Is It Time to Put a Moratorium on New Infant Formulas that Are Not Adequately Investigated? Steven A. Abrams, MD
I
nfant formula development in the US is an ongoing process of development and regulation. For many years, there were few infant formulas in use in the US. Formulas were either “routine” cow milk proteinbased, soy protein-based, or uncommonly, specialized formulas such as those for infants with a documented cow milk protein allergy or metabolic diseases. Decisions about formula selection were almost entirely at the discretion of a child’s pediatrician, and public advertising and marketing of infant formulas was not done or was extremely limited. This changed in the late 1980s with the introduction of several new formulas and a new infant formula company to the US marketplace. Currently, virtually every infant formula company in the US markets directly to consumers using a large range of media.1 Formulas with or without slightly different components are being released on a regular basis. Sometimes “older” marketed names are used; in other cases new names are introduced. There is no database for the public or pediatricians to track these introductions. However, many such changes and additions are occurring every year. Advertising is intense, and, in the US, includes the use of websites targeted directly to the consumer. The consequences of this marketing on both consumer and pediatric caregiver behavior have not been extensively studied, although limited data suggest it may affect consumer’s willingness to change formulas.2 Nonetheless, it is not surprising that there is considerable consumer confusion about choosing infant formulas, and it is almost impossible for any family member or even their pediatrician to know the subtle differences among formulas on the store shelf. In this discussion, I will consider specific issues related to new and modified infant formulas, some consequences of the changes in formula composition and marketing in recent years, and question whether the population might best be suited by slowing down the introduction of new formulas until clearer guidance and research are available about these formulas.
AAP FDA IFA IOM USDA WHO WIC
American Academy of Pediatrics Food and Drug Administration Infant Formula Act Institute of Medicine US Department of Agriculture World Health Organization Special Supplemental Nutrition Program for Women, Infants, and Children
Regulatory and Other Guidance Related to Infant Formulas and Their Marketing in the US Statutory and Food and Drug Administration Regulations The modern regulatory era began with a law, called the Infant Formula Act (IFA), passed in 1980 and amended in 1986. This act set standards for the production and testing of infant formulas and was developed primarily because of a serious incident in which chloride was inadequately provided in some batches of infant formula.3 Further Food and Drug Administration (FDA) guidance established regulations for the introduction of new infant formulas and changes to existing formulas. These regulations were most recently updated and finalized in its current form in and made effective on July 10, 2014.4 These recent changes were mostly technical related to formula preparation and safety testing but did contain relatively minor new guidance describing testing process related to the introduction of new formulas or changes in existing formulas. The most common misconception about the development and release of new infant formulas is that all changes in infant formulas are extensively tested by the manufacturer and then are approved by the FDA based on substantial clinical data. This is inaccurate and leads to the perception that all marketed infant formulas are not only safe but have health benefits compared with alternative formula options as described by their marketing description. The FDA does not “approve” infant formulas. This surprises almost everyone but is an accurate description of the FDA process. Rather, they review the proposed formula composition and explanation of use that has been provided by the formula company and then relay any concerns about the marketing of the product to the company. This distinction is more than just semantics and can be reviewed by considering the detailed explanation about infant formula approvals provided at the FDA website.5 The important concept in this process is that the FDA is fundamentally more empowered to assess safety than efficacy related to marketing of infant formulas. This is true
From the Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX S.A. is the principal investigator of an investigator-initiated study related to postdischarge management of preterm infants funded by Mead Johnson Nutrition (Evansville, Indiana). 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.11.003
756
Vol. 166, No. 3 March 2015 whether they are small compositional changes or represent very different forms of key components such as protein. Infant formulas are regulated as food products, not as medications, and thus, are not subject to the same guidelines as medications for testing and evaluation. When components that are categorized by the FDA as “Generally Recognized as Safe” for infant use are added or varied, there is little the FDA can do to restrict their use. Furthermore, compositional variations or changes that fall within the guidelines of the IFA are unlikely to be blocked by the FDA. For example, small changes in protein, energy, or mineral amounts are at the discretion of the manufacturers as long as they meet the relatively broad ranges deemed acceptable in the IFA. Where this issue becomes more confusing and even less transparent to consumers or pediatricians is when the form of a component is changed, such as when a different fat blend or mineral form is used in the formula. Again, whereas the public might imagine that each of these changes requires detailed laboratory, animal, and then human testing, this is not the case. It depends on the history of use of these components, the “Generally Recognized as Safe” status of the components for infant use, and the submission material provided by the manufacturer to the FDA to explain the changes. Simply put, such changes and variations are not always extensively tested before being released in the marketplace. Small scale metabolic and growth testing when available may be inadequate to assure safety when given to tens of thousands of infants and is likely to be inadequate to assure any unique benefit. Postmarketing surveillance is unlikely to be adequate to identify minor or unexpected problems with formulas and is subject to ascertainment bias. Institute of Medicine Guidelines Recognizing these problems, the Institute of Medicine (IOM) formed a committee specifically to make recommendations about the testing and evaluation of infant formulas. The IOM process led to the publication in 2004 of a very detailed document that includes recommendations related to in vitro, animal, and human studies that should be done prior to marketing new or significantly altered infant formulas. This remarkable document has never been implemented in the US, either voluntarily by manufacturer or by statute, nor does it appear to be used in a significant manner elsewhere in the world.6 However, several recent suggestions have been made based on the IOM recommendations regarding ways in which preclinical testing might be improved for infant formulas.7,8 World Health Organization International Code of Marketing of Breast-Milk Substitutes The aim of the World Health Organization (WHO) International Code of Marketing of Breast-Milk Substitutes is to provide for safe and adequate nutrition of infants worldwide through the protection and promotion of breastfeeding while ensuring that infant formulas (breast milk
substitutes) are not inappropriately marketed. Further details of both the WHO Code as well as the Baby Friendly Hospital Initiative (also commonly referred to as the 10 Steps program) are beyond this discussion. However, several points are relevant. First, the WHO Code, originally published in 1981, has not been implemented in the US, the only country to originally vote against it.9 Nor does the American Academy of Pediatrics (AAP) have a policy recommending it be followed. Of importance is that the Code does not permit direct advertising of infant formula to the public. Specifically, Article 5 states “There should be no advertising or other form of promotion to the general public of products within the scope of this Code.”10 Many other aspects of the code are often not followed in the US, as illustrated by the provision of free formula to health care workers. By following the WHO Code of Marketing of Breast-Milk Substitutes, along with the Baby Friendly Hospital Initiative to enhance health of infants through support of breastfeeding, many countries have greatly increased their breastfeeding rates.11 The Code clearly does not permit confusing mothers by marketing formulas as being equal or comparable with breast milk. This issue is very much in doubt in the marketing of breastfeeding “supplement” formulas as described below.12 Even more important is that the accessibility through many media and online sources of direct marketing by companies of their products makes it difficult for pediatricians and other caregivers to guide families in their formula choices. Other Guidance Approximately one-half of infant formula in the US is distributed via the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) which is administered by the US Department of Agriculture (USDA). This is critical in that the WIC program must decide, on statewide and national levels, how new formulas should be handled based on their state contracts. As such, the WIC program and thus, the USDA is a key partner in evaluating formula changes in the US without a clear, pediatrician-directed process by which they evaluate these changes other than the infrequent overall review of WIC nutritional programming via the IOM. This recently became important when the WIC program (with variations in approach on a stateby-state basis) chose not to routinely allow the use of lower energy infant formulas without a medical request for the use of these formulas.
Specific Examples of Recent Formula Introduction Intended for Healthy Children and Possible Consequences of Their Marketing Provided below is a discussion of several types of changes or novel formulas that have been introduced, or more widely marketed, in the last several years. In general, they are intended for healthy infants or those with relatively nonspecific symptoms such as mild-moderate colic or reflux. 757
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www.jpeds.com
Breast-Feeding Supplement and Newborn Formulas Each of the three largest commercial companies in the US providing infant formulas has developed and is marketing a formula specifically for breast-feeding supplementation. Of note is that each of these formulas is dissimilar to the other two. Variations in the formulas from the “standard” for each company are generally limited to minor variations in components such as vitamin D and prebiotics. There are no published studies showing any particular benefit to these formulas or similarly marketed “newborn” formulas compared with routine formulas for breast-feeding infants whose mothers choose to provide some formula supplementation. Marketing formulas in this way is almost always done directly to the consumer market. It is potentially misleading and may confuse families into believing that there actually is a best alternative to breastfeeding. It may also discourage the use of less expensive routine formulas. Overall, there is no scientific evidence that the use of breast-feeding supplement and newborn formulas offer any benefit to infants.12 Lower Energy or Protein Formulas Recently, one company introduced a slightly lower protein and energy formula in the US. This formula contains 19 kcal/oz energy or about 5% below the existing common standard of 20 kcal/oz. It is claimed that this energy concentration is more consistent with that of human milk. Concern about obesity in formula-fed infants, although not a direct aspect of the marketing of lower energy formulas, may also be considered part of the underlying rationale in using a lower energy formula. To date, there are no published studies of outcomes from 19 kcal/oz formulas in the US. There are no peer-reviewed published data indicating any short- or long-term benefit to a 5% decrease in energy and protein concentration, nor are there data showing that changes in infants’ intake based on scoop size occur when measured by families at home. Although it is unlikely that this type of trivial change in formula would be harmful to the vast majority of infants, from a policy perspective, there are several important concerns. First, as noted above, the USDA, via its role in the WIC program, does not currently permit the routine use of 19 kcal/oz formula in its administered programs. Because of the important role of the WIC program in providing infant formula, stores must often carry both a 20 kcal/oz and a 19 kcal/oz version of several of their formulas. At present, this is a highly dynamic and confusing situation in the marketplace environment with a substantial risk for error in selecting or preparing formulas. It is virtually impossible for the consumer to distinguish the differences between 19 and 20 kcal/oz formulas at the store. Equally concerning is the effect of this type of variation on hospital formularies. Hospitals provide formula both for healthy infants and also for infants, such as late preterm infants, or those with need for minimal fluid restriction, 758
Vol. 166, No. 3 who might often be receiving standard 20 kcal/oz formula. The use of a slightly lower energy concentration in this setting has not been tested and may never be subject to a safety or efficacy trial. Hospital formularies are struggling with this issue as ready-to-feed formula, as used in the hospital setting, can now be found in 19 kcal/oz and 20 kcal/oz strength. Low Lactose-Containing Infant Formulas Several formulas are marketed as being low lactose. It is extremely difficult and almost impossible for consumers to identify at the retail level what makes them different than ordinary formulas. In fact, the lactose content of these low lactose formulas ranges from 2%-70% lactose, thus, adding to the confusion in the marketplace. They are marketed using terms such as “gentle” and “sensitive” that imply they might be better for symptoms such as colic than routine formulas. Minimal objective evidence supports this suggestion, and there are inadequate data about the effects of such changes on the microbiome. There are data showing increased breath hydrogen production in colicky infants receiving normal levels of lactose compared with those receiving a low lactose-containing formula.13 However, adequately powered clinical studies do not exist related to a clinical benefit of low lactose formulas, nor is it clear what actually defines “low” lactose clinically. The very limited database provides no strong rational for the widespread practice of using low lactose formulas for large numbers of infants with minimal and typical mild to moderate colic symptoms.14 One problem with the use of these and similar variations in formulas is that often families will be switched repeatedly between formulas in the first weeks or months of life. These changes are often done without harmful consequence, but without identifying the most likely feeding problems or recognizing that normal infant behavior is occurring. This can cause increased parental anxiety, higher costs to families, and a potential delay in the diagnosis of genuine cow milk protein intolerance or other medical disorders. Variations of Prebiotics and Probiotics in Infant Formulas The use of both nondigestible carbohydrates (prebiotics), which may affect the gastrointestinal flora by supporting the growth of favorable bacteria or the actual provision of probiotic bacteria in formula has rapidly increased in recent years. Although there is substantial evidence to support some benefits to these additions, and prebiotics are now widely added to many formulas, there are constant changes and additions to these components being marketed. Furthermore, the amount and type of prebiotics and probiotics varies among formulas with little supporting evidence for these variations. It is virtually impossible for the pediatrician or consumer to identify the evidence supporting these frequent changes or to readily identify which marketed formulas have what bioactive components. Abrams
COMMENTARY
March 2015
Table. Policy interventions to improve evidence-base for introductions of new formulas Intervention
Groups
Outcome
Barrier to implementation
Follow IOM guidelines for testing of infant formulas Apply key aspects of WHO code of infant formula marketing
Government and industry partnership
Evidence of efficacy and safety and post-marketing monitoring process Decreased or no direct public marketing of infant formulas
Baby Friendly Hospital Initiative implementation
Hospitals, pediatricians
Establishment of working groups (AAP, FDA, industry, and others) to evaluate new formulas
Pediatricians, government agencies
Likely needs statutory authority for FDA to implement Advertising infant formulas has become standard and is income generating for many groups This is underway but is a slow process as it requires that hospitals pay fair market value for formulas they provide Cost, as there is no clear funding source or leadership for this
Industry and possibly federal or state legislatures
Specific Suggestions for Improving the Ability of Families and Pediatric Health Care Providers to Select Infant Formulas The problems described are very well known in the pediatric community. In this section, I would like to consider some possible steps forward to improve the situation (Table). A true mandatory or even a voluntary “moratorium” on the release of new formulas is presently unlikely based on the regulatory environment that exists in the US. Rather, the chaos of the marketplace and the degree to which it has created a disservice to pediatricians and other health care providers should ignite families and the government to recommend a gradual series of interventions to enhance the care of infants who are formula-fed. I have described some of these below, which might lead to more rational development and marketing of new formulas. Development of infant formula recommendations should be done to include key stakeholders. This includes the FDA, the AAP, the USDA, and corporate representatives. A council of these groups should be established to consider policy guidelines described below. The establishment of this council should be mandated by statute or federal policy, and the use of any new formula for healthy infants or those with mild-moderate symptoms of feeding intolerance by the WIC program should not be permitted without a full evidence-based review. This review should assess not just safety but a benefit appropriate for any increase in public cost of providing this formula as part of the WIC program. Regulatory The regulatory framework for infant formulas in the US is focused on safety and not efficacy. I recommend addressing this by changing the statutory rules under which the FDA evaluates new formulas and changes in existing formulas. This regulatory change should be guided by the not yet implemented IOM recommendations6 and by the advice of other independent groups such as the AAP. Specifically, formula manufacturers should be mandated to present multiple trials in which novel formulas and changes in existing formulas demonstrate a benefit to infants.
Improved breast-feeding rates, limiting co-marketing of infant formulas by hospitals and physicians Clear unbiased information for pediatricians about formulas
Marketing The 1981 WHO International Code of Marketing of Breast-Milk Substitutes should be adopted in the US or at least a commission should determine those aspects that should be introduced.15 In particular, the direct-toconsumer advertising of formula brands by manufacturers should not be an acceptable practice in the US or, at a minimum, should have substantial oversight and regulation. Marketing of infant formulas is optimally done via traditional media and the internet only to health care professionals. It would be ideal for pediatricians and other pediatric health care providers to be provided with tools such as unbiased evidence-based reviews with which they can respond to consumer concerns. This may be via the AAP or similar mechanisms. Second, key organizations, including the AAP and other medical societies and groups, should use tremendous caution in allowing their name and resources to be used by infant formula manufacturers in educational materials. There should be a clear wall delineating all marketing efforts by companies from pediatric organizations such that, for example, breast-feeding educational and supportive materials do not contain infant formula company logos. The use of hospital discharge bags with formula company materials included in them should not occur. Role of Health Care Providers Ultimately, it is the job of the pediatrician or other health care providers to help guide, through parental education and public advocacy, those standards not set by statute or other federal regulation. These providers should recognize bias in the marketplace and counsel families based on the evidence base whenever recommending formulas, especially when the recommendation is for a formula that is not the lowest cost to the family or to the government. To assist them, urgent unbiased development of guidance related to existing formulas is needed. WHO guidance about providing free samples to pediatric caregivers should be respected and more generally, pediatricians and other health care providers should act independently of corporate influences in making formula recommendations.
Is It Time to Put a Moratorium on New Infant Formulas that Are Not Adequately Investigated?
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Vol. 166, No. 3
Conclusions
References
Infant formula sales in the US are a competitive and profitable marketplace environment. As such, there is a tendency for companies to release a variety of new products to seek a competitive advantage and to market them to consumers who are unaware of the scientific framework for their use. FDA restrictions on such releases are designed to ensure that there is minimal evidence of risk, but often the evidence for benefit is not established. Some of these products may confuse families relative to the value of breast-feeding or to the value of spending money on more expensive formulas than are medically needed. In other cases, they lead to multiple formula switches over relatively minor symptoms that would best be managed through parental education. They may also pose risks for populations including late preterm infants or infants with other risk factors for poor growth. This recent explosion of formulas on the marketplace has served little if any benefit for infants, parents, or pediatricians. It would be best if manufacturers would voluntarily call a moratorium on releasing more such formulas until the evidence base is expanded. Meanwhile, because a voluntary moratorium is unlikely to occur, regulatory and marketplace changes should rapidly be developed by nonbiased information sources including involvement from the AAP and the IOM to help pediatricians and other health care providers make decisions on infant formula choices. n
1. Greer FR, Apple RD. Physicians, formula companies, and advertising. A historical perspective. Am J Dis Child 1991;145:282-6. 2. Huang Y, Labiner-Wolfe J, Huang H, Choiniere CJ, Fein SB. Association of health profession and direct-to-consumer marketing with infant formula choice and switching. Birth 2013;40:24-31. 3. FDA: Regulations and Information on the Manufacture and Distribution of Infant Formula, March 2002. http://www.fda.gov/Food/ GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ InfantFormula/ucm136118.htm. Accessed November 27, 2014. 4. Federal Register. Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula, A Rule by the Food and Drug Administration on 06/10/2014. https://www.federalregister.gov/articles/ 2014/06/10/2014-13384/current-good-manufacturing-practices-qualitycontrol-procedures-quality-factors-notification. Accessed November 27, 2014. 5. FDA: Frequently Asked Questions about FDA’s Regulation of Infant Formula, March 1, 2006. http://www.fda.gov/Food/GuidanceRegulation/ GuidanceDocumentsRegulatoryInformation/ucm056524.htm. Accessed November 27, 2014. 6. IOM: Infant Formula: Evaluating the Safety of New Ingredients, Released March,1, 2004. http://www.iom.edu/Reports/2004/Infant-FormulaEvaluating-the-Safety-of-New-Ingredients.aspx. Accessed November 27, 2014. 7. L€ onnerdal B. Preclinical assessment of infant formula. Ann Nutr Metab 2012;60:196-9. 8. Flamm EG. Neonatal animal testing paradigms and their suitability for testing infant formula. Toxicol Mech Methods 2013;23:57-67. 9. Brady JP. Marketing breast milk substitutes: problems and perils throughout the world. Arch Dis Child 2012;97:529-32. 10. WHO: International Code of Marketing of Breast-milk Substitutes. http://www.who.int/nutrition/publications/code_english.pdf. Accessed November 27, 2014. 11. Labbok MH. Global baby-friendly hospital initiative monitoring data: update and discussion. Breastfeed Med 2012;7:210-22. 12. Abrams SA, Schanler RJ. Data do not support claims that ‘supplement formulas’ are better than standard formulas for breastfed infants. AAP News 2014;35:26. 13. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr 1988; 113:979-84. 14. Infante D, Segarra O, Luyer BL. Dietary treatment of colic caused by excess gas in infants: biochemical evidence. World J Gastroenterol 2011;17:2104-8. 15. Forsyth S. Three decades of the WHO code and marketing of infant formulas. Curr Opin Clin Nutr Metab Care 2012;15:273-7.
I would like to note the recent passing of a friend and colleague, Benson Silverman, MD, a neonatologist who for many years was the lead at the FDA regarding infant formula regulation. His passing occurred just prior to the release in 2014 of the FDA final rules on infant formula manufacturing described in this article. He will be greatly missed by all those interested in infant nutrition. Submitted for publication Jul 31, 2014; last revision received Oct 10, 2014; accepted Nov 3, 2014. Reprint requests: Steven A. Abrams, MD, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, 1100 Bates St, Houston, TX 77030. E-mail: [email protected]
760
Abrams
I
nfant formula development in the US is an ongoing process of development and regulation. For many years, there were few infant formulas in use in the US. Formulas were either “routine” cow milk proteinbased, soy protein-based, or uncommonly, specialized formulas such as those for infants with a documented cow milk protein allergy or metabolic diseases. Decisions about formula selection were almost entirely at the discretion of a child’s pediatrician, and public advertising and marketing of infant formulas was not done or was extremely limited. This changed in the late 1980s with the introduction of several new formulas and a new infant formula company to the US marketplace. Currently, virtually every infant formula company in the US markets directly to consumers using a large range of media.1 Formulas with or without slightly different components are being released on a regular basis. Sometimes “older” marketed names are used; in other cases new names are introduced. There is no database for the public or pediatricians to track these introductions. However, many such changes and additions are occurring every year. Advertising is intense, and, in the US, includes the use of websites targeted directly to the consumer. The consequences of this marketing on both consumer and pediatric caregiver behavior have not been extensively studied, although limited data suggest it may affect consumer’s willingness to change formulas.2 Nonetheless, it is not surprising that there is considerable consumer confusion about choosing infant formulas, and it is almost impossible for any family member or even their pediatrician to know the subtle differences among formulas on the store shelf. In this discussion, I will consider specific issues related to new and modified infant formulas, some consequences of the changes in formula composition and marketing in recent years, and question whether the population might best be suited by slowing down the introduction of new formulas until clearer guidance and research are available about these formulas.
AAP FDA IFA IOM USDA WHO WIC
American Academy of Pediatrics Food and Drug Administration Infant Formula Act Institute of Medicine US Department of Agriculture World Health Organization Special Supplemental Nutrition Program for Women, Infants, and Children
Regulatory and Other Guidance Related to Infant Formulas and Their Marketing in the US Statutory and Food and Drug Administration Regulations The modern regulatory era began with a law, called the Infant Formula Act (IFA), passed in 1980 and amended in 1986. This act set standards for the production and testing of infant formulas and was developed primarily because of a serious incident in which chloride was inadequately provided in some batches of infant formula.3 Further Food and Drug Administration (FDA) guidance established regulations for the introduction of new infant formulas and changes to existing formulas. These regulations were most recently updated and finalized in its current form in and made effective on July 10, 2014.4 These recent changes were mostly technical related to formula preparation and safety testing but did contain relatively minor new guidance describing testing process related to the introduction of new formulas or changes in existing formulas. The most common misconception about the development and release of new infant formulas is that all changes in infant formulas are extensively tested by the manufacturer and then are approved by the FDA based on substantial clinical data. This is inaccurate and leads to the perception that all marketed infant formulas are not only safe but have health benefits compared with alternative formula options as described by their marketing description. The FDA does not “approve” infant formulas. This surprises almost everyone but is an accurate description of the FDA process. Rather, they review the proposed formula composition and explanation of use that has been provided by the formula company and then relay any concerns about the marketing of the product to the company. This distinction is more than just semantics and can be reviewed by considering the detailed explanation about infant formula approvals provided at the FDA website.5 The important concept in this process is that the FDA is fundamentally more empowered to assess safety than efficacy related to marketing of infant formulas. This is true
From the Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX S.A. is the principal investigator of an investigator-initiated study related to postdischarge management of preterm infants funded by Mead Johnson Nutrition (Evansville, Indiana). 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.11.003
756
Vol. 166, No. 3 March 2015 whether they are small compositional changes or represent very different forms of key components such as protein. Infant formulas are regulated as food products, not as medications, and thus, are not subject to the same guidelines as medications for testing and evaluation. When components that are categorized by the FDA as “Generally Recognized as Safe” for infant use are added or varied, there is little the FDA can do to restrict their use. Furthermore, compositional variations or changes that fall within the guidelines of the IFA are unlikely to be blocked by the FDA. For example, small changes in protein, energy, or mineral amounts are at the discretion of the manufacturers as long as they meet the relatively broad ranges deemed acceptable in the IFA. Where this issue becomes more confusing and even less transparent to consumers or pediatricians is when the form of a component is changed, such as when a different fat blend or mineral form is used in the formula. Again, whereas the public might imagine that each of these changes requires detailed laboratory, animal, and then human testing, this is not the case. It depends on the history of use of these components, the “Generally Recognized as Safe” status of the components for infant use, and the submission material provided by the manufacturer to the FDA to explain the changes. Simply put, such changes and variations are not always extensively tested before being released in the marketplace. Small scale metabolic and growth testing when available may be inadequate to assure safety when given to tens of thousands of infants and is likely to be inadequate to assure any unique benefit. Postmarketing surveillance is unlikely to be adequate to identify minor or unexpected problems with formulas and is subject to ascertainment bias. Institute of Medicine Guidelines Recognizing these problems, the Institute of Medicine (IOM) formed a committee specifically to make recommendations about the testing and evaluation of infant formulas. The IOM process led to the publication in 2004 of a very detailed document that includes recommendations related to in vitro, animal, and human studies that should be done prior to marketing new or significantly altered infant formulas. This remarkable document has never been implemented in the US, either voluntarily by manufacturer or by statute, nor does it appear to be used in a significant manner elsewhere in the world.6 However, several recent suggestions have been made based on the IOM recommendations regarding ways in which preclinical testing might be improved for infant formulas.7,8 World Health Organization International Code of Marketing of Breast-Milk Substitutes The aim of the World Health Organization (WHO) International Code of Marketing of Breast-Milk Substitutes is to provide for safe and adequate nutrition of infants worldwide through the protection and promotion of breastfeeding while ensuring that infant formulas (breast milk
substitutes) are not inappropriately marketed. Further details of both the WHO Code as well as the Baby Friendly Hospital Initiative (also commonly referred to as the 10 Steps program) are beyond this discussion. However, several points are relevant. First, the WHO Code, originally published in 1981, has not been implemented in the US, the only country to originally vote against it.9 Nor does the American Academy of Pediatrics (AAP) have a policy recommending it be followed. Of importance is that the Code does not permit direct advertising of infant formula to the public. Specifically, Article 5 states “There should be no advertising or other form of promotion to the general public of products within the scope of this Code.”10 Many other aspects of the code are often not followed in the US, as illustrated by the provision of free formula to health care workers. By following the WHO Code of Marketing of Breast-Milk Substitutes, along with the Baby Friendly Hospital Initiative to enhance health of infants through support of breastfeeding, many countries have greatly increased their breastfeeding rates.11 The Code clearly does not permit confusing mothers by marketing formulas as being equal or comparable with breast milk. This issue is very much in doubt in the marketing of breastfeeding “supplement” formulas as described below.12 Even more important is that the accessibility through many media and online sources of direct marketing by companies of their products makes it difficult for pediatricians and other caregivers to guide families in their formula choices. Other Guidance Approximately one-half of infant formula in the US is distributed via the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) which is administered by the US Department of Agriculture (USDA). This is critical in that the WIC program must decide, on statewide and national levels, how new formulas should be handled based on their state contracts. As such, the WIC program and thus, the USDA is a key partner in evaluating formula changes in the US without a clear, pediatrician-directed process by which they evaluate these changes other than the infrequent overall review of WIC nutritional programming via the IOM. This recently became important when the WIC program (with variations in approach on a stateby-state basis) chose not to routinely allow the use of lower energy infant formulas without a medical request for the use of these formulas.
Specific Examples of Recent Formula Introduction Intended for Healthy Children and Possible Consequences of Their Marketing Provided below is a discussion of several types of changes or novel formulas that have been introduced, or more widely marketed, in the last several years. In general, they are intended for healthy infants or those with relatively nonspecific symptoms such as mild-moderate colic or reflux. 757
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Breast-Feeding Supplement and Newborn Formulas Each of the three largest commercial companies in the US providing infant formulas has developed and is marketing a formula specifically for breast-feeding supplementation. Of note is that each of these formulas is dissimilar to the other two. Variations in the formulas from the “standard” for each company are generally limited to minor variations in components such as vitamin D and prebiotics. There are no published studies showing any particular benefit to these formulas or similarly marketed “newborn” formulas compared with routine formulas for breast-feeding infants whose mothers choose to provide some formula supplementation. Marketing formulas in this way is almost always done directly to the consumer market. It is potentially misleading and may confuse families into believing that there actually is a best alternative to breastfeeding. It may also discourage the use of less expensive routine formulas. Overall, there is no scientific evidence that the use of breast-feeding supplement and newborn formulas offer any benefit to infants.12 Lower Energy or Protein Formulas Recently, one company introduced a slightly lower protein and energy formula in the US. This formula contains 19 kcal/oz energy or about 5% below the existing common standard of 20 kcal/oz. It is claimed that this energy concentration is more consistent with that of human milk. Concern about obesity in formula-fed infants, although not a direct aspect of the marketing of lower energy formulas, may also be considered part of the underlying rationale in using a lower energy formula. To date, there are no published studies of outcomes from 19 kcal/oz formulas in the US. There are no peer-reviewed published data indicating any short- or long-term benefit to a 5% decrease in energy and protein concentration, nor are there data showing that changes in infants’ intake based on scoop size occur when measured by families at home. Although it is unlikely that this type of trivial change in formula would be harmful to the vast majority of infants, from a policy perspective, there are several important concerns. First, as noted above, the USDA, via its role in the WIC program, does not currently permit the routine use of 19 kcal/oz formula in its administered programs. Because of the important role of the WIC program in providing infant formula, stores must often carry both a 20 kcal/oz and a 19 kcal/oz version of several of their formulas. At present, this is a highly dynamic and confusing situation in the marketplace environment with a substantial risk for error in selecting or preparing formulas. It is virtually impossible for the consumer to distinguish the differences between 19 and 20 kcal/oz formulas at the store. Equally concerning is the effect of this type of variation on hospital formularies. Hospitals provide formula both for healthy infants and also for infants, such as late preterm infants, or those with need for minimal fluid restriction, 758
Vol. 166, No. 3 who might often be receiving standard 20 kcal/oz formula. The use of a slightly lower energy concentration in this setting has not been tested and may never be subject to a safety or efficacy trial. Hospital formularies are struggling with this issue as ready-to-feed formula, as used in the hospital setting, can now be found in 19 kcal/oz and 20 kcal/oz strength. Low Lactose-Containing Infant Formulas Several formulas are marketed as being low lactose. It is extremely difficult and almost impossible for consumers to identify at the retail level what makes them different than ordinary formulas. In fact, the lactose content of these low lactose formulas ranges from 2%-70% lactose, thus, adding to the confusion in the marketplace. They are marketed using terms such as “gentle” and “sensitive” that imply they might be better for symptoms such as colic than routine formulas. Minimal objective evidence supports this suggestion, and there are inadequate data about the effects of such changes on the microbiome. There are data showing increased breath hydrogen production in colicky infants receiving normal levels of lactose compared with those receiving a low lactose-containing formula.13 However, adequately powered clinical studies do not exist related to a clinical benefit of low lactose formulas, nor is it clear what actually defines “low” lactose clinically. The very limited database provides no strong rational for the widespread practice of using low lactose formulas for large numbers of infants with minimal and typical mild to moderate colic symptoms.14 One problem with the use of these and similar variations in formulas is that often families will be switched repeatedly between formulas in the first weeks or months of life. These changes are often done without harmful consequence, but without identifying the most likely feeding problems or recognizing that normal infant behavior is occurring. This can cause increased parental anxiety, higher costs to families, and a potential delay in the diagnosis of genuine cow milk protein intolerance or other medical disorders. Variations of Prebiotics and Probiotics in Infant Formulas The use of both nondigestible carbohydrates (prebiotics), which may affect the gastrointestinal flora by supporting the growth of favorable bacteria or the actual provision of probiotic bacteria in formula has rapidly increased in recent years. Although there is substantial evidence to support some benefits to these additions, and prebiotics are now widely added to many formulas, there are constant changes and additions to these components being marketed. Furthermore, the amount and type of prebiotics and probiotics varies among formulas with little supporting evidence for these variations. It is virtually impossible for the pediatrician or consumer to identify the evidence supporting these frequent changes or to readily identify which marketed formulas have what bioactive components. Abrams
COMMENTARY
March 2015
Table. Policy interventions to improve evidence-base for introductions of new formulas Intervention
Groups
Outcome
Barrier to implementation
Follow IOM guidelines for testing of infant formulas Apply key aspects of WHO code of infant formula marketing
Government and industry partnership
Evidence of efficacy and safety and post-marketing monitoring process Decreased or no direct public marketing of infant formulas
Baby Friendly Hospital Initiative implementation
Hospitals, pediatricians
Establishment of working groups (AAP, FDA, industry, and others) to evaluate new formulas
Pediatricians, government agencies
Likely needs statutory authority for FDA to implement Advertising infant formulas has become standard and is income generating for many groups This is underway but is a slow process as it requires that hospitals pay fair market value for formulas they provide Cost, as there is no clear funding source or leadership for this
Industry and possibly federal or state legislatures
Specific Suggestions for Improving the Ability of Families and Pediatric Health Care Providers to Select Infant Formulas The problems described are very well known in the pediatric community. In this section, I would like to consider some possible steps forward to improve the situation (Table). A true mandatory or even a voluntary “moratorium” on the release of new formulas is presently unlikely based on the regulatory environment that exists in the US. Rather, the chaos of the marketplace and the degree to which it has created a disservice to pediatricians and other health care providers should ignite families and the government to recommend a gradual series of interventions to enhance the care of infants who are formula-fed. I have described some of these below, which might lead to more rational development and marketing of new formulas. Development of infant formula recommendations should be done to include key stakeholders. This includes the FDA, the AAP, the USDA, and corporate representatives. A council of these groups should be established to consider policy guidelines described below. The establishment of this council should be mandated by statute or federal policy, and the use of any new formula for healthy infants or those with mild-moderate symptoms of feeding intolerance by the WIC program should not be permitted without a full evidence-based review. This review should assess not just safety but a benefit appropriate for any increase in public cost of providing this formula as part of the WIC program. Regulatory The regulatory framework for infant formulas in the US is focused on safety and not efficacy. I recommend addressing this by changing the statutory rules under which the FDA evaluates new formulas and changes in existing formulas. This regulatory change should be guided by the not yet implemented IOM recommendations6 and by the advice of other independent groups such as the AAP. Specifically, formula manufacturers should be mandated to present multiple trials in which novel formulas and changes in existing formulas demonstrate a benefit to infants.
Improved breast-feeding rates, limiting co-marketing of infant formulas by hospitals and physicians Clear unbiased information for pediatricians about formulas
Marketing The 1981 WHO International Code of Marketing of Breast-Milk Substitutes should be adopted in the US or at least a commission should determine those aspects that should be introduced.15 In particular, the direct-toconsumer advertising of formula brands by manufacturers should not be an acceptable practice in the US or, at a minimum, should have substantial oversight and regulation. Marketing of infant formulas is optimally done via traditional media and the internet only to health care professionals. It would be ideal for pediatricians and other pediatric health care providers to be provided with tools such as unbiased evidence-based reviews with which they can respond to consumer concerns. This may be via the AAP or similar mechanisms. Second, key organizations, including the AAP and other medical societies and groups, should use tremendous caution in allowing their name and resources to be used by infant formula manufacturers in educational materials. There should be a clear wall delineating all marketing efforts by companies from pediatric organizations such that, for example, breast-feeding educational and supportive materials do not contain infant formula company logos. The use of hospital discharge bags with formula company materials included in them should not occur. Role of Health Care Providers Ultimately, it is the job of the pediatrician or other health care providers to help guide, through parental education and public advocacy, those standards not set by statute or other federal regulation. These providers should recognize bias in the marketplace and counsel families based on the evidence base whenever recommending formulas, especially when the recommendation is for a formula that is not the lowest cost to the family or to the government. To assist them, urgent unbiased development of guidance related to existing formulas is needed. WHO guidance about providing free samples to pediatric caregivers should be respected and more generally, pediatricians and other health care providers should act independently of corporate influences in making formula recommendations.
Is It Time to Put a Moratorium on New Infant Formulas that Are Not Adequately Investigated?
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Conclusions
References
Infant formula sales in the US are a competitive and profitable marketplace environment. As such, there is a tendency for companies to release a variety of new products to seek a competitive advantage and to market them to consumers who are unaware of the scientific framework for their use. FDA restrictions on such releases are designed to ensure that there is minimal evidence of risk, but often the evidence for benefit is not established. Some of these products may confuse families relative to the value of breast-feeding or to the value of spending money on more expensive formulas than are medically needed. In other cases, they lead to multiple formula switches over relatively minor symptoms that would best be managed through parental education. They may also pose risks for populations including late preterm infants or infants with other risk factors for poor growth. This recent explosion of formulas on the marketplace has served little if any benefit for infants, parents, or pediatricians. It would be best if manufacturers would voluntarily call a moratorium on releasing more such formulas until the evidence base is expanded. Meanwhile, because a voluntary moratorium is unlikely to occur, regulatory and marketplace changes should rapidly be developed by nonbiased information sources including involvement from the AAP and the IOM to help pediatricians and other health care providers make decisions on infant formula choices. n
1. Greer FR, Apple RD. Physicians, formula companies, and advertising. A historical perspective. Am J Dis Child 1991;145:282-6. 2. Huang Y, Labiner-Wolfe J, Huang H, Choiniere CJ, Fein SB. Association of health profession and direct-to-consumer marketing with infant formula choice and switching. Birth 2013;40:24-31. 3. FDA: Regulations and Information on the Manufacture and Distribution of Infant Formula, March 2002. http://www.fda.gov/Food/ GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ InfantFormula/ucm136118.htm. Accessed November 27, 2014. 4. Federal Register. Current Good Manufacturing Practices, Quality Control Procedures, Quality Factors, Notification Requirements, and Records and Reports, for Infant Formula, A Rule by the Food and Drug Administration on 06/10/2014. https://www.federalregister.gov/articles/ 2014/06/10/2014-13384/current-good-manufacturing-practices-qualitycontrol-procedures-quality-factors-notification. Accessed November 27, 2014. 5. FDA: Frequently Asked Questions about FDA’s Regulation of Infant Formula, March 1, 2006. http://www.fda.gov/Food/GuidanceRegulation/ GuidanceDocumentsRegulatoryInformation/ucm056524.htm. Accessed November 27, 2014. 6. IOM: Infant Formula: Evaluating the Safety of New Ingredients, Released March,1, 2004. http://www.iom.edu/Reports/2004/Infant-FormulaEvaluating-the-Safety-of-New-Ingredients.aspx. Accessed November 27, 2014. 7. L€ onnerdal B. Preclinical assessment of infant formula. Ann Nutr Metab 2012;60:196-9. 8. Flamm EG. Neonatal animal testing paradigms and their suitability for testing infant formula. Toxicol Mech Methods 2013;23:57-67. 9. Brady JP. Marketing breast milk substitutes: problems and perils throughout the world. Arch Dis Child 2012;97:529-32. 10. WHO: International Code of Marketing of Breast-milk Substitutes. http://www.who.int/nutrition/publications/code_english.pdf. Accessed November 27, 2014. 11. Labbok MH. Global baby-friendly hospital initiative monitoring data: update and discussion. Breastfeed Med 2012;7:210-22. 12. Abrams SA, Schanler RJ. Data do not support claims that ‘supplement formulas’ are better than standard formulas for breastfed infants. AAP News 2014;35:26. 13. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr 1988; 113:979-84. 14. Infante D, Segarra O, Luyer BL. Dietary treatment of colic caused by excess gas in infants: biochemical evidence. World J Gastroenterol 2011;17:2104-8. 15. Forsyth S. Three decades of the WHO code and marketing of infant formulas. Curr Opin Clin Nutr Metab Care 2012;15:273-7.
I would like to note the recent passing of a friend and colleague, Benson Silverman, MD, a neonatologist who for many years was the lead at the FDA regarding infant formula regulation. His passing occurred just prior to the release in 2014 of the FDA final rules on infant formula manufacturing described in this article. He will be greatly missed by all those interested in infant nutrition. Submitted for publication Jul 31, 2014; last revision received Oct 10, 2014; accepted Nov 3, 2014. Reprint requests: Steven A. Abrams, MD, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, 1100 Bates St, Houston, TX 77030. E-mail: [email protected]
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