Contains Nonbinding Recommendations 
Draft-Not for Implementation 
Substantiation for Structure/Function 
Claims Made in Infant Formula Labels 
and Labeling: 
Guidance for Industry  
Draft Guidance
This guidance is being distributed for comment purposes only. 
Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to 
ensure that the agency considers your comment on this draft guidance before it begins work 
on the final version of the guidance, submit either electronic or written comments on the draft 
guidance within 60 days of publication in the Federal Register of the notice announcing the 
availability of the draft guidance.  Submit electronic comments to 
http://www.regulations.gov.  Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.  All comments should be identified with the docket number listed in 
the notice of availability that publishes in the Federal Register.  
For questions regarding this draft document, contact the Center for Food Safety and Applied 
Nutrition (CFSAN) at 240-402-1451. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Food Safety and Applied Nutrition 
September 2016 
1  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
Table of Contents
  
 
I.  Introduction 
 
II. Discussion 
A. The Substantiation Standard 
B. Identifying the Meaning of the Structure/Function Claim 
C. Recommended Process for Evaluating the Scientific Evidence for a 
Structure/Function Claim   
D. Identifying Relevant Studies on the Relationship between the Product or 
Constituent and the Claimed Effect on the Structure or Function of the Body 
E. Critical Elements for Intervention Studies  
F. Quality Considerations for Intervention Studies 
G. Evaluating the Strength of the Totality of the Evidence and Applying the 
Substantiation Standard 
 
III. Conclusion 
 
IV. References 
 
2 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
  
Substantiation for Structure/Function Claims Made in 
Infant Formula Labels and Labeling 
1
Guidance for Industry  
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or we) on this topic.  It does not establish any rights for any person and is 
not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
contact the FDA staff responsible for this guidance as listed on the title page.  
 
 
 
I.    Introduction  
 
This guidance document describes the type and quality of evidence that the Food and Drug 
Administration (FDA or we) recommends infant formula manufacturers and distributors have to 
substantiate claims about effects on the structure or function of the body (structure/function 
claims) made on the label and in other labeling of nonexempt and exempt2 infant formulas.  The 
purpose of this guidance document is to help infant formula manufacturers and distributors 
making structure/function claims to comply with the statutory requirement that all claims in food 
labeling must be truthful and not misleading under section 403(a)(1) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 343(a)(1)). 
 
FDA regulates infant formula under the FD&C Act.  Section 201(z) of the FD&C Act (21 U.S.C. 
321(z)) defines infant formula as a food which purports to be or is represented for special 
dietary use solely as a food for infants by reason of its simulation of human milk or its suitability 
as a complete or partial substitute for human milk.  FDA regulations in Title 21 of the Code of 
Federal Regulations (21 CFR) define the term infant as a person not more than 12 months 
old (21 CFR 106.3).  Although human milk is the recommended source of nutrition for infants 
(Ref. 1), infant formula nonetheless provides the sole source of nutrition for many infants during 
a vulnerable period of life when diet plays a critical role in affecting long-term growth and 
development.  
                                                 
1 This guidance has been prepared by the Office of Nutrition and Food Labeling in the Center for Food Safety and 
Applied Nutrition at the U.S. Food and Drug Administration.  
2 Nonexempt infant formulas are represented and labeled for use by healthy, full-term infants.  Such formulas are 
subject to the requirements set forth in section 412(a), (b), and (c) of the FD&C Act (21 U.S.C. 350a(a), (b), and 
(c)).  Exempt infant formulas are represented and labeled for use by infants who have an inborn error of metabolism 
or low birth weight or who otherwise have an unusual medical or dietary problem.  Under section 412(h) of the 
FD&C Act (21 U.S.C. 350a(h)), these infant formulas are exempt from the requirements of section 412(a), (b), and 
(c) of the FD&C Act; exempt infant formulas are, however, subject to the requirements of 21 CFR part 107, subpart 
C, Exempt Infant Formulas. 
3 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
Under the FD&C Act, claims about foods, including infant formula, may be made in labeling to 
the extent that those claims are not prohibited by law.  As with all FDA-regulated foods, under 
section 403(a)(1) of the FD&C Act (21 U.S.C. 343(a)(1)), claims made in the labeling of infant 
formula must be truthful and not misleading.  If a claim in infant formula labeling is false or 
misleading in any particular, the formula is misbranded.   
 
This guidance focuses on structure/function claims in infant formula labeling.3  A 
structure/function claim is a claim about an effect on the normal structure or function of the 
human body.  For example, a structure/function claim might describe the role of an infant 
formula constituent4 intended to affect normal structure or function in the human body (see 
http://www.fda.gov/foodlabelingguide) (Ref. 2), or might characterize the mechanism by which 
the constituent acts to maintain such structure or function.  FDA does not preapprove 
structure/function claims in the labeling of conventional foods and dietary supplements.   
 
We have not previously issued guidance on the substantiation of structure/function claims in the 
labeling of conventional foods, including infant formula.  However, we have issued guidance on 
the substantiation of structure/function claims in dietary supplement labeling.  See Guidance for 
Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the 
Federal Food, Drug, and Cosmetic Act (Ref. 3).  
 
Under the Dietary Supplement Health and Education Act of 1994 (DSHEA) (Pub. L. 103-417), 
which created a distinct regulatory scheme for dietary supplements, structure/function claims for 
dietary supplements may relate to non-nutritive effects on the structure or function of the body, 
as well as to nutritive effects.  DSHEA excepted from the definition of drug under section 
201(g)(1) of the FD&C Act (21 U.S.C. 321(g)(1)) a dietary supplement for which the label or 
labeling contains certain truthful and not misleading statements, including claims about effects 
on the structure or function of the body, when such statements are made in accordance with 
section 403(r)(6) of the FD&C Act (21 U.S.C. 343(r)(6)).  Section 403(r)(6) pertains to dietary 
supplements exclusively, meaning that this provision does not govern structure/function claims 
for conventional foods; therefore, structure/function claims on the labeling of conventional foods 
do not have the same broad scope.  The narrower scope of structure/function claims for 
conventional foods derives from section 201(g)(1)(C) of the FD&C Act (21 U.S.C. 
321(g)(1)(C)), which defines drug to include articles (other than foods) intended to affect the 
structure or any function of the body.  Case law has interpreted the other than food exception 
as applying to articles consumed primarily for taste, aroma, or nutritive value (see Nutrilab v. 
                                                 
3 Structure/function claims are one of three categories of claims related to nutrition made on food labeling.  The 
other two types of claims are health claims and nutrient content claims.  Health claims characterize the 
relationship between a food or food component and the risk of a disease or health-related condition.  Under 21 CFR 
101.14(e)(5), health claims may not appear on infant formulas unless such use is specifically provided for in 21 CFR 
part 101, subpart E.  Under 21 CFR 101.14(f)(1), the requirements of 21 CFR 101.14 do not apply to infant formulas 
subject to section 412(h) of the FD&C Act (i.e., exempt infant formulas).  Nutrient content claims characterize the 
level of a nutrient in a food.  With a few exceptions, nutrient content claims are prohibited under 21 CFR 
101.13(b)(3) for use on foods specifically intended for infants and children less than 2 years of age, unless the claim 
is specifically provided for under 21 CFR parts 101, 105, or 107. 
4 We use the term constituent in this guidance to include substances that are inherent components of a product as 
well as those that are added ingredients. 
4 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
Schweiker, 713 F.2d 335 (7th Cir. 1983)).  Foods affect the structure and function of the body by 
virtue of providing nutrition to sustain life and health.  Accordingly, to remain within the scope 
of the other than food exception and avoid the possibility of subjecting the product to 
regulation as a drug, a structure/function claim in the labeling of infant formula should derive 
from the products character as a food.     
 
We are aware that infant formula products also may bear labeling claims that suggest that the 
product contains constituents found in breast milk or that the product is closer to breast milk 
than other formulas.  These are not structure/function claims and are not addressed in this 
guidance.  We also note that infant formula manufacturers must establish the safety of 
constituents before adding them to their products.  Because infancy is a unique, vulnerable 
period when critical growth and development occur, great care is necessary to ensure the safety 
of all modifications to infant formula (Ref. 4, pp. 1, 39), even if the purpose of the modification 
is to more closely mirror the composition and health benefits of human milk.    
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe our current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDA guidances means that something is suggested or 
recommended, but not required.  
 
II.  Discussion 
A.  The Substantiation Standard 
 
We have recommended that dietary supplement firms substantiate structure/function claims for 
their products with evidence that meets the competent and reliable scientific evidence standard 
originally developed by the Federal Trade Commission (FTC) (see 
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Dieta
rySupplements/ucm073200.htm) (Ref. 3).  As with dietary supplements, FDA and FTC have 
overlapping jurisdiction with regard to infant formula products.  Under the FD&C Act, we have 
exclusive jurisdiction over the safety, and primary jurisdiction over the labeling, of infant 
formula products.  FTC has primary jurisdiction over advertisements for infant formula products. 
Given these jurisdictional assignments, we and the FTC share an interest in providing guidance 
on what substantiation means.  FDA therefore intends to apply the competent and reliable 
evidence standard for the substantiation of infant formula claims in a manner that is consistent 
with FTCs and FDAs approach for the substantiation of dietary supplement claims. 
 
5 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
Although there is no general rule for how many studies or what combination of study types are 
sufficient to substantiate a structure/function claim, the replication of research results in 
independent, well-conducted studies makes it more likely that the totality of the scientific 
evidence will substantiate a claim.  In the context of infant formulas, we believe that competent 
and reliable scientific evidence means evidence that includes findings from well-designed and 
controlled intervention studies in an appropriate population of U.S. infants (or infants with 
similar nutrition and general health status) using an appropriate formula matrix with and without 
the constituent of interest, as described more fully below.  In addition, we believe that the 
scientific evidence should include any other relevant studies that have used similar infant 
formula matrices with the same constituent fed to an appropriate population.  All studies relied 
on to substantiate a claim should be evaluated using the methods described in this guidance.    
 
B.  Identifying the Meaning of the Structure/Function Claim 
 
The first step in determining what information is needed to substantiate a structure/function 
claim for an infant formula is to understand the meaning of the claim and to clearly identify each 
express and implied claim.  Consumer testing may be useful to determine consumer 
understanding of each claim in context.     
 
Manufacturers and distributors should focus not only on individual statements or phrases, but 
also on what effects on the structure or function of the body are being claimed when all 
statements being made for the product are considered together (i.e., in the context of the labeling 
as a whole).  Although it is important to substantiate individual statements that make express 
claims, it is equally important to substantiate the overall message conveyed when all the 
statements and graphics in the labeling are considered together.  
 
C.  Recommended Process for Evaluating the Scientific Evidence for a Structure/Function 
Claim 
 
In determining whether there is adequate scientific evidence to substantiate a structure/function 
claim, we recommend that infant formula manufacturers and distributors consider the use of a 
systematic evidence-based review process for evaluating the strength of the evidence.  Infant 
formula manufacturers and distributors should evaluate the strength of the scientific evidence to 
determine whether it substantiates their proposed claim about a relationship between a product or 
constituent and a beneficial effect on the structure or function of the body.  The evaluation 
process should involve the following series of steps: 
 
  Identifying relevant studies on the relationship between the specific product or 
constituent and the claimed structure/function benefit in infants. 
  Eliminating studies from which no conclusions can be drawn about the relationship 
between the product or constituent and a structure/function benefit in infants. 
  Evaluating methodological and design quality of the studies from which scientific 
conclusions can be drawn. 
  Evaluating the strength of the totality of scientific evidence to determine whether the 
substantiation of the evidence meets the competent and reliable scientific evidence 
standard. 
6 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
For further examples of, and information on, systematic evidence-based reviews, see the 
websites below: 
 
  FDAs Guidance for Industry: Evidence-Based Review System for the Scientific 
Evaluation of Health Claims  Final  (January 2009),  
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation
/LabelingNutrition/ucm073332.htm.   
  Lichtenstein AH, Yetley EA, Lau J. Application of Systematic Review Methodology to the 
Field of Nutrition: Nutritional Research Series, Vol. 1. Rockville (MD): Agency for 
Healthcare Research and Quality (US); 2009 Jan.  (Technical Reviews, No. 17.1.) 
Available at http://www.ncbi.nlm.nih.gov/books/NBK44076/.    
  Agency for Healthcare Research and Quality website:  
http://www.ahrq.gov/research/findings/evidence-based-
reports/technical/methodology/index.html.  Accessed July 29, 2016. 
  National Institutes of Health, Office of Dietary Supplements, Evidence-Based Review 
Program website:  https://ods.od.nih.gov/Research/Evidence-
Based_Review_Program.aspx.  Accessed July 29, 2016. 
 
D.  Identifying Relevant Studies on the Relationship between the Product or Constituent 
and the Claimed Effect on the Structure or Function of the Body   
  
Direct evidence provides the strongest basis for showing a cause-and-effect relationship between 
an infant formula product or constituent and a beneficial effect on the structure or function of the 
body in infants (e.g., support for brain development, immune system, or digestion).  Because 
results of randomized, controlled, double-blind intervention studies provide the most direct 
evidence for a cause-and-effect relationship (Ref. 5), we recommend that the substantiation for 
structure/function claims in infant formula labeling rely primarily on the results of infant feeding 
intervention studies.  We consider the most appropriate design for an intervention study for an 
infant formula to be randomized, double blind, and parallel-controlled.  When such a study is 
properly conducted and a statistically significant difference is shown between the infants fed the 
formula with the new constituent and the infants fed a control formula without the new 
constituent, the study can provide evidence of a cause-and-effect relationship (Ref. 5, Ref. 6, pp. 
8-12, 57, 71).  
  
Although intervention studies are the only type of study that can demonstrate a cause-and-effect 
relationship, other types of studies may be useful as supportive evidence in evaluating the 
relationship between an infant formula product or constituent and a structure/function benefit.  
Such studies could include the following:  
 
  Observational studies, which provide evidence for an association, but cannot be used to 
determine whether the association is causal (Ref. 7).  
  Research synthesis studies, which are useful as background and for identifying relevant 
studies, but do not provide enough information to evaluate the quality of individual 
studies. 
7 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
  Animal and in vitro studies, which can be useful models for generating hypotheses and 
studying mechanisms of action (Ref. 4, p. 7).   
 
Manufacturers and distributors could use results from studies with these designs as evidence to 
establish an association between a product or constituent and the claimed structure/function 
benefit, or to support a biologically plausible mechanism.  However, results from such studies do 
not provide direct evidence for a cause-and-effect relationship.  Although these other study 
designs are limited in their usefulness to substantiate a structure/function claim in infant formula 
labeling, they can provide additional supportive evidence for a claim if they are consistent with 
the findings of well-designed and conducted intervention studies.   
 
E.  Critical Elements for Intervention Studies 
Certain critical elements of a study, such as design, data collection, and data analysis, may be so 
flawed that they make it impossible to draw scientific conclusions from the study.  Such 
seriously flawed studies should be eliminated from the review of the evidence.  The following 
paragraphs describe some aspects of intervention studies that manufacturers and distributors 
should consider in deciding whether any conclusions can be drawn from an intervention study 
about the relationship between an infant formula product or constituent and an effect on the 
structure or function of the body.    
 
Ethical considerations.  Any study considered for evaluation must comply with 21 CFR part 50, 
Protection of Human Subjects; 21 CFR part 56, Institutional Review Boards; and/or 45 CFR part 
46, Protection of Human Subjects.   
 
Appropriate population.  Infancy is a critical period of growth and development during which 
breast milk or infant formula (or a combination of the two) is the sole source of nutrition for the 
first 4 to 6 months of life and remains an important source of nutrition for the next 6 to 8 months.  
Research conducted in other age groups may not be generalizable to this vulnerable population.   
 
In general, we would not consider a study in non-infant populations as evidence to substantiate a 
structure/function claim in the labeling of infant formula.  However, if studies have been 
conducted and have concluded that the mechanism of action for the cause-and-effect relationship 
being claimed in infants is the same as in non-infant populations, then a well-designed and 
conducted study in a non-infant population could provide supporting evidence.  
 
Appropriate endpoints.  An important consideration is whether the studies provide evidence to 
support a relationship between the infant formula product or constituent and the claimed effect 
on the structure or function of the body.  Studies should identify one or more specific endpoints 
that are measures for the claimed benefit.  For example, a claim of support for brain development 
could be supported by an age-appropriate assessment of neurological development as an 
endpoint.  There should be a plausible biological and physiological relationship between the 
endpoint measured and the benefit that is claimed for the infant formula product or constituent.  
The endpoints for measuring the claimed structure/function benefit, as well as the nature of the 
benefit itself, should be clearly defined in the study design.  Scientific conclusions cannot be 
8 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
drawn about the relationship between the constituent or product and the claimed 
structure/function benefit if the endpoint being evaluated is not linked to the claimed benefit.   
 
We recommend that the endpoints measured in studies used to substantiate a structure/function 
claim be recognized and accepted as measures of the claimed benefit by experts in the field or a 
recognized, authoritative scientific body.  We would expect that the primary endpoint be readily 
measurable and interpretable so that it can provide reliable evidence about whether the 
intervention provides a clinically meaningful benefit (Ref. 8).  Additionally, to be informative, 
we would expect that clinical trials would use primary endpoints and outcome measures that are 
well defined, valid, reliable, and clinically relevant (Ref. 9).  Examples of documentation that 
an endpoint is recognized and accepted by qualified experts or an authoritative scientific body 
include (a) the opinion of an expert panel that is specifically convened for this purpose by an 
authoritative body such as the National Academy of Sciences, or (b) the opinion or 
recommendation of a federal government scientific body with relevant expertise, such as the 
National Institutes of Health or the Centers for Disease Control and Prevention. 
 
Adequate statistical power.  Adequate statistical power is central to the design of a study and 
interpretation of the study results.  We recommend that manufacturers and distributors carefully 
consider how many subjects are needed in each study group to ensure that the study is adequately 
powered to address the study objective.  Furthermore, studies are typically powered to be able to 
detect a difference in the primary study endpoint.  If the beneficial outcome that is the subject of 
the claim is not measured by the primary endpoint of the study, then the sample size should be 
adequate to address the desired outcome (Ref. 6, pp. 13-15, 57-65).  An inadequate sample size 
can result in a failure to address the study objective and to detect a difference if one actually 
exists, making the study inconclusive.  Without adequate statistical power, scientific conclusions 
cannot be drawn about a cause-and-effect relationship between a product or constituent and the 
claimed effect on structure or function in infants. 
 
Appropriate intervention.  When studying the effects of individual nutrients or other 
constituents, the control formula should be identical to the test formula, except that the control 
formula does not contain the constituent that is the subject of the claim (Ref. 10, pp. 10-18).  
Otherwise, differences between the test and control formulas can confound the study results and 
prevent researchers from drawing scientific conclusions about a cause-and-effect relationship 
between the nutrient or constituent and the claimed structure/function benefit. 
 
Appropriate control group.  An appropriate control group is a sample of infants drawn from 
the same population as the test group and concurrently fed a control formula that is identical to 
the test formula, except that the formula used for the control group does not contain the 
constituent that is the subject of the claim or have some other characteristic(s) of the infant 
formula product that is the subject of the claim.  If an appropriate control group is not included, 
then it is not possible to ascertain whether changes in the endpoints of interest were due to the 
constituent in the infant formula or the relevant infant formula product characteristic(s) or due to 
unrelated and uncontrolled extraneous factors.  Thus, without an appropriate control group, 
scientific conclusions cannot be drawn about a cause-and-effect relationship between a 
constituent or infant formula product and the claimed structure/function benefit (Ref. 6, pp. 70-
71; Ref. 10, p. 13).  
9 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
 
Baseline measurements.  Measurements of endpoints for the claimed effect on the structure or 
function of the body need to be taken at the beginning of the study to provide a baseline for 
interpreting the results of the intervention.  For example, in a study of bone mass in infants, any 
observed effect that might have resulted from the intervention could not be interpreted with 
certainty if the bone mineral content in the intervention and control groups differed at baseline 
(Ref. 6, pp. 61-62; Ref. 10, p. 13).  Thus, if the baseline measurements are significantly different 
between groups, no scientific conclusions can be drawn about whether the constituent or product 
actually provides the claimed benefit to structure or function. 
 
Statistical analysis.  Statistical analysis of the study data is a critical factor for interpreting the 
results because it provides the basis to interpret any differences between participants consuming 
the test formula and those consuming the control formula (Ref. 11).  When statistical analyses 
between the control and intervention groups are not performed, scientific conclusions cannot be 
drawn about the relationship between the constituent or product and the claimed effect on the 
structure or function of the body.   
 
F.  Quality Considerations for Intervention Studies 
 
Infant formula manufacturers and distributors should consider the scientific quality (e.g., design 
and methodology) of the studies when deciding whether the results of the studies substantiate a 
claim.  It is possible for a study to have numerous and/or significant problems with respect to 
quality such that scientific conclusions may not be drawn about the relationship between the 
constituent or product and the claimed structural or functional benefit.  Such poor-quality studies 
should be eliminated from consideration.  We recommend that infant formula manufacturers and 
distributors consider the following aspects of intervention studies in evaluating study quality. 
 
Adequate criteria for selecting participants in the study.  The study should establish 
recruitment criteria for the study participants.  Inclusion and exclusion criteria for selection of 
study participants should be set before recruitment to ensure that the population of interest is 
clearly defined, and these criteria should be well described in the study protocol and in the 
methods section of a research paper or study report (Ref. 6, p. 14; Ref. 12, pp. 90-92).   
 
Attrition.  Because a high dropout rate can affect the interpretation of study results, it is 
important to know how many participants leave the study before it ends and whether the 
dropouts are evenly distributed between groups.  The study should describe why each participant 
dropped out and whether the reason for dropping out was related to the intervention (Ref. 6, pp. 
64-65; Ref. 10, pp. 10-18).  In addition, if there is a marked number of dropouts, the study may 
no longer be adequately powered to detect a statistical difference between the groups (Ref. 6, pp. 
14-15, 57-61). 
 
Study conduct.  Compliance with the study protocol should be verified.  For example, were all 
case report forms reviewed for completeness, accuracy, and legibility by the principal 
investigator?  Collecting and recording data as specified in the study protocol maintain the 
credibility of the research.  The study protocol should address elements of study conduct such as 
10 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
ongoing compliance monitoring, staff training, calibrating instruments, and the use of validated 
metrics. 
 
Study length.  If the claim mentions a timeframe within which the claimed effects are expected 
to occur, the length of supporting studies should be sufficient to substantiate the claimed duration 
of the benefit.  For example, if benefits have been observed in infants at a certain age, it should 
not be assumed that the benefit will continue into adolescence or adulthood (Ref. 6, p. 230) 
without data from studies that evaluated adolescents or adults.  Follow-up studies should be 
undertaken to substantiate any claims for structure/function benefits that continue past infancy. 
 
Specificity of study results.  If a structure/function claim is being made in the labeling of an 
infant formula that is intended for healthy, term infants, then studies including an appropriate 
sample of healthy, term infants are most relevant.  Conversely, if a claim is being made on an 
infant formula that is intended for a particular population of infants (e.g., colicky infants), then 
the studies included in the evaluation should be studies of that population of infants because 
benefits observed in one infant population may not be generalizable to another infant population 
(Ref. 6, p. 108; Ref. 13). 
 
For studies relating to specific nutrients or other constituents, a structure/function benefit 
demonstrated for the constituent in one matrix (e.g., cow milk-based formula) may not be 
generalizable to other matrices (e.g., soy protein isolate-based formula) because the beneficial 
outcome may vary among matrices due to different interactions within each matrix.  In addition, 
the effect of the constituent may be influenced by the processing conditions, which can vary with 
the matrix.  For example, the heat processing of infant formulas will affect the survival of 
microorganisms intentionally added to infant formulas (see 21 CFR part 113).  
 
In evaluating the relevance of a particular study to your claim, one important factor is whether 
the constituent that is the subject of the claim was used in the same form and amount in the study 
as in the infant formula that will bear the claim.  If the study did not use the same form and 
amount of the constituent, then its usefulness as evidence to substantiate the claim is limited 
because different forms and amounts of the constituent contained in infant formulas may yield 
different effects.  Therefore, we recommend that the studies use the same form and amount of the 
constituent in the same or similar formula matrix as the infant formula that will bear the claim.   
 
Statistical analysis approach.  The statistical approach used in a study should be part of the 
study design and should be determined before the study begins.  The statistical analysis should 
account for any confounding variables (e.g., sex, birth weight, and age at study day one in a 
growth monitoring study).  Post-hoc analyses should not be added after the study is underway, as 
this will likely lead to erroneous conclusions (Ref. 6, pp. 106-108).  Normally, statistical analysis 
should be conducted on baseline data for all subjects initially enrolled in the study, not just for 
those who completed the study.  However, an analysis with the baseline data from all subjects 
initially enrolled may not be appropriate if attrition from the study was significant and affected 
the composition of the intervention group differently from the control group. 
 
 
11 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
G.  Evaluating the Strength of the Totality of the Evidence and Applying the Substantiation 
Standard 
 
We recommend that infant formula manufacturers and distributors systematically review all 
evidence, favorable and unfavorable, and consider the strength of the entire body of evidence in 
terms of study type, methodological and design quality, number of studies of each type, sample 
sizes, relevance of the evidence to the targeted infant population, replication of results, and 
overall consistency of the total body of evidence.  The evidence should include well-designed 
and conducted intervention studies in U.S. infants (or infants with similar nutrition and general 
health status) using a formula matrix with and without the constituent of interest.  When 
assessing the relevance of individual studies, manufacturers and distributors should consider how 
the formula matrix studied compares to the formula matrix in which the constituent is to be 
marketed.   
 
Infant formula manufacturers and distributors should also consider the statistical and clinical 
significance of each studys results.  For an intervention study to demonstrate an effect, the 
difference in endpoints demonstrated between the intervention group and control group should 
be statistically significant, based on the level of significance determined as part of the study 
design (e.g., p < 0.05).  Manufacturers and distributors should also consider whether the results 
of the studies are clinically meaningful, since a statistically significant difference between the 
intervention and control groups may not be clinically significant (Ref. 6, pp. 106-108; Ref. 10, 
pp. 10-18).   
 
Conflicting or inconsistent results among those studies that were not eliminated from 
consideration due to critical flaws or multiple quality deficiencies do not necessarily disprove an 
association; however, without a plausible explanation based on consideration of study quality or 
type (e.g., intervention vs. observational) or other factors, disparities in study results raise 
questions about the scientific basis for the claim.  In general, there will be greater confidence that 
a relationship between the constituent or product and the claimed benefit exists if there is 
consistency among multiple studies in showing the claimed structure or function benefit.  If there 
is no plausible explanation for the conflicting results, further studies may be necessary to 
elucidate the reasons for the discrepancies and to substantiate the proposed claim.   
 
After assessing the totality of the evidence, infant formula manufacturers and distributors should 
consider whether the totality of the evidence reaches the substantiation standard of competent 
and reliable scientific evidence.  We consider the following factors important to establish 
whether information would constitute "competent and reliable scientific evidence": 
  What are the individual studys strengths and weaknesses?  For example, consider the 
quality of the study and the peer review. 
  If multiple studies exist, do the studies that have the highest quality suggest a particular 
outcome? 
  If multiple studies exist, what do most studies suggest or find?  Does the totality of the 
evidence agree with the claim(s)? 
12 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
    
  Do other study designs that are limited in their usefulness to substantiate a 
structure/function claim in infant formula labeling provide additional supportive evidence 
for a claim? 
 
III.  Conclusion 
 
Structure/function claims on infant formula labeling generally describe the role of a product or 
constituent intended to affect normal structure or function in infants or the means by which a 
product or constituent acts to maintain structure or function.  Such claims should derive from the 
infant formulas character as a food.  In determining what evidence is needed to substantiate a 
structure/function claim, the infant formula manufacturer and distributor should understand and 
consider the meaning of the claims in the context of the labeling as a whole.  Because results of 
well-designed and conducted intervention studies provide the most direct evidence for a cause-
and-effect relationship, we recommend that the substantiation for structure/function claims in 
infant formula labeling rely on the results of infant feeding intervention studies that are 
randomized, double-blind, and parallel-controlled.   
 
In considering studies for the substantiation of structure/function claims, we recommend that 
infant formula manufacturers and distributors conduct a systematic, evidence-based review.  
Infant formula manufacturers and distributors should use the results of this review to determine if 
the structure/function claims meet the competent and reliable scientific evidence standard.   
 
We recommend that infant formula manufacturers and distributors retain in their files the 
documentation substantiating each of their claims so that they can readily address any questions 
that may arise.    
 
IV.  References 
 
We have placed the following references on display in the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  You may 
see them at that location between 9 a.m. and 4 p.m., Monday through Friday.  As of July 29, 
2016, FDA had verified the website address for the references it makes available as hyperlinks 
from the Internet copy of this guidance, but FDA is not responsible for any subsequent changes 
to Non-FDA website references after July 29, 2016.  
 
1.  American Academy of Pediatrics, Section of Breastfeeding.  Breastfeeding and the use of 
human milk.  Pediatrics. Vol. 115 No. 2 February 2005, pp. 496-506. 
 
2.  FDA.  Guidance for Industry:  A Food Labeling Guide.  Revised January 2013.  
http://www.fda.gov/foodlabelingguide.   
 
3.  FDA.  Guidance for Industry:  Substantiation for Dietary Supplement Claims Made Under 
Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act.  December 2008. 
13 
  Contains Nonbinding Recommendations 
Draft-Not for Implementation 
http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/Dietar
ySupplements/ucm073200.htm.  
 
4.  Institute of Medicine.  Infant  formula:  Evaluating the safety of new ingredients.  National 
Academies Press.  Washington, DC.  2004.  pp. 1, 7, 39. 
 
5. Merrill, R. Introduction to Epidemiology - 7th Ed. Jones & Bartlett Learning, Sudbury, MA. 
2015.  Chapter 8. STAT!Ref Online Electronic Medical Library: 
http://online.statref.com/Document.aspx?fxId=451&docId=118.    
 
6.  Riegelman, R.K.  Studying a Study and Testing a Test.  Fourth Edition.  Lippincott Williams 
& Wilkens.  Philadelphia.  2000.  pp. 8-15, 57-65, 70-71, 106-108, 230. 
 
7.  Sempos, C.T., Liu, K., Earnst, N.D.  Food and nutrient exposures:  What to consider when 
evaluating epidemiologic data.  American Journal of Clinical Nutrition 1999; 69:1330S-1338S.  
 
8. Fleming T.R., Powers, J.H. Biomarkers and surrogate endpoints in clinical trials. Statistics in 
Medicine 2012; 31 pp. 2973-2984. 
 
9.  Sun H, Como PG, Downey LC, Murphy D, Ariagno RL, Rodriguez W. Infant formula and 
neurocognitive outcomes: Impact of study end-point selection.  J Perinatol. 2015 Oct;35 pp. 847-
874. 
 
10.  Derr, J.A.  Chapter 2 Statistical aspects of controlled diet studies.  In:  Dennis, B.H., 
Ershow, A.G, Obarzzanek, E., Clevidence, B., Editors, Well-Controlled Diet Studies in Humans - 
A Practical Guide to Design and Management, American Dietetic Association.  Chicago, IL.   
1997.  pp. 10-18. 
 
11.  Cheney, C.L., Chapter 27, Statistical Applications. In:  Monsen, E.R. Editor, Analytic 
Research Designs.  American Dietetic Association.  Chicago, IL.  2003.  pp. 399-415. 
 
12. Dennis, B.H., Kris-Etherton, P.M.,  Chapter 7.  Designing, managing and conducting a  
clinical nutrition study.  In:  Monsen, E.R. Editor, Analytic Research Designs.  American 
Dietetic Association.  Chicago, IL.  2003.  pp. 90-92. 
 
13.  FDA Food Advisory Committee.  Transcript of Committee Meeting on Infant Formula.  
Greenbelt, MD.  April 4-5, 2002.  http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm.   
14