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100% Whey-Protein Partially Hydrolyzed Infant Formula and Reduced Risk of Atopic Dermatitis

Back to Qualified Health Claims: Letters of Enforcement Discretion

May 24, 2011

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").[1] 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.[2] 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.[3]

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.[4] 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.[5]

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,[6] review articles,[7] 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[8] 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.[9] 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,[10] and the overall consistency[11] of the total body of evidence.[12] 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[13] 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[14] 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.[15] 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[16] and confidence intervals (CI)[17] 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[18] 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.[19] 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.[20] 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.[21] Statistical analysis between the 100 percent whey-protein partially hydrolyzed formula and cow's milk formula groups was also not reported by the authors.[22] 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.

Chan et al. (2002) reported on a randomized, single-blind 4 month intervention study of moderate methodological quality with 110 Singaporean infants with a family history (first degree relative) of atopy. The exclusively formula fed infants received either 100 percent whey-protein partially hydrolyzed infant formula (n=53) or cow's milk based formula (n=57) (control). Infants were monitored by a physician for atopic dermatitis at 3, 6, 12, 18, 24, and 30 months. Compliance with the intervention was not addressed and there were no restrictions with regard to consumption of weaning foods. Factors that could exacerbate atopic dermatitis such as socioeconomic status, house pets and use of air-conditioning were considered; however, other factors, such as timing and types of weaning foods consumed were not addressed. There was a significantly lower incidence of atopic dermatitis for the treatment group compared to the control group from 3 months of age (odd ratio[23] = 0.20; chi-square (Χ2) [24] 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,[25] and the overall consistency of the total body of evidence.[26] 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.[27]

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.[28] 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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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.

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Notes:

[1] "Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements" (July 10, 2003).
[http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/
FoodLabelingNutrition/ucm053832.htm
]

[2] 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).

[3] 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/GuidanceDocuments/
FoodLabelingNutrition/ucm073332.htm
]

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

[5] 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.

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

[7] Review articles summarize the findings of individual studies.

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

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

[10] 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).

[11] 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."

[12] See supra, note 3.

[13] 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_dermatitis_ff.pdf]

[14] 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.

[15] 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]

[16] 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).

[17] 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.

[18] See supra, note 6.

[19] See supra note 3.

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

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

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

[23] Odds ratio is the odds of developing the disease in exposed compared to unexposed individuals (Epidemiology: Beyond the Basics, page 29, Aspen Publishers, 2000). Odds ratio is a measure of risk and is calculated in case-control studies by measuring development of a disease.

[24] Chi-square (Χ2) is a test to determine whether observed differences in proportions between study groups are statistically significant. (Epidemiology in Medicine, page 249, Little, Brown and Co. 1987).

[25] See supra note 3.

[26] See supra note 3.

[27] See supra note 3.

[28] See supra note 3.