

2-1 Topics/Questions for Consideration by the Committee

2-2 Additional Information from FDA During Open Session

3-1 Indispensable and Conditionally Indispensable Amino Acids

3-2 Key Point from EFSA and Codex

3-3 In Vivo Digestibility Methods

3-4 In Vitro Digestibility Methods

4-1 Examples of a Major Change in Infant Formula as Defined by the Code of Federal Regulations (21 CFR § 106.3)

FIGURES

2-1 PRISMA flow diagram of selection process for scoping review on methods to examine protein quality of infant formula in in vitro and animal models

2-2 PRISMA flow diagram of selection process for scoping review on methods to examine protein quality of infant formula and normal physical growth

D-1 PRISMA flow diagram of selection process for scoping review on methods to examine protein quality of infant formula in in vitro and animal models

D-2 Number of studies meeting inclusion criteria according to publication year

D-3 Number of studies meeting inclusion criteria by country of publication

D-4 Designs of included studies examining methods and outcomes to measure protein quality in infant formula

D-5 Designs of included studies by global region in which they were conducted for scoping review examining methods for measuring protein quality in infant formula

D-6 Types of formula examined in included studies measuring protein quality in infant formulas

E-1 PRISMA flowchart for the infant formula and growth scoping review

E-2 Number of studies meeting inclusion criteria by study design

E-3 Number of studies meeting inclusion criteria by publication year

E-4 Number of studies meeting inclusion criteria by country of publication

E-5 Number of studies meeting inclusion criteria by funding and location

E-6 Number of studies meeting inclusion criteria by study population size and location

E-7 Number of studies meeting inclusion criteria by studies that reported race or ethnicity by location

E-8 Percentage of studies meeting inclusion criteria by number of FDA standards reported

E-9 Number of studies meeting inclusion criteria that evaluated infant formula modifications by location

E-10 Number of studies meeting inclusion criteria that evaluated outcomes of interest by location

TABLES

S-1 Timeline of Legislative and Regulatory Actions on Quality Factors

S-2 Decision Matrix for the Assessment of Protein Quality in Infant Formula

2-1 Eligibility Criteria for Examining Literature Describing Methods for Evaluating Protein Quality in Infant Formula

2-2 Eligibility Criteria for Scoping Review Examining Availability of Literature Describing Methods for Assessing the Ability of Modified Formula to Support Infant Growth

3-1 Regulatory Definition of Quality Factors

3-2 Timeline of Legislative and Regulatory Actions on Quality Factors

3-3 EFSA Recommended Minimum and Maximum Protein Composition for Infant Formula

3-4 Proposed Minimum Requirement for Indispensable and Conditionally Indispensable Amino Acids for Infant Formula to Align with Human Milk Reference

3-5 Pattern of Change in Indispensable Amino Acids Over the First 6 Months of Lactation

3-6 Overview of Protein Quality Assessment Methods in Humans

3-7 Assumptions and Possible Regulatory Applications Related to Protein Quality Assessments

3-8 Decision Matrix for the Assessment of Protein Quality in Infant Formula

4-1 Number of Studies Conducted Within and Outside of the United States Reporting the Food and Drug Administration Regulatory Requirements for Growth Monitoring Studies for Infant Formulas Based on Published Articles in the Scoping Review

4-2 Alternative Study Designs for Consideration to Demonstrate That a Formula Supports Normal Physical Growth

D-1 Eligibility Criteria for Scoping Review Examining Availability of Literature Describing Methods for Evaluating Protein Quality in Infant Formula

D-2 Sample MEDLINE Search Strategy for Scoping Review on Methods for Assessing Protein Quality in Infant Formula

D-3 Methods and Measures to Examine Protein Quality in Infant Formulas Using Animal Models (N = 11)

D-4 Methods and Measures to Examine Protein Quality in Infant Formulas Using in Vitro Models (N = 26)

E-1 Eligibility Criteria for Scoping Review Examining Availability of Literature Describing Methods for Assessing the Ability of Modified Formula to Support Infant Growth

E-2 Sample MEDLINE Search Strategy for Scoping Review on Methods for Assessing Modification of Infant Formula and Growth

E-3 Number of Studies Meeting Food and Drug Administration Regulations for Evaluation of Modifications of Infant Formula Conducted Within and Outside of the United States

E-4 Number of Studies Reporting the Statistical Significance Between Modified and Standard Infant Formulas by Location

E-5 Characteristics of Systematic Reviews Meeting Inclusion Criteria of the Infant Formula Scoping Review

Preface

While, globally, breastfeeding is consistently recommended as the preferred food for infants until at least 6 months, many receive commercially manufactured infant formula for a variety of reasons; in the United States, many infants receive formula as the sole source of nutrition prior to introduction of complementary foods. Regulations from various agencies around the world provide guidance on ensuring the safety and adequacy of infant formula; in the United States, this is done by the U.S. Food and Drug Administration (FDA). FDA regulations on quality factors in infant formula were first set out in 1996, with a final rule in 2014, but have not been updated since then. The 2023 Consolidated Appropriations Act (P.L. 117-328) directed FDA to enter into an agreement with the National Academies of Sciences, Engineering, and Medicine (the National Academies) “to examine and report on challenges in supply, market competition, and regulation of infant formula in the United States.” FDA requested that the National Academies examine and report on the state of the science regarding methodologies for assessing the biological quality of protein in an infant formula and the ability of an infant formula to support normal physical growth. In particular, the statement of task requested appraisal of regulatory requirements from other global jurisdictions to explore alternative methods and study designs for approval of infant formula for market.

It was an honor and pleasure to be asked to chair the committee that was tasked to undertake this assignment. As a former pediatric dietitian and then a research-intensive academic nutrition clinician-scientist, I have had a career-long dedication to research in nutrition for both prematurely

born and term infants. The call to serve on this committee was an opportunity that was appealing because it encompassed appraisal of current regulations of infant formulas for the market from a global perspective and review of evidence that might provide opportunities for alternate approaches to approval of new infant formulas. Thus, the hope is to improve nutrition for infants who are not able to be breastfed.

The committee was able to obtain insights beyond the statement of task through virtual open meetings with the FDA Deputy Director, Office of Nutrition and Food Labeling, Center for Food Safety and Applied Nutrition and staff that allowed it to further understand the intent of the task and assist in focusing its approach to the issues. Such information included (1) exploring the quality factor of sufficient biological quality of protein by evaluating the currently regulated use of protein efficiency ratio (PER) for that purpose and identifying alternative methods for determining protein quality and gaps in research and future directions, and (2) addressing quality factors of normal physical growth by considering the benefits and limitations of the growth monitoring study (GMS) design described in 21 CFR § 106.96(b) and identifying alternative methods or study designs and gaps in research related to GMS and future research directions.

A preplanned element of information gathering was a scoping review of relevant literature that was undertaken with the involvement of the Evidence Analysis Division of the Academy of Nutrition and Dietetics (AND). The committee worked with the AND director and staff to establish two separate protocols focused on different questions—one for protein quality and one for growth as a quality factor. We are grateful for the assistance provided by Deepa Handu, senior scientific director, and nutrition researchers Mary Rozga and Lisa Moloney. The AND team met with the committee initially to orient it to the methodology by which the evidence scan would be completed and develop the protocol for the two defined questions (protein quality and infant growth as a quality factor), address issues as they arose, and share the output from each of the two evidence scans.

Responding to the statement of task and preparing the report required a team effort. The committee concentrated on each of the issues by dividing into two working groups—one related to protein quality and the other to normal physical growth as a quality factor. In addition to planning the evidence scans, each group carried out narrative reviews to address questions that arose at working group meetings. This involved considerable time commitment, since each working group met weekly virtually, in addition to biweekly meetings of the whole committee, other meetings regarding the evidence scan or open sessions with the sponsor or other experts, and three in-person meetings held in Washington, D.C., and Toronto.

An information-gathering workshop was planned by the committee and held virtually in July 2024 (see program in Appendix C) at which the committee sought answers to specific questions from speakers from three continents and several countries who brought expertise and insights from their work in protein quality in food, including infant formula, and clinical trials in infants and scientists currently or formerly associated with infant formula companies in the United States and globally. Open sessions were held to obtain additional insights with some of the speakers, including researchers in the field and current or former employees in the infant formula industry. The scoping review information was not available until October/November 2024. For protein quality, the results of the scan had limited usefulness. For growth as a quality factor, the scan provided insights into variables used in published clinical trials and a comparison of how the variables measured differed between studies conducted in and outside of the United States (mostly from Europe).

In assembling the findings from all avenues of investigation, the committee developed three recommendations related to measurement of protein quality. The overall conclusion was that PER should not be used to establish the biological quality of protein in infant formula but rather that FDA should adopt the human milk amino acid pattern as the reference, as currently recommended by Codex, the European Food Safety Authority, and the European Union. This would embrace the concept of global harmonization. In addressing the task to offer alternate study designs, the committee proposed a decision matrix to assess protein quality.

For the question of normal physical growth as a quality factor, the committee established two recommendations that centered on the need for detailed guidance documents for the conduct of GMSs designed to evaluate modified infant formulas as currently used in regulations in other countries in Europe and Australia. Furthermore, such guidance documents should allow for flexibility in requirements relative to the modification in the formula being tested. Finally, the committee offered suggestions for research to advance knowledge in the relevant fields.

Expertise in the committee spanned protein chemistry and clinical biochemistry, clinical pediatric research, epidemiology related to growth, public health at a global level, current standards for good practice in regulatory analysis of formula, and animal and basic science, including animal models. I am extremely grateful to the members of the committee: Steven A. Abrams, Teresa A. Davis, Rajavel Elango, Shibani Ghosh, James D. House, Daniel Roth, John C. Wallingford, and Xiaobin Wang, (see Appendix A). On behalf of the committee, I would like to pay special tribute to our colleague Dr. James (Jim) Duncan House, who passed away on September 10, 2024, from a disease he had been bravely fighting while contributing to the project on a weekly basis with scientific rigor and

enthusiasm. His passing was a great shock that created a profound sadness and sorrow among our committee. Jim brought outstanding expertise in the fields of food and human nutritional sciences and sustainable protein. He made impactful contributions to developing Chapter 3 (on protein quality) until August 2024. My sincere thanks for consultative support of the committee’s deliberations are also extended to Hildegard Przyrembel, BfR Institute, Berlin, Germany (retired), who contributed her expertise in regulations for infant formula in Europe, and Melissa MaitinShepard, science writer, MMS Health Strategies, LLC.

It was an immense personal pleasure to work once again with Ann Yaktine, Food and Nutrition Board director, whose incredible experience in such projects provided valuable guidance throughout the project that was greatly appreciated by the committee. The committee is also extremely grateful to Katherine Delaney, who supported it as a study director in the final stages. Finally, the committee wishes to sincerely thank the excellent staff at the National Academies, including research associates Sarah Poncet Landolt and Jen Stephenson, research assistant Melanie Arthur, Andi Reiser, senior program assistant, and Alice Vorosmarti, associate program officer.

Stephanie A. Atkinson, Chair
Committee on Protein Quality and Growth Monitoring Studies to Satisfy Quality Factor Requirements for Infant Formula

Acronyms and Abbreviations

This page intentionally left blank.