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Infant Formula: Evaluating the Safety of New Ingredients 6 Going Beyond Current Clinical Studies ABSTRACT Clinical studies are essential to ensure the safety of infant formulas and any systematic deviation from normal physical growth and development attributable to a new ingredient should be considered a safety threat. Growth studies, currently a centerpiece of clinical evaluation of infant formulas, should include precise and reliable measurements of weight and length velocity and head circumference. Appropriate measures of body composition also require assessment. Duration of follow-up measurements should at least cover the period when infant formula remains the sole source of nutrients in the diet of the infant. However the committee believes that growth studies are not sufficient on their own to assess ingredients new to infant formulas. Specific guidelines are needed to determine “normal” growth and to establish what represents a biologically meaningful difference among groups of infants consuming different formulas. Specific recommendations are needed to establish a level of difference that represents a safety concern. Regulatory guidelines should ensure that infant outcomes encompass, as the Food and Drug Administration (FDA) has proposed, “all aspects of physical growth and normal maturational development.” Any systematic differences in clinical outcomes that can be attributed to an ingredient new to infant formulas should be considered a safety concern that requires careful evaluation and, if needed, further clinical study to identify the pathway through which the infant has been affected. The committee recommends that a hierarchy of two levels of clinical assessment be implemented with regard to growth and organ systems. Level 1 assessments should include checking for signs of all adverse laboratory indicators of the major organ systems. Level 2 assessments should include in-depth measures of organ systems or functions that would be performed to explain abnormalities found in level 1 assessments or specific theoretical concerns not typically addressed by level 1 tests.
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Infant Formula: Evaluating the Safety of New Ingredients There are a number of reasons why it is equally important to include developmental-behavioral outcomes in future studies of the safety of ingredients new to infant formulas: the measures are sensitive to exposure to toxic substances, they can have long-term predictive value, and bidirectional brain-behavior links exist. Therefore, assessment of clinical endpoints should include measurement of infant sensory-motor, cognitive, affectual, and neural function with instruments that follow recommended criteria. The committee recommends that a hierarchy of three levels of clinical assessment be developed and implemented to determine what levels are appropriate to apply with regard to developmental-behavioral-neural outcomes. The levels of assessment are: level 1 assessments, including developmental screening measures; level 2 assessments, including in-depth measures of infant functions in major developmental areas (single assessment for each area with one instrument); and level 3 assessments, including in-depth measures of infant functions in major developmental areas (repeated assessment with multiple instruments). The instruments used for these assessments should satisfy the following criteria: be age appropriate, have predictive value for long-term consequences, be adequately sensitive, have documented brain-behavior links, have cross-species generalizability, assess specific function, and be easy to administer. In addition, the committee considers that certain design features (e.g., adequate statistical power) are essential in all clinical studies. INTRODUCTION This chapter provides an overview of clinical studies and a brief overview of the current regulatory requirements for them. The first part of the chapter includes a rationale for clinical assessment of growth, specific recommendations on what should be measured, and guidelines for interpretation of results. In the second part, the committee describes more specific clinical endpoints in each of the organ systems likely to be affected by ingredients new to infant formulas. In the last part of the chapter considerable attention is paid to behavioral and developmental endpoints because of the young infant’s heightened sensitivity to potentially toxic substances and the long-term consequences of such exposures. THE IMPORTANCE OF CLINICAL STUDIES While preclinical laboratory and animal studies have substantial value for identifying potential safety concerns, they are limited in their ability to predict what may happen in human infants. Clinical studies in human infants are needed for several reasons. First, extrapolation from animal studies may be limited by differences between animal and human structure, physiology, and development. Second, extrapolation from isolated tissue studies is limited by the inability of such models to assess functions in the context of whole organ systems where coordination and integration are the rule. For example, the digestion and absorption of nutrients requires coordination of numerous gastrointestinal functions. Third, there may be no available animal or tissue models to test specific functions. For example, it is not possible to use animal models to duplicate clinically relevant allergic reactions to foreign proteins, to determine the effects of a substance on acceptance or tolerance of an infant formula, or to test some of the higher cognitive functions found only in humans.
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Infant Formula: Evaluating the Safety of New Ingredients CURRENT REGULATORY GUIDELINES FOR CLINICAL STUDIES Canada’s Food and Drug Regulations There are no specific requirements for clinical testing of infant formulas set out under Canada’s Food and Drug Regulations in Division 16 (Food Additives), Division 25 (Infant Formula), or Division 28 (Novel Foods) (Canada, 2001). Division 25 of the Regulations requires that a premarket submission with respect to a new infant formula or an infant formula that has undergone a major change in composition, manufacturing, or packaging include the evidence relied on to establish that the infant formula is nutritionally adequate to promote acceptable growth and development in infants when consumed in accordance with the directions for use. Divisions 16 and 28 require that data be submitted to Health Canada that include information used to establish the safety of a food additive or a novel food, respectively. Health Canada refers manufacturers to internationally accepted guidelines for clinical testing or asks to be consulted because decisions are made on a case-by-case basis. Sections 409 and 412 of the Federal Food, Drug and Cosmetic Act There are no explicit requirements for clinical testing of infant formulas specified under Section 409 of the Food, Drug and Cosmetic (FD&C) Act. Section 409 stipulates that a petition to establish safety of a food additive shall contain “all relevant data bearing on the physical or other technical effect such additive is intended to produce …,” but it does not dictate a specific type of clinical study. Current regulations for infant formulas under Section 412 of the FD&C Act do not define quality factor requirements, such as physical growth, but only describe required nutrient levels, without considering bioavailability. This gap is addressed in a proposed rule (FDA, 1996), where assessment of physical growth, using anthropometry, is proposed “as an integrative indicator of net overall nutritional quality of the formula.” The proposed rule further states, “as the science evolves, FDA anticipates being able to progress beyond generalized, nonspecific indicators of overall nutritional intakes (e.g., measures of physical growth) to more specific and sensitive measures of biochemical and functional nutritional status” (FDA, 1996, P. 36181). Thus neither the current nor the proposed rules identify specific requirements for other clinical studies. FDA Redbook FDA does not require petitioners to conduct human clinical studies to support the safety of food additives or color additives used in food, but, if deemed necessary, it recommends that the studies conform to guidelines presented in section VI.A. of the Redbook (OFAS, 2001, 2003). These guidelines are comprehensive and relevant for the clinical testing of ingredients new to infant formulas. General guidance is provided to identify the scientific and ethical principles for clinical studies, including the need for presentation of a defensible rationale for human studies. The Redbook states that this rationale should be based on: adequate preclinical investigations, results of clinical studies conducted elsewhere, consideration of the organs and organ systems that may be affected, and
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Infant Formula: Evaluating the Safety of New Ingredients careful attention to the qualifications of investigators and the safety and ethical treatment of subjects in clinical trials. The Redbook suggests the sequence of and subjects for clinical studies. Early clinical studies are to determine the “metabolism and level of the food or food additive that gives an adverse or toxic response in man” (specifically physiological studies of the additive’s disposition, its potential to induce enzyme levels or increase activity, and its interactions with other nutrients) (OFAS, 2001, P. 183). In general children are to be excluded from these early (typically acute or shorter duration) clinical studies. However tolerance studies, which are to be included among early studies, need to be conducted in infants because of the special nature of infant formulas. Infants are more likely to be included in what the Redbook describes as chronic intake studies, which are to be conducted once general safety in humans is established in the early adult studies. Here, the Redbook provides specific guidance on protocol design, study population, and statistical analyses, as well as on how reports of clinical studies should be presented. Box 6-1 lists questions that should be answered when conducting studies to determine the safety of a proposed additive. GENERAL APPROACH TO CONDUCTING CLINICAL STUDIES In the conceptualization of the range of infant health concerns, the committee was guided by the following: “FDA considers the concept of ‘healthy growth’ to be broad, encompassing all aspects of physical growth and normal maturational development, including maturation of organ systems and achievement of normal functional development of motor, neurocognitive, and immune systems. All of these growth and maturational developmental processes are major determinants of an infant’s ability to achieve his/her biological potential, and all can be affected by the nutritional status of an infant” (FDA, 1996, P. 36179). The committee proposes the use of a multilevel approach to establish more comprehensive guidelines to ensure that infant outcomes encompass “all aspects of physical growth and normal maturational development.” Figure 6-1 illustrates the three different types of clinical studies recommended by the committee, including assessment of growth, organ systems, and development and behavior. Figures 6-2 and 6-3 further explain the clinical studies through the proposed two-level approach to organ systems and the three-level approach to development- BOX 6-1 Questions That Should Be Answered When Conducting Clinical Studies How is the food or food additive absorbed, metabolized, deposited in tissue, and excreted? What is the half-life of the food or food additive in the human body? How may interactions between the food or food additive and nutrients or medications compromise the availability of any of these substances (including the consideration of the matrix)? How does the food or food additive affect the function of human organs and organ systems (including infant growth and development)? What are the possible adverse reactions to the food or food additive in the general population of individuals who are likely to use the substance and in special (more sensitive) populations? SOURCE: OFAS (2001, 2003).
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Infant Formula: Evaluating the Safety of New Ingredients FIGURE 6-1 Proposed clinical assessment algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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Infant Formula: Evaluating the Safety of New Ingredients FIGURE 6-2 Proposed levels of clinical assessment of major organ, immune, and endocrine systems algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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Infant Formula: Evaluating the Safety of New Ingredients FIGURE 6-3 Proposed levels of clinical assessment of development and behavior algorithm. = a state or condition, = a decision point, = an action, sidebar = an elaboration of recommendation or statement.
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Infant Formula: Evaluating the Safety of New Ingredients behavior. There are decision-making points within each of these three types of clinical studies that will be discussed in detail in subsequent sections of this chapter. (In keeping with the charge to the committee, proposed guidelines focus on the health and well-being of term infants only.) The committee recognizes that all clinical studies would need to be reviewed and approved by human-subject research review boards. Because the clinical studies to determine the safety of new ingredients will be carried out in healthy infants, the committee does not recommend the use of highly invasive tests, such as tissue biopsies or gastrointestinal incubations. OVERVIEW OF RECOMMENDED LEVELS OF ASSESSMENT RECOMMENDATION: Any adverse systematic differences in clinical outcomes that can be attributed to an ingredient new to infant formulas should be considered a safety concern that requires careful evaluation and, if needed, further clinical study to identify the pathway through which the infant has been affected. A hierarchy of two levels of clinical assessment should be implemented for organ systems: Level 1 assessments. Check of signs for all adverse laboratory indicators. Level 2 assessments. In-depth measures of organ systems or functions that would be performed to explain abnormalities found in level 1 assessments or specific theoretical concerns not typically addressed by level 1 tests. A hierarchy of three levels of clinical assessment should be implemented for developmental-behavioral measures: Level 1 assessments. Developmental screening measures. Level 2 assessments. In-depth measures of infant functions in major developmental areas (single assessment for each area with one instrument). Level 3 assessments. In-depth measures of infant functions in major developmental areas (repeated assessment with multiple instruments). GROWTH Growth is well recognized as a sensitive, but nonspecific, indicator of the overall health and nutritional status of an infant. Monitoring infant growth has always been an integral part of pediatric care and is particularly important for young infants. Growth and nutrient requirements per kilogram of body weight are higher during the first few months of infancy than during any other period of life. Furthermore, the greatest percentage of dietary intake is devoted to supporting growth at this time, and thus nutritional imbalances are likely to be reflected in growth rates. The committee believes that the inability of a formula to support normal growth represents a significant harm to infants and therefore growth is an essential endpoint for all safety assessments of an ingredient new to infant formulas. Any systematic deviation from normal physical growth attributable to a new ingredient should be considered a safety threat. Under current regulations the core of the requirements focuses on meeting certain levels of specific nutrients. The concept of quality factors has not been defined, but proposed
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Infant Formula: Evaluating the Safety of New Ingredients regulations include a subsection on quality factors, with a focus on physical growth. Despite the absence of quality factors in current legislation, there appears to be a strong consensus that growth should be a quality factor for infant formulas. In the United States FDA recognized the need for clear guidelines on the assessment of growth and commissioned a report from the American Academy of Pediatrics’ (AAP) Committee on Nutrition Task Force on clinical testing of infant formulas with respect to nutritional suitability for term infants (AAP, 1988). The task force identified the following types of clinical studies as useful in the premarket evaluation of formulas: acceptance or tolerance studies, gains in weight and length, food intake, body composition, serum chemical indices, and metabolic balance studies. Most of the recommendations of the task force were incorporated into the proposed changes to the infant formula act (FDA, 1996). Currently clinical studies tend to follow the proposed rule, the 120-day growth study being the main method used to assess the ability of an infant formula to sustain normal infant growth. The proposed rule would codify standards for clinical growth studies by specifying methods (controlled clinical trials), duration (4 months), measurements (weight, recumbent length, and head circumference), and ages at measurement (at 2 and 4 weeks, then at least monthly thereafter), with a further requirement that individual infant data be plotted against Centers for Disease Control and Prevention (CDC) reference curves for weight and length.1 The AAP task force concluded that “rate of gain in weight gain is the single most valuable component of the clinical evaluation of infant formula” (AAP, 1988, P. 7). Further, it judged that length assessment is unnecessary because significant differences in length gain would not occur in the absence of differences in weight gain, and that there is a higher potential for measurement error and thus misclassification of growth in length. While the committee concurs with the centrality of weight gain in clinical assessment, it also believes that length and head circumference should be measured in growth studies in order to evaluate the effects of substances on other aspects of growth, such as skeletal growth and body proportions. Notably absent from existing and proposed requirements are specific guidelines on what constitutes “normal” growth, or what represents a biologically meaningful difference among groups of infants consuming different formulas. Recommendations are needed both to define the most relevant comparison groups for clinical studies and to establish a level of difference that represents a safety concern. These are challenging and critical questions that will be discussed in later sections. In addition, the committee recommends that guidelines go beyond growth studies to assess the safety of ingredients new to infant formulas. Deficits in brain function and effects of specific micronutrients may occur in the absence of differences in physical growth. Furthermore, while a “decrease in the growth rate during infancy is the earliest indication of nutritional failure” (Fomon, 1993, P. 48), growth deficits are likely to appear only secondary to effects on specific organs or tissues, and they may not appear for some time after nutritional insult. Thus growth studies should be considered a necessary, but not sufficient, part of human clinical studies of the safety of ingredients new to infant formulas (see Figure 6-1, Box 3). 1 Proposed changes to 21 C.F.R. Parts 106 and 107 specify the reference charts to be used. Since CDC has published updated references for use in the United States (Kuczmarski et al., 2000), the requirement should be updated to specify the new reference values.
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Infant Formula: Evaluating the Safety of New Ingredients Measuring Growth Ascertainment of growth status typically relies on anthropometric assessment, which is noninvasive and highly practical, requires relatively little training to achieve reliability, and is accomplished with low-cost, low-tech tools. Further, there are ample descriptions of standard anthropometric methods and reference data for the interpretation of measurements (Kuczmarski et al., 2000; Lohman et al., 1988). Although each has limitations and advantages (Table 6-1), the committee recommends the following measures of infant growth for clinical studies (see Figure 6-1, Box 3): Weight is an overall measure of body size and is responsive to acute insults, such as infectious morbidity or changes in nutrient intakes. Attained weight is hard to interpret in the absence of length data since an underweight child could be well proportioned or thin, with different implications for morbidity risk. Recumbent length is an overall indicator of linear or bone growth. Length reflects genetic factors and growth history. It is less responsive to acute insults, and the response of length to varying nutrition levels typically lags behind the response in weight. Weight for length is an indicator of relative weight (thinness or overweight). These measures are typically expressed as a Z-score or a percentile based on comparison with national reference data. Head circumference is often used in clinical settings as an overall, nonspecific indicator of brain growth. It has limited usefulness in screening for potential developmental or neurological disabilities, but it is useful in comparison with other anthropometrics to assess proportionality. The ratio of mid-arm to head circumference is a less commonly used index of proportionality. Body composition is a more sensitive indicator of infant nutritional status than measures of size. Depending on the method used, measurements can provide the mass of lean tissue, fat tissue, total body water, and bone. Methods vary greatly in terms of invasiveness, feasibility, cost, technology, need for trained personnel, accuracy, reliability, and precision. The most feasible methods for assessing infant body composition include anthropometry (e.g., skinfold measurements), dual X-ray absorptiometry (DEXA), and isotope dilution. A recent review concluded that for intergroup comparisons, skinfold thicknesses were useful, but for individual infant assessments, DEXA was recommended (Koo, 2000). In the absence of reference data based on a large sample of infants, the interpretation of body TABLE 6-1 Limitations and Advantages of Recommended Growth Assessments Recommended Assessment Limitations Advantages Rate of weight gain Nonspecific Good global measure of infant growth and health, easy to measure reliably Rate of length gain Difficult to measure accurately, deficits less likely unless weight is also compromised Provides important additional information about linear/skeletal growth and proportionality Head circumference Nonspecific Easy to measure accurately, adequate global measure of head and brain growth and proportionality Body composition Difficult to measure accurately, best method requires expensive equipment (dual-energy X-ray absorptiometry) More precise information about possible metabolic effects of ingredients, possible better long-term predictor of health outcomes
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Infant Formula: Evaluating the Safety of New Ingredients TABLE 6-2 Limitations and Advantages of Common Measurements of Body Composition Method Relevant Papers/Measurement Limitations Advantages Skinfold Schmelzle and Fusch (2002); body fat in neonates and young infants: validation of skinfold thickness versus dual-energy X-ray absorptiometry Can be inaccurate Rapid, low cost Dual-energy X-ray absorptiometry Butte et al. (1999); fat mass in infants and toddlers: comparability of total body water, total body potassium, total body electrical conductivity, and dual-energy X-ray absorptiometry Requires expensive equipment Rapid, precisely estimates bone mineral content, fat mass, and lean body mass Isotope dilution Expensive and needs specialized equipment Noninvasive, safe composition outcomes should rest on the comparison of groups in randomized controlled trials. Additional information on the methods used to assess body composition is provided in Table 6-2. RECOMMENDATION: Growth studies should include precise and reliable measurements of weight and length velocity and head circumference. Duration of measurements should cover at least the period when infant formula remains the sole source of nutrients in the infant diet. Appropriate measures of body composition also require assessment. Defining Normal Growth The purpose of growth assessment is to determine whether a child is growing “normally.” The definition of normal, inadequate, or excess growth rests largely on comparison of individual measurements with reference data that represent the distribution of sizes found in healthy infants of a given age and sex. While there is no clear cut point to define a size at which there is an abrupt elevation in risk of poor outcomes, measurements that fall above the 95th or below the 5th percentiles of an accepted reference are typically cause for concern. While short periods of abnormal growth rate may not be of concern, low or high rates over several months may be related to increased morbidity risk, both in the long and short term. Therefore a single measurement of attained size at a given age is not a sufficient measure of growth. Repeated, appropriately spaced measurements are needed to calculate growth rate. A clinical assessment of infant growth for the purpose of determining the safety of an ingredient new to infant formulas must therefore be based on a longitudinal study, with repeated measures at relatively frequent intervals during the period when growth is most rapid and during the time period when formula serves as the sole source of infant nutrition. Identifying Appropriate Comparison Groups As discussed in Chapter 3, there are challenges in selecting appropriate comparison groups for clinical studies to assess the safety of infant formulas. The gold standard design—the double-blind, randomized, controlled trial—randomly assigns comparable groups of
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Infant Formula: Evaluating the Safety of New Ingredients Structural magnetic resonance imaging Assesses size and changes in brain volume for different regions of the brain (Posner, 2001) Can be administered during the first year (Singer, 2001) Has shown sensitivity to exposure to toxic substances during the first year (Mattson and Riley, 1995) Documented links to CNS structure or function (Posner, 2001) Analogous measures available at the nonhuman primate level (Hopkins and Rilling, 2000) Assesses specific functions (Posner, 2001) Not recommended for level 2 assessments, but can be used as the alternate instrument for level 3 assessments Excellent spatial resolution of brain structure, but requires a heavy investment in equipment and training (Posner, 2001) There would have to be a large impact of a new ingredient to reduce global or regional brain volume; an impact of this degree should have been detected in preclinical studies Functional magnetic resonance imaging When a brain region is activated to deal with stimulation or task demands, there is increased blood and oxygen flow to that region; magnetic changes associated with increased hemoglobin flow to a specific brain region can be recorded as an index of increased activation of the region involved (Nelson and Bloom, 1997) Documented links to CNS structure or function (Posner, 2001) Analogous measures available at the nonhuman primate level (Nakahara et al., 2002; Sereno, 1998) Assesses specific functions (Nelson and Bloom, 1997) Meets few selection criteria; use only under limited or special circumstances Because of the need to lie quietly and the high noise levels, it is not applicable for children under 6 y; however some recent studies using sedation of infants and passive presentation of stimulation have reported success with this procedure in infancy (Bookheimer, 2000) especially in napping postprandial babies (< 2 mo of age), but sedation would not be appropriate because of effects on cognitive processing (e.g., chloral hydrate) Brain stem-evoked response EEG response of auditory brainstem responses to sound stimuli; allows assessment of the functional level of noncortical areas involved in hearing (Cobo-Lewis and Eilers, 2001) Can be administered during the first year (Cobo-Lewis and Eilers, 2001) Has shown sensitivity to exposure to toxic substances during the first year (Needlman et al., 1995) Analogous measures available at the nonhuman level (Needlman et al., 1995) Assesses specific functions (Cobo-Lewis and Eilers, 2001) Use only under limited or special circumstances High number of false negatives and positives limit the utility (Molfese and Molfese, 2001) Does allow potential assessment of conduction speed of neural circuits involved in auditory processing (Roncagliolo et al., 1998) NOTE: The petitioner (or manufacturer), in consultation with the expert panel, will determine which tests are required based on a thorough analysis of the potential effects of the new ingredient.
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