Ms. Melanie Fairchild-Dzanis

Regulatory Discretion, Inc

12 Vreeland Road – Box 697

Florham Park, NJ 08932-0697

RE:  Qualified Health Claim Petition for the Relationship Between 100%
Whey-Protein Partially Hydrolyzed Infant Formula and Reduced Risk of
Atopic Dermatitis (Docket No. FDA-2009-Q-0301)

Dear Ms. Fairchild-Dzanis:

This letter responds to the qualified health claim petition received by
the Food and Drug Administration (FDA or the agency) on May 22, 2009,
which you submitted on behalf of Nestlé Nutrition.  The petition was
submitted pursuant to Section 403(r)(4) of the Federal Food, Drug, and
Cosmetic Act (the Act) (21 U.S.C. § 343(r)(4)) and in accordance with
FDA’s guidance on the procedures for the submission of qualified
health claim petitions (“FDA procedures guidance”).  The petition
requested that the agency exercise enforcement discretion for a
qualified health claim characterizing the relationship between the
consumption of 100 percent whey-protein partially hydrolyzed infant
formula and reduced risk of atopic dermatitis.

 

The petition proposed the following model health claim to be used on the
labels or in the labeling of infant formulas: 

Breastfeeding is the best way to nourish infants.  For infants who are
not exclusively breastfed, emerging clinical research shows that, in
healthy infants with family history of allergy, feeding a 100%
Whey-Protein Partially Hydrolyzed infant formula instead of a formula
containing intact cow’s milk proteins may reduce the risk of
developing the most common allergic disease of infancy – atopic
dermatitis – throughout the 1st year of life and up to 3 years of age.
 

Partially hydrolyzed formulas are not intended to treat existing food
allergy symptoms.  If you suspect your baby is already allergic to milk,
or if your baby is on a special formula for the treatment of allergy,
your baby’s care and feeding choices should be under a doctor’s
supervision.

FDA filed the petition on July 6, 2009 and posted the petition on the
FDA website for a 60-day comment period, consistent with the FDA
procedures guidance. One comment was submitted to the docket; however,
the comment concerned nutrition labeling issues that were unrelated to
the qualified health claim petition and the agency’s decision
concerning such petition.  Therefore, the agency is not addressing the
comment in this letter.  

The initial date for the agency’s response to your petition was
February 16, 2010. After mutual agreements, the date for the agency’s
response was extended to April 16, 2010. Based on your March 2, 2010
request to meet with FDA to discuss the scientific evidence supporting
the claim, FDA met with Nestlé on May 11, 2010.  At the May 11, 2010
meeting, FDA requested additional data from Nestlé in order for FDA to
complete its review of the petition.  On November 8, 2010, FDA received
the requested information from Nestlé, which included a supplemental to
Section B of the original petition and a pamphlet from the American
Academy of Allergy Asthma and Immunology. On February 4, 2011, FDA
requested specific information from Nestlé on the infant formulas used
in the studies to support the petitioned claim. Nestlé provided this
information on February 11, 2011.

FDA has determined that the current scientific evidence is appropriate
for considering the exercise of enforcement discretion with respect to a
qualified health claim concerning the relationship between 100%
whey-protein partially hydrolyzed infant formula and a reduced risk of
atopic dermatitis for a specific infant population who is fed such
formula during a specific period of time.  

Accordingly, this letter sets forth the basis of FDA’s determination
that the current scientific evidence is appropriate for consideration of
a qualified health claim on 100 percent whey-protein partially
hydrolyzed infant formulas.  In addition, this letter sets forth (in the
“Conclusions” section) qualified health claim language for which FDA
intends to exercise enforcement discretion. This letter also sets out
the factors that FDA intends to consider in the exercise of its
enforcement discretion for a qualified health claim with respect to
consumption of 100 percent whey-protein partially hydrolyzed infant
formula and a reduced risk of atopic dermatitis.

I.  Overview of Data and Eligibility for a Qualified Health Claim

A health claim characterizes the relationship between a substance and a
disease or health-related condition (21 CFR 101.14(a)(1)).  The
substance must be associated with a disease or health-related condition
for which the general U.S. population, or an identified U.S. population
subgroup is at risk (21 CFR 101.14(b)(1)).  Health claims characterize
the relationship between the substance and a reduction in risk of
contracting a particular disease or health-related condition.  In a
review of a qualified health claim, the agency first identifies the
substance and disease or health-related condition that is the subject of
the proposed claim and the population to which the claim is targeted. 

FDA considers the data and information provided in the petition, in
addition to other written data and information available to the agency,
to determine whether the data and information could support a
relationship between the substance and the disease or health-related
condition.  The agency then separates individual reports of human
studies from other types of data and information.  FDA focuses its
review on reports of human intervention and observational studies.

In addition to individual reports of human studies, the agency also
considers other types of data and information in its review, such as
meta-analyses, review articles, and animal and in vitro studies.  These
other types of data and information may be useful to assist the agency
in understanding the scientific issues about the substance, the disease,
or both, but cannot by themselves support a health claim relationship. 
Reports that discuss a number of different studies, such as
meta-analyses and review articles, do not provide sufficient information
on the individual studies reviewed for FDA to determine critical
elements such as the study population characteristics and the
composition of the products used.  Similarly, the lack of detailed
information on studies summarized in review articles and meta-analyses
prevents FDA from determining whether the studies are flawed in critical
elements such as design, conduct of studies, and data analysis.  FDA
must be able to review the critical elements of a study to determine
whether any scientific conclusions can be drawn from it.  Therefore, FDA
uses meta-analyses, review articles, and similar publications to
identify reports of additional studies that may be useful to the health
claim review and as background about the substance-disease relationship.
 If additional studies are identified, the agency evaluates them
individually.

FDA uses animal and in vitro studies as background information regarding
mechanisms of action that might be involved in any relationship between
the substance and the disease.  The physiology of animals is different
than that of humans.  In vitro studies are conducted in an artificial
environment and cannot account for a multitude of normal physiological
processes such as digestion, absorption, distribution, and metabolism
that affect how humans respond to the consumption of foods and dietary
substances (IOM, 2005).  Animal and in vitro studies can be used to
generate hypotheses or to explore a mechanism of action but cannot
adequately support a relationship between the substance and the disease.


FDA evaluates the individual reports of human studies to determine
whether any scientific conclusions can be drawn from each study.  The
absence of critical factors such as a control group or a statistical
analysis means that scientific conclusions cannot be drawn from the
study (Spilker et al., 1991, Federal Judicial Center, 2000).  Studies
from which FDA cannot draw any scientific conclusions do not support the
health claim relationship, and these are eliminated from further review.
 

Because health claims involve reducing the risk of a disease in people
who do not already have the disease that is the subject of the claim,
FDA considers evidence from studies in individuals diagnosed with the
disease that is the subject of the health claim only if it is
scientifically appropriate to extrapolate to individuals who do not have
the disease.  That is, the available scientific evidence must
demonstrate that: (1) the mechanism(s) for the mitigation or treatment
effects measured in the diseased populations are the same as the
mechanism(s) for risk reduction effects in non-diseased populations; and
(2) the substance affects these mechanisms in the same way in both
diseased people and healthy people.  If such evidence is not available,
the agency cannot draw any scientific conclusions from studies that use
diseased subjects to evaluate the substance-disease relationship.  

Next, FDA rates the remaining human intervention and observational
studies for methodological quality.  This quality rating is based on
several criteria related to study design (e.g., use of a placebo control
versus a non-placebo controlled group), data collection (e.g., type of
dietary assessment method), the quality of the statistical analysis, the
type of outcome measured (e.g., disease incidence versus validated
surrogate endpoint), and study population characteristics other than
relevance to the U.S. population (e.g., selection bias and whether
important information about the study subjects – e.g., age, smoker vs.
non-smoker – was gathered and reported).  For example, if the
scientific study adequately addressed all or most of the above criteria,
it would receive a high methodological quality rating.  Moderate or low
quality ratings would be given based on the extent of the deficiencies
or uncertainties in the quality criteria.  

Studies that are so deficient that scientific conclusions cannot be
drawn from them cannot be used to support the health claim relationship,
and these are eliminated from further review.  

Finally, FDA evaluates the results of the remaining studies.  The agency
then rates the strength of the total body of publicly available
evidence.  The agency conducts this rating evaluation by considering the
study type (e.g., intervention, prospective cohort, case-control,
cross-sectional), the methodological quality rating previously assigned,
the quantity of evidence (number of the various types of studies and
sample sizes), whether the body of scientific evidence supports a health
claim relationship for the U.S. population or target subgroup, whether
study results supporting the proposed claim have been replicated, and
the overall consistency of the total body of evidence.  Based on the
totality of the scientific evidence, FDA determines whether such
evidence is credible to support the substance/disease relationship, and,
if so, determines the ranking that reflects the level of comfort among
qualified scientists that such a relationship is scientifically valid. 

A. Substance

A health claim characterizes the relationship between a substance and a
disease or health-related condition (21 CFR 101.14(a)(1)).  A substance
means a specific food or component of food, regardless of whether the
food is in conventional food form or a dietary supplement (21 CFR
101.14(a)(2)).  The petition identified 100 percent whey-protein
partially hydrolyzed infant formula as the substance for the proposed
health claims. Infant formulas are foods (Section 201(z) of the Act (21
U.S.C. § 321(z)); therefore, the agency concludes that 100 percent
whey-protein partially hydrolyzed infant formula meets the definition of
substance in the health claim regulation (21 CFR 101.14(a)(2)).

B. Disease or Health-Related Condition

A disease or health-related condition means damage to an organ, part,
structure, or system of the body such that it does not function properly
or a state of health leading to such dysfunctioning (21 CFR
101.14(a)(5)). The petition has identified atopic dermatitis as the
disease or health-related condition for the proposed claim. Atopic
dermatitis is a complex disease with unknown cause and many factors that
can make it worse. It is likely caused by genetic and environmental
factors. Atopic dermatitis is a form of eczema that generally begins in
early infancy. In severe cases, scratching the skin can cause redness,
swelling, cracking, scaling and occasionally oozing clear fluid and
crusting that is more commonly seen in early life (Sampson 2005). Atopic
dermatitis is identified by a constellation of symptoms using standard
diagnostic criteria (Hanifin-Rajka, 1980). The agency concludes that
atopic dermatitis is a disease or health-related condition because there
is damage to an organ, part, structure, or system of the body such that
is does not function properly, or a state of health leading to such
dysfunctioning. Therefore, FDA concludes that the petitioner has
satisfied the requirement in 21 CFR 101.14(a)(5).

C. Safety Review

Under 21 CFR 101.14(b)(3)(ii), if the substance is to be consumed at
other than decreased dietary levels, the substance must be a food or a
food ingredient or a component of a food ingredient whose use at levels
necessary to justify a claim has been demonstrated by the proponent of
the claim, to FDA’s satisfaction, to be safe and lawful under the
applicable food safety provisions of the Act.

FDA evaluates whether the substance is “safe and lawful” under the
applicable food safety provisions of the Act. For conventional foods,
this evaluation involves considering whether the substance, which is
either a food or an ingredient that is the source of the substance, is
generally recognized as safe (GRAS), approved as a food additive, or
authorized by a prior sanction issued by FDA (see 21 CFR 101.70(f)). 

100 percent whey-protein partially hydrolyzed infant formula is a
substance as defined in 101.14(a)(2). Section 201(z) of the Act 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. 

100 percent whey-protein partially hydrolyzed infant formulas have been
marketed in the United States for decades. Nestlé’s 100 percent
whey-protein partially hydrolyzed infant formulas have been the subject
of several New Infant Formula notifications filed pursuant to Section
412 of the Act and are safely and lawfully marketed in this country. 
Based on the evidence above, FDA concludes that under the preliminary
requirements of 21 CFR 101.14(b)(3)(ii), the use of 100 percent
whey-protein partially hydrolyzed infant formula as described in the
qualified health claim petition is safe and lawful.

However, 100 percent whey-protein partially hydrolyzed infant formula is
not safe for all populations.  100 percent whey-protein partially
hydrolyzed infant formulas are not considered hypoallergenic and may
cause allergic reactions in one-third to one-half of milk allergic
infants (Ellis et al, 1991; Gampietro et al., 2001; Bahna et al. 2008). 
Hypersensitivity reactions in milk allergy infants represent a
significant medical concern, as they may range from cutaneous reactions
(e.g., urticaria, worsening eczema) to severe gastrointestinal reactions
(food protein induced enterocolitis syndrome) or life-threatening
anaphylaxis.  Although rare, death from cow’s milk anaphylaxis has
been reported in voluntary registries of fatal food anaphylaxis cases
(Chapman et al, 2006; Bock et al., 2001; Bock et al., 2007).  Therefore,
100 percent whey-protein partially hydrolyzed infant formula should not
be fed to infants who are known to be allergic to milk or who have
existing milk allergy symptoms.

II. The Agency's Consideration of a Qualified Health Claim

FDA has identified the following endpoint to use in identifying a
reduced risk of atopic dermatitis for purposes of a health claim:
incident cases of atopic dermatitis. FDA identified no validated
surrogate endpoints to use in assessing atopic dermatitis risk
reduction. The diagnosis of atopic dermatitis is based on health history
and physical examination (Fitzpatrick, 1993). Physical examination using
the Hanifin-Rajka criteria must include 3 or more basic findings:
pruritus, typical morphology and distribution; facial and extensor
involvement in infants and children; chronic or chronically-relapsing
dermatitis; and/or personal or family history of atopy (asthma, allergic
rhinitis, atopic dermatitis) (Hanifin-Rajka, 1980). 

The petition cited 128 articles/reports as evidence to substantiate the
relationship for the claim. The articles submitted consisted of 19 book
chapters, review articles, or federal reports; 1 website; 4 editorials;
1 article written in a foreign language with no translation; 9
abstracts; 2 animal studies; 1 reference to computer software; 71
articles describing studies that did not provide 100% whey-protein
hydrolyzed infant formula to subjects and/or did not measure atopic
dermatitis in the study subjects, the substance and disease that are the
subject of the proposed claim, (e.g., studies involving other types of
infant formula or studies of family history and allergies); and 20
articles on infant studies relevant to the proposed qualified health
claim on 100 percent whey-protein partially hydrolyzed infant formula
and reduced risk of atopic dermatitis (see docket number 2009-Q-0301 for
bibliography).

In addition, a supplement to the petition dated November 8, 2010
provided 20 references including 5 book chapters, review articles, or
federal reports; 2 meta-analyses, 1 website reference, 1 educational
pamphlet, and 11 articles describing studies that did not provide 100
percent whey-protein hydrolyzed infant formula to subjects and/or did
not measure atopic dermatitis in the study subjects to substantiate the
relationship for the claim. The two meta-analyses submitted as a
supplement to the petition (Szajewksa and Horvath, 2010; Alexander and
Cabana, 2010) also provided an analysis of the relative risk and
confidence intervals (CI) for two individual studies (Marini et al.,
1996; Vandenplas et al., 1995) that lacked statistical analysis in the
original articles. They are discussed in section II C. It is important
to note that the meta-analyses were not relied upon for the combined
results of all studies included.

A. Assessment of Review Articles, Meta-analyses, and Book Chapters 

Although useful for background information, the review articles,
meta-analyses, and book chapters that were provided as part of your
petition do not contain sufficient information on the individual studies
reviewed and, therefore, FDA could not draw any scientific conclusions
from this information. The lack of detailed information on studies
summarized in the review articles, meta-analyses, and book chapters
prevented FDA from determining whether the studies were flawed in
critical elements such as design, conduct of studies, and data analysis.
FDA must be able to review the critical elements of a study to determine
whether any scientific conclusions can be drawn from it. As a result,
the review articles, meta-analyses, and book chapters submitted with the
petition or during the public comment period did not provide information
from which scientific conclusions can be drawn regarding the
substance-disease relationships claimed by the petitioner. 

B. Assessment of Animal Studies

FDA uses animal studies as background information regarding mechanisms
of action that might be involved in any relationship between the
substance and the disease, and they can also be used to generate
hypotheses or to explore a mechanism of action, but they cannot
adequately support a relationship between the substance and the disease
in humans.  FDA did not consider the animal studies submitted with the
petition as providing any supportive information about the
substance-disease relationship because such studies cannot mimic the
normal human physiology that may be involved in the risk reduction of
atopic dermatitis, nor can the studies mimic the human body's response
to the consumption of 100 percent whey-protein partially hydrolyzed
infant formula.  Therefore, FDA could not draw any scientific
conclusions regarding the intake of 100 percent whey-protein partially
hydrolyzed infant formula and the reduction of risk of atopic
dermatitis. 

C. Assessment of the Intervention Studies

FDA evaluated 20 reports of intervention studies that were designed to
evaluate the relationship between the consumption of 100 percent
whey-protein partially hydrolyzed infant formula and a reduced risk of
atopic dermatitis for which the petition requested a qualified health
claim. Scientific conclusions could not be drawn from 16 of these 20
reports for the reasons discussed below.

Three studies (Exl et al. 2000; Vandenplas et al., 1989, von Berg et
al., 2008) were a republication of another study being evaluated (Exl et
al. 1998; Vandenplas et al., 1988; von Berg et al., 2003, 2007) for the
substance and disease relationship. Since these republications provided
no new data or information pertinent to the qualified health claim, the
original publications were relied upon for review.

Three studies were excluded from the scientific review due to unresolved
concerns regarding data integrity (Chandra et al., 1989, 1991 and 1997).
Nestlé has excluded them from their scientific review submitted with
this petition (see docket 2009-Q-0301, sections B and I). 

Two studies did not select infants that were healthy and had a family
history of allergy (Exl et al. 1998; Fukushima et al. 1997), the
population identified by the qualified health claim. Since the petition
focuses on infants at risk of developing atopic dermatitis, these
publications were not relied upon for review.

Six studies did not definitively diagnose cases of atopic dermatitis in
the study's subjects (D'Agata et al., 1996; Exl et al., 1998; Fukushima
et al., 1997; Tsai et al., 1991; Vandenplas et al., 1988; Williems et
al., 1993). As discussed above, diagnosing atopic dermatitis is based on
a combination of historic and morphologic findings because there are no
single distinguishing features of atopic dermatitis (Fitzpatrick, 1993).
As there is no objective laboratory biomarker for this disease, the
Hanifin-Rajka criteria remain a standard for the diagnosis of atopic
dermatitis and are frequently used in randomized controlled clinical
trials (Hanifin-Rajka, 1980). For a study to measure atopic dermatitis
incidence, physical examination using the Hanifin-Rajka criteria must
include three or more basic findings: pruritus (itching); typical
morphology and distribution; facial and extensor (outer surface of
limbs) involvement in infants and children; chronic or
chronically-relapsing dermatitis; and/or personal or family history of
atopy (e.g., asthma, allergic rhinitis, atopic dermatitis)
(Hanifin-Rajka, 1980). Atopic dermatitis is a complex disease both
multifactorial and heterogeneous with regard to etiology and aggravating
factors (Fitzpatrick, 1993). Extensive research has been performed but
interpretation of the literature is complicated by the lack of
standardization with regard to diagnosis, measures of severity and the
lack of an objective test to measure the activity of disease
(Fitzpatrick, 1993). Since these studies did not definitively diagnose
atopic dermatitis, no scientific conclusions can be drawn from them
concerning the incidence of atopic dermatitis in the subjects.

One study by Chirico et al. (1997) did not specify that 100 percent
whey-protein hydrolyzed infant formula, the substance of the claim, was
used in the study nor did supplemental information in the petition
confirm that the formula used was the substance of the claim. Partially
hydrolyzed infant formulas made from cow’s milk may contain casein in
addition to whey protein. Because the formula was not specifically
described as 100 percent whey protein hydrolyzed infant formula, the
agency could not determine that the formula used in the study was the
substance of the claim. Thus, scientific conclusions could not be drawn
from this study about the relationship between 100 percent whey-protein
partially hydrolyzed infant formula and reduced risk of atopic
dermatitis.

One study by De Seta et al. (1994) was a randomized study not designed
with atopic dermatitis as a primary outcome. Infants at risk for atopy
were randomized to 100 percent whey-protein partially hydrolyzed formula
(n=23) or conventional cow’s milk formula (n=39) for six months.
Information on blinding of the study, compliance with formula
consumption, and weaning recommendations were not reported. Therefore,
the agency could not determine if infants consumed their assigned
formulas and adhered to the study protocol. In addition, no information
was provided about factors that could influence atopic dermatitis (e.g.,
house pets, dust mites, smoking in the home, weaning foods). Known
modifiers of disease risk need to be collected and adjusted for to
minimize bias so that the substance-disease relationship is accurately
measured. Furthermore, results for cumulative incidence of atopic
dermatitis and cow’s milk protein allergy intolerance were combined
and reported together (e.g., at 24 months, there were 3 cases of atopic
dermatitis and cow’s milk protein allergy intolerance combined in the
100 percent whey-protein partially hydrolyzed formula group). Thus, the
agency could not determine the independent role of the substance in
reducing the risk of disease. Statistical analysis between the 100
percent whey-protein partially hydrolyzed formula and cow’s milk
formula groups was also not reported by the authors. Due to the
shortcomings described above, this study is so deficient in
methodological quality that it is considered to be of low-quality
design. Based on the above reasons, scientific conclusions could not be
drawn from this study about the relationship between 100 percent
whey-protein partially hydrolyzed formula and reduced risk of atopic
dermatitis.

There were four intervention studies (Vandenplas et al. (1992), Chan et
al. (2002), von Berg et al. (2003), Marini et al. (1996)) published in
six reports (two studies have follow-up analysis to the initial study
report, von Berg et al. (2007), Vandenplas et al. (1995)) available from
which scientific conclusions could be drawn about the relationship
between the consumption of 100 percent whey-protein partially hydrolyzed
infant formula and a reduced risk of atopic dermatitis for which the
petition requested a qualified health claim. These studies are discussed
below. 

Vandenplas et al. (1992, 1995) was a randomized, partially blinded 6
month intervention study of moderate methodological quality. A total of
58 Belgian infants with family history of atopy (two first degree
relatives) were randomly assigned to receive either 100 percent
whey-protein partially hydrolyzed infant formula (n=28) or cow’s milk
infant formula (n=30) (control) exclusively for 6 months. The incidence
of atopic dermatitis, including eczema, was determined by physical exams
conducted every 6 months from the age of 6 months to 5 years. Direct
statistical comparisons of the incidence of eczema between the two
groups were not reported by the authors. However, an analysis of the
Vandenplas et al. (1995) data by Szajewksa and Horvath (2010) showed no
significant difference between the two groups when relative risk and 95%
CI were calculated from the cumulative incidence data. At 0 to 12 months
of age, the relative risk was 0.46 and CI was 0.13 – 1.60. At 0 to 36
months of age, the relative risk was 1.07 and the CI = 0.43 – 2.67. 

Χ2)  p value = 0.011) up to 2 years of age (odds ratio = 0.37; Χ2 p
value = 0.019).

von Berg et al. (2003, 2007) was a high quality, randomized, double
blind 4 month intervention trial that compared the effect of differently
hydrolyzed infant formulas with cow's milk formula on allergic diseases
including atopic dermatitis in infants with family history of atopy.
Mothers were encouraged to exclusively breast-feed for at least 4
months. If mothers chose not to breast-feed exclusively or not at all,
infants were randomized to 100 percent whey-protein partially hydrolyzed
formula (n=241) or cow’s milk formula (control) (n=256).  Information
on the quantity of breast milk fed and duration of breastfeeding was not
reported.  The intervention consisted of study formula for the first 4
months of age and recommendations on introduction and type of weaning
foods after 4 months. Atopic dermatitis was determined by clinical exams
conducted at 1, 4, 8, 12, and 36 months of age. The incidence of atopic
dermatitis from birth to one year of age was 22 in the 100 percent
whey-protein partially hydrolyzed formula group and 38 in the cow’s
milk formula group. There was a significantly lower incidence of atopic
dermatitis when infants consumed the 100 percent whey-protein partially
hydrolyzed formula compared to the control group (odds ratio = 0.56; CI
= 0.32 – 0.99) when adjusted for atopic dermatitis in family history,
sex, and maternal smoking after birth. At follow-up at 3 years of age,
the incidence of atopic dermatitis from birth to 3 years of age was 34
in the 100 percent whey-protein partially hydrolyzed formula group
(n=229) and 55 in the cow’s milk formula group (n=245). The
significant effect of 100 percent whey-protein partially hydrolyzed
formula on reduced risk of atopic dermatitis persisted at 3 years of age
(odds ratio = 0.60; CI = 0.37-0.97 when adjusted for atopic dermatitis
in family history, sex, and maternal smoking after birth) (von Berg et
al., 2007).

Marini et al. (1996) reported on a 5 to 6 month intervention study of
moderate methodological quality with 279 Italian infants with parental
history of atopy. The intervention included randomization to formula,
instruction on maternal diet and weaning foods, as well as environmental
advice. Exclusively formula fed infants received 100 percent
whey-protein partially hydrolyzed formula (n=48) or conventional cow’s
milk formula (n= 47) (control group). Data were reported for infants
that received breast milk in addition to 100 percent whey-protein
partially hydrolyzed formula (n=32) and breast milk in addition to
cow’s milk formula (n=28). Atopic dermatitis was determined by
clinical exams conducted at 3, 6, 12, 24, and 36 months of age.
Compliance with maternal and infant diet recommendations and
environmental advice was collected. Statistical comparison of cumulative
incidence of atopic dermatitis for the treatment and control groups was
not reported by the authors. However, an analysis of the incidence data
from 0 to 12 and 0 to 36 months (Marini et al.,1996) by Alexander and
Cabana (2010) showed no significant difference between the treatment and
control group at 1 year of age (relative risk = 0.48; CI=0.13-1.78) and
at 3 years of age (relative risk = 0.42; CI= 0.14-1.26). 

D. Assessment of Observational Studies

There were no observational studies that evaluated the relationship
between 100 percent whey-protein partially hydrolyzed infant formula and
a reduced risk of atopic dermatitis.

III. Strength of the Scientific Evidence

Below, the agency rates the strength of the total body of publicly
available evidence. The agency conducts this rating evaluation by
considering the study type (e.g., intervention, prospective cohort,
case-control, cross-sectional), the methodological quality rating
previously assigned, the number of studies and number of subjects per
group, whether the body of scientific evidence supports a health claim
relationship for the U.S. population or target subgroup, whether study
results supporting the proposed claim have been replicated, and the
overall consistency of the total body of evidence.  Based on the
totality of the scientific evidence, FDA determines whether such
evidence is credible to support a qualified health claim for the
substance/disease relationship and, if so, considers what qualifying
language should be included to convey the limits on the level of
scientific evidence supporting the relationship or to prevent the claim
from being misleading in other ways.

As discussed in section II, the evidence about a possible relationship
between 100 percent whey-protein partially hydrolyzed infant formula and
reduced risk of atopic dermatitis is based on four intervention studies
published in six reports (Chan et al., 2002; Marini et al., 1996;
Vandenplas et al. 1992 and 1995; von Berg et al., 2003 and 2007).  Of
the four above studies, two studies (Chan et al., 2002; von Berg et al.,
2003 and 2007) reported a beneficial relationship between 100 percent
whey-protein partially hydrolyzed infant formula and reduced risk of
atopic dermatitis.

von Berg et al. (2003, 2007) reported a large, high quality intervention
study in which infants were randomized to either 100% whey protein
partially hydrolyzed infant formula (n=241) or cow’s milk formula
(n=256) for the first 4 months of life. Infants in both groups may have
had breast milk in addition to the study formula. The study found a
statistically significant reduction in the incidence of atopic
dermatitis at 1 and 3 years of age in infants who consumed 100 percent
whey-protein partially hydrolyzed infant formula compared to those who
consumed cow’s milk formula. Chan et al. (2002) was a moderate quality
intervention study in which exclusively formula fed infants were given
either 100 percent whey-protein partially hydrolyzed infant formula or
cow’s milk formula for the first 4 months of life. The study found a
statistically significant reduction in the incidence of atopic
dermatitis throughout the first year of life and up to 2 years of age
for infants who consumed the 100 percent whey-protein partially
hydrolyzed infant formula compared to those who consumed cow’s milk
formula. 

Two other studies showed no beneficial relationship in exclusively
formula fed infants who consumed 100 percent whey-protein partially
hydrolyzed infant formula and reduced risk of atopic dermatitis up to 3
years of age (Marini et al., 1996; Vandenplas et al., 1992 and 1995). 
Both studies were of moderate methodological quality with intervention
periods from birth through 5 to 6 months of age. There were no
significant reductions in risk of atopic dermatitis between the
intervention and control groups at 1 year and 3 years of age.
Consistency of findings among similar and different study designs is
important for evaluating the strength of the scientific evidence.

Thus, two studies (von Berg et al., 2003; Chan et al., 2002) supported a
beneficial relationship between the consumption of 100 percent
whey-protein partially hydrolyzed infant formula during the first 4
months of life and reduced risk of atopic dermatitis throughout the
first year of life. One was a large high quality intervention study (n=
241 in the treatment and n=256 in the control group) while the other was
a smaller moderate quality intervention study (n=53 in the treatment and
n=57 in the control group). Two studies did not support a beneficial
relationship between the consumption of 100 percent whey-protein
partially hydrolyzed infant formula during the first 4 months of life
and risk of atopic dermatitis throughout the first year of life. Both
were smaller moderate quality intervention studies (n=48 and 28 in the
treatment and n=47 and 30 in the control groups, respectively). Because
there are only two intervention studies that support the
substance-disease relationship throughout the first year of life, while
two other intervention studies do not support that relationship, there
is little evidence from which to conclude that a risk reduction
relationship actually exists during this timeframe. 

Based on the above, FDA concludes that there is little credible evidence
for a qualified health claim about the relationship between feeding a
100 percent whey-protein partially hydrolyzed infant formula for the
first four months of life and a reduced risk of atopic dermatitis
throughout the first year of life. The agency concludes that the
relationship between feeding a 100 percent whey-protein partially
hydrolyzed infant formula for the first four months of life and a
reduced the risk of atopic dermatitis throughout the first year of life
is uncertain.

Only one study reported a beneficial relationship when feeding a 100
percent whey-protein partially hydrolyzed infant formula for the first 4
months of life and reduced risk of atopic dermatitis up to 3 years of
age (von Berg et al., 2007). Although the study was a large high quality
intervention study (n=241 in the treatment and n=256 in the control
group), these findings at 3 years of age have not been replicated, and
replication of scientific findings is important in order to substantiate
results.  Two studies did not support a beneficial relationship of
feeding a 100 percent whey-protein partially hydrolyzed infant formula
for the first 4 months of life and reduced risk of atopic dermatitis up
to 3 years of age. Both were smaller moderate quality intervention
studies (n=48 and 28 in the treatment and n=47 and 30 in the control
groups, respectively). Because there is only one intervention study that
supports the substance-disease relationship throughout the first year of
life and up to 3 years of age, while two intervention studies do not
support that relationship, there is very little evidence from which to
conclude that a risk reduction relationship actually exists during this
timeframe. 

Based on the above, FDA concludes that there is very little credible
evidence for a qualified health claim about the relationship between
feeding a 100 percent whey-protein partially hydrolyzed infant formula
for the first 4 months of life and a reduced risk of atopic dermatitis
throughout the first year of life and up to 3 years of age.  The agency
concludes that the relationship between feeding a 100 percent
whey-protein partially hydrolyzed infant formula for the first 4 months
of life and a reduced risk of atopic dermatitis throughout the first
year of life and up to 3 years of age is uncertain.

Early infant nutrition may have an important influence on the
development of atopic diseases such as atopic dermatitis (Greer et al.
2008).  Further, the study design of the two intervention studies (von
Berg et al., 2003; Chan et al., 2002) that supported a beneficial
relationship between the consumption of 100 percent whey-protein
partially hydrolyzed infant formula and reduced risk of atopic
dermatitis included the feeding of such formula to infants only during
the first 4 months of life. Therefore, the agency is considering, as a
factor in the exercise of its enforcement discretion, that the claim
language state the time period in which the infants in these studies
were fed the formula (i.e., from birth up to 4 months).  Without this
information, the agency would consider the qualified health claim to be
misleading under sections 403(a)(1) and 201(n) of the Act because the
record contains no evidence that feeding an infant the formula at a
different time period would have any effect on reducing the risk of
atopic dermatitis.  

IV. Other Enforcement Discretion Factors

The proposed qualified health claim contains more information than the
substance-disease relationship, as italicized below:

Breastfeeding is the best way to nourish infants.  For infants who are
not exclusively breastfed, emerging clinical research shows that, in
healthy infants with family history of allergy, feeding a 100%
Whey-Protein Partially Hydrolyzed infant formula instead of a formula
containing intact cow’s milk proteins may reduce the risk of
developing the most common allergic disease of infancy – atopic
dermatitis – throughout the 1st year of life and up to 3 years of age.


Partially hydrolyzed formulas are not intended to treat existing food
allergy symptoms.  If you suspect your baby is already allergic to milk,
or if your baby is on a special formula for the treatment of allergy,
your baby’s care and feeding choices should be under a doctor’s
supervision.

The first sentence in the first paragraph states “Breastfeeding is the
best way to nourish infants.”  FDA does not object to the placement of
this statement in the labeling based on the context in which such
language is used, but FDA does not consider it to be part of the
qualified health claim because it does not relate to the substance and
disease relationship of the qualified health claim.  

FDA also does not object to the placement of the phrase “the most
common allergic disease of infancy” in the second sentence of the
first paragraph, but FDA does not consider this phrase to be part of the
qualified health claim because it does not relate to the substance and
disease relationship of the qualified health claim.

The second paragraph of the proposed language explains that partially
hydrolyzed formulas are not intended to treat existing food allergy
symptoms. As Nestlé appears to have recognized, a second paragraph is
necessary because the first paragraph identifies a relationship between
the consumption of 100% whey-protein partially hydrolyzed infant formula
and a reduced risk of developing the allergic disease of atopic
dermatitis. The articulation of this relationship could mislead
consumers into thinking that 100% whey-protein partially hydrolyzed
infant formula is appropriate to feed to infants who are allergic to
milk and to infants with existing food allergy symptoms.  This would
pose a significant public health risk because 100 percent whey-protein
partially hydrolyzed infant formulas may cause allergic reactions in
one-third to one-half of milk allergic infants (Ellis et al, 1991;
Gampietro et al., 2001; Bahna et al. 2008); these reactions can be
serious and even life-threatening. 

The language proposed by Nestlé is not sufficient to prevent consumers
from being misled in the manner described above.  Nestlé’s proposed
language states that these formulas are not intended to treat existing
food allergy symptoms, but it does not make clear that these formulas
should not be fed to infants who are allergic to milk or to infants with
existing milk allergy symptoms. Therefore, the agency is considering, as
a factor in the exercise of its enforcement discretion, that the second
paragraph state:  

Partially hydrolyzed formulas should not be fed to infants who are
allergic to milk or to infants with existing milk allergy symptoms.  If
you suspect your baby is already allergic to milk, or if your baby is on
a special formula for the treatment of allergy, your baby's care and
feeding choices should be under a doctor's supervision.

Without this information, and without the bold text, the agency would
consider the qualified health claim to be misleading under sections
403(a)(1) and 201(n) of the Act because it would fail to reveal facts
material in the light of the representations being made and facts
material with respect to consequences which may result from the use of
these formulas. FDA has concluded that the use of bold type as set forth
above is necessary, in light of the significant public health risk that
would be created by the feeding of these formulas to infants who are
allergic to milk or to infants with existing milk allergy symptoms, and
the fact that the articulation of a relationship between the consumption
of 100% whey-protein partially hydrolyzed infant formula and a reduced
risk of developing the allergic disease of atopic dermatitis could
mislead consumers to think that these formulas are an appropriate choice
for such infants. 

V. Conclusions

Based on FDA's consideration of the scientific evidence submitted with
the petition and other pertinent scientific evidence, FDA concludes that
that the current scientific evidence is appropriate for consideration of
a qualified health claim regarding the relationship between the
consumption of 100 percent whey-protein partially hydrolyzed infant
formula and a reduced risk of atopic dermatitis, provided that the
qualified health claims are appropriately worded so as not to mislead
consumers. 

The proposed qualified health claim states "emerging clinical research"
shows that 100 percent whey-protein partially hydrolyzed infant formula
may reduce the risk of atopic dermatitis that is the subject of the
proposed claims.  As discussed in sections II and III of this letter,
only two studies showed a reduced risk of atopic dermatitis throughout
the first year of life, and only one study showed a reduced risk of
atopic dermatitis up to 3 years of age; two other studies showed no
beneficial relationship at 1 year of age or at 3 years of age.  The
agency concludes that the language requested in the petition, "emerging
clinical research," mischaracterizes the strength of the evidence and is
misleading because such language suggests that there is currently more
scientific evidence available than what is described or that such
evidence will soon be available to show that consumption of 100 percent
whey-protein partially hydrolyzed infant formula reduces the risk of
atopic dermatitis.  

Furthermore, the reduced risk of atopic dermatitis was observed only
when infants consumed the 100 percent whey-protein partially hydrolyzed
infant formula during the first 4 months of life. Without this
information regarding the time period in which the formula was fed to
infants, the evidence does not support the proposed claim.

In light of the above considerations, FDA intends to consider the
exercise of its enforcement discretion for the following qualified
health claims:

1.  “Very little scientific evidence suggests that, for healthy
infants who are not exclusively breastfed and who have a family history
of allergy, feeding a 100 % Whey-Protein Partially Hydrolyzed infant
formula from birth up to 4 months of age instead of a formula containing
intact cow's milk proteins may reduce the risk of developing atopic
dermatitis throughout the 1st year of life and up to 3 years of age.” 

2.  “Little scientific evidence suggests that, for healthy infants who
are not exclusively breastfed and who have a family history of allergy,
feeding a 100 % Whey-Protein Partially Hydrolyzed infant formula from
birth up to 4 months of age instead of a formula containing intact cow's
milk proteins may reduce the risk of developing atopic dermatitis
throughout the 1st year of life.”

3.  “For healthy infants who are not exclusively breastfed and who
have a family history of allergy, feeding a 100% Whey-Protein Partially
Hydrolyzed infant formula from birth up to 4 months of age instead of a
formula containing intact cow’s milk proteins may reduce the risk of
developing atopic dermatitis throughout the 1st year of life and up to 3
years of age.  FDA has concluded that the relationship between 100%
Whey-Protein Partially Hydrolyzed infant formulas and the reduced risk
of atopic dermatitis is uncertain, because there is very little
scientific evidence for the relationship.”

4.  “For healthy infants who are not exclusively breastfed and who
have a family history of allergy, feeding a 100% Whey-Protein Partially
Hydrolyzed infant formula from birth up to 4 months of age instead of a
formula containing intact cow’s milk proteins may reduce the risk of
developing atopic dermatitis throughout the 1st year of life.  FDA has
concluded that the relationship between 100% Whey-Protein Partially
Hydrolyzed infant formulas and the reduced risk of atopic dermatitis is
uncertain, because there is little scientific evidence for the
relationship.”

As discussed above, inclusion of the following language with any of the
above qualified health claims is a factor in FDA’s consideration of
enforcement discretion:  

“Partially hydrolyzed formulas should not be fed to infants who are
allergic to milk or to infants with existing milk allergy symptoms.  If
you suspect your baby is already allergic to milk, or if your baby is on
a special formula for the treatment of allergy, your baby's care and
feeding choices should be under a doctor's supervision.”

FDA intends to consider exercising its enforcement discretion for the
above qualified health claims when all the factors for enforcement
discretion identified in this letter are met.

Please note that scientific information is subject to change, as are
consumer consumption patterns. FDA intends to evaluate new information
that becomes available to determine whether it necessitates a change in
this decision.  For example, scientific evidence may become available
that will support significant scientific agreement, that will support a
qualified health claim for one or more claims that were denied, that
will no longer support the use of the above qualified health claims, or
that may raise safety concerns about the substance that is the subject
of the claims.

Sincerely yours,

								Barbara O. Schneeman, Ph.D.

								Director

			Office of Nutrition, Labeling, 

				and Dietary Supplements

								Center for Food Safety 

									and Applied Nutrition

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Bahna, S. Hypoallergenic formulas: optimal choices for treatment versus
prevention. Ann Allergy Asthma Immunol. 2008; 101:453-459.

Bock, S., Muñoz-Furlong, A., Sampson, H. Fatalities due to anaphylactic
reactions to foods. J Allergy Clin Immunol. 2001;107:191–193.

Bock, S., Muñoz-Furlong, A., Sampson, H. Further fatalities caused by
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Chan YH, Shek LP, Aw M, Quak SH, Lee BW. Use of hypoallergenic formula
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Chandra RK. Five-year follow-up of high-risk infants with family history
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hydrolysate, soy, and conventional cow's milk formulas. J Pediatr
Gastroenterol Nutr 1997; 24(4):380-388.

Chandra RK, Hamed A. Cumulative incidence of atopic disorders in high
risk infants fed whey hydrolysate, soy, and conventional cow milk
formulas. Ann Allergy. 1991 Aug;67(2 Pt 1):129-32.

Chandra RK, Puri S, Hamed A. Influence of maternal diet during lactation
and use of formula feeds on development of atopic eczema in high risk
infants. BMJ. 1989 Jul 22;299 (6693):228-30.

Chapman, J. et al.  “Food allergy: a practice parameter.” Ann
Allergy Asthma Immunol. 2006; 96:S1-S68.

Chirico G, Gasparoni A, Ciardelli L, De AM, Colombo A, Rondini G.
Immunogenicity and antigenicity of a partially hydrolyzed cow's milk
infant formula. Allergy 1997; 52(1):82-88.

D'Agata A, Betta P, Sciacca P, Morano C, Pratico G, Curreri R et al.
[Role of dietary prevention in newborns at risk for atopy. Results of a
follow-up study]. Pediatr Med Chir 1996; 18(5):469-

472.

De Seta SL, Siani P, Cirillo G, Di GM, Cimaduomo L, Coletta S. [The
prevention of allergic diseases with a hypoallergenic formula: a
follow-up at 24 months. The preliminary results]. Pediatr Med Chir 1994;
16(3):251-254.

Ellis, M., Short, J., Heiner, D.  Anaphylaxis after ingestion of a
recently introduced hydrolyzed whey protein formula. J Pediatr. 1991;
118:74-77.

Exl BM, Deland U, Secretin MC, Preysch U, Wall M, Shmerling DH. Improved
general health status in an unselected infant population following an
allergen-reduced dietary intervention programme: the
ZUFF-STUDY-PROGRAMME. Part II: infant growth and health status to age 6
months. ZUg-FrauenFeld. Eur J Nutr 2000; 39(4):145-156.

Exl BM, Deland U, Wall M, Preysch U, Secretin MC, Shmerling DH.
Zug-Frauenfeld nutritional survey ("Zuff Study"): allergen-reduced
nutrition in normal infant population and its healthrelated effects:
results at the age of six months. Nutrition Research 1998;
18(8):1443-1462.

Fitzpatrick, T. Dermatology in General Medicine. Fourth Edition.
McGraw-Hill Inc. 1993. Chapter 120 Atopic dermatitis. Pages 1543-1564.

Fukushima Y, Iwamoto K, Takeuchi-Nakashima A, Akamatsu N, Fujino-Numata
N,

Yoshikoshi M, Onda T, Kitagawa M. Preventive effect of whey hydrolysate
formulas for

mothers and infants against allergy development in infants for the first
2 years. J Nutr Sci

Vitaminol (Tokyo). 1997 Jun;43(3):397-411

Giampietro, P., Kjellman, N., Oldaeus, G., Bouters-Wesseling, W.,
Businco, L. Hypoallergencity of an extensively hydrolyzed whey formula. 
Pediatr Allergy Immunol. 2001; 12:83-86.

Greer FR, Sicherer SH, Burks AW; American Academy of Pediatrics
Committee on Nutrition; American Academy of Pediatrics Section on
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the development of atopic disease in infants and children: the role of
maternal dietary restriction, breastfeeding, timing of introduction of
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Sampson, Hugh A. "The evaluation and management of food allergy in
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S et al. The longterm effect of a partial whey hydrolysate formula on
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von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer
CP et al. The effect of hydrolyzed cow's milk formula for allergy
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von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grubl A,
Wichmann HE et al. Certain hydrolyzed formulas reduce the incidence of
atopic dermatitis but not that of asthma: Three-year results of the
German Infant Nutritional Intervention Study. J Allergy Clin Immunol
2007 Mar;119(3):718-25.

von Berg A, Filipiak-Pittroff B, Kramer U, Link E, Bollrath C, Brockow I
et al. Preventive effect of hydrolyzed infant formulas persists until
age 6 years: Long-term results from the German Infant Nutritional
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121(6):1442-1447.

Willems R, Duchateau J, Magrez P, Denis R, Casimir G. Influence of
hypoallergenic milk formula on the incidence of early allergic
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1993; 71(2):147-150.

Drafted: HFS-830: CChung, JKevala: 3/2/11

Cleared: HFS-830: PTrumbo: 3/3/11

Edited: OCC: BGoldberg, GOverholser: 5/3/11

Edited: HFS-830: CChung, JKevala: 5/5/11

Cleared: HFS-830: PTrumbo: 5/6/11

Cleared: OCC: BGoldberg, GOverholser; 5/12/11

Edited: HFS-830: CChung: 5/13/11

Edited: HFS-830: CChung: 5/23/11

 “Interim Procedures for Qualified Health Claims in the Labeling of
Conventional Human Food and Human Dietary Supplements” (July 10,
2003).  

[  HYPERLINK
"http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidanc
eDocuments/FoodLabelingNutrition/ucm053832.htm" 
http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidance
Documents/FoodLabelingNutrition/ucm053832.htm ] 

 See Whitaker v. Thompson, 353 F.3d 947, 950-51 (D.C. Cir.) (upholding
FDA's interpretation of what constitutes a health claim), cert. denied,
125 S. Ct. 310 (2004).

 See guidance entitled "Guidance for Industry: Evidence-Based Review
System for the Scientific Evaluation of Health Claims - Final," January
2009.
[http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidanc
eDocuments/FoodLabelingNutrition/ucm073332.htm]

 For brevity, "disease" will be used as shorthand for "disease or
health-related condition" in the rest of this letter.

 In an intervention study, subjects similar to each other are randomly
assigned to either receive the intervention or not to receive the
intervention, whereas in an observational study, the subjects (or their
medical records) are observed for a certain outcome (i.e., disease). 
Intervention studies provide the strongest evidence for an effect.  See
supra note 3.

 A meta-analysis is the process of systematically combining and
evaluating the results of clinical trials that have been completed or
terminated (Spilker, 1991). 

 Review articles summarize the findings of individual studies.

 Other examples include book chapters, abstracts, letters to the editor,
and committee reports.

 Certain meta-analyses may be used as part of the health-claim review
process. See supra, note 3. 

 Replication of scientific findings is important for evaluating the
strength of scientific evidence (An Introduction to Scientific Research,
E. Bright Wilson Jr., pages 46-48, Dover Publications, 1990).

 Consistency of findings among similar and different study designs is
important for evaluating causation and the strength of scientific
evidence (Hill A.B. The environment and disease: association or
causation? Proc R Soc Med 1965;58:295-300); See also Systems to rate the
scientific evidence, Agency for Healthcare Research and Quality
[http://archive.ahrq.gov/clinic/epcsums/strengthsum.htm], defining
"consistency" as "the extent to which similar findings are reported
using similar and different study designs." 

 See supra, note 3.

 National Institute of Arthritis and Musculoskeletal and Skin Diseases
Fact Sheet:  What is atopic dermatitis?
[http://www.niams.nih.gov/Health_Info/Atopic_Dermatitis/atopic_dermatiti
s_ff.pdf]

 The distribution of the rash varies with age and involves the cheeks
and outer surfaces of the arms and legs in infancy, the inner surfaces
of the arms and legs in the young child, and inner surfaces of the arms
and legs, hands, and feet in teenagers and young adults. See supra, note
13.

 National Institute of Arthritis and Musculoskeletal and Skin Diseases,
Handout on health: Atopic Dermatitis.
[http://www.niams.nih.gov/Health_Info/Atopic_Dermatitis/default.asp]

 Relative risk, also known as risk ratio, is expressed as the ratio of
the risk (e.g., incidence of the disease) in exposed individuals to that
in unexposed individuals (Epidemiology: Beyond the Basics, page 93,
Aspen Publishers, 2000).

 Confidence intervals are ranges that provide a statistical analysis of
comparative measures of risk (e.g., relative risk, odds ratio and hazard
ratio).  Confidence intervals are significant when the entire range is
less than or greater than "1" (e.g., 0.7-0.9 or 1.1-1.5). If the
confidence interval includes "1", then it can be concluded that a
relationship does not exist between the substance and the disease.

 See supra, note 6.

 See supra note 3.

 See supra, note 3 [Section III.E].

 See supra, note 3 [Section III.D].

 See supra, note 3 [Section III.D].

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 See supra note 3.

 See supra note 3.

 See supra note 3.

 See supra note 3.

 PAGE   

 PAGE   21 

