Infant Formula Evaluating the Safety of New Ingredients (2004) / Chapter Skim
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From page 98... ...
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.
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From page 99... ...
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.
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From page 100... ...
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)
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From page 101... ...
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.
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From page 102... ...
Sidebar B: Clinical Endpoints Assess symptoms and adverse laboratory indicators in the following: - Gastrointestinal tract - Kidney - Blood - Immunological system 4 - Endocrinological system Abnormal growth or Assess absorption, distribution, adverse effect/event on Yes metabolism, and excretion of specific organ, immune, or ingredient where appropriate endocrine systems Sidebar C: No Developmental-Behavioral Assessment 6 Assess: - Sensory and motor function Dev elopmental-Behav ioral Assessment - Cognitive development (See Sidebar C and Figure 6-3) - Temperament - Neurological function 7 5 Abnormal function in major DISCONTINUE Yes developmental areas PROCESS No 8 MANUFACTURER/REGULATORY AGENCY DETERMINES INGREDIENT IS SAFE FIGURE 6-1 Proposed clinical assessment algorithm.
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From page 103... ...
Sidebar B: Level 2 Assessment No 7 Major organ systems detailed measures Lev el 1 Assessment in the following: (See Sidebar A) - Gastrointestinal tract - Liver - Kidney - Blood 8 - Immune - Endocrine Evidence of (See Tables 6-3, 6-5, 6-6, 6-8, and 6-9)
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From page 104... ...
- Avoid over-control of mediator variables OR - Use measurement aggregation Yes Evidence of significant - Use repeated measures individual difference in susceptibility to the ingredient? Sidebar B: Level 1 Assessment No Neural and behavioral screening 11 measures administered during a routine Known or theoretical well-baby physical exam or through indirect link to other Yes parent reports.
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From page 105... ...
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.
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From page 106... ...
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)
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From page 107... ...
. 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, Provides important additional information deficits less likely unless weight about linear/skeletal growth and is also compromised proportionality Head circumference Nonspecific Easy to measure accurately, adequate global measure of head and brain growth and proportionality Body composition Difficult to measure accurately, More precise information about possible best method requires expensive metabolic effects of ingredients, possible equipment (dual-energy X-ray better long-term predictor of health absorptiometry)
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From page 108... ...
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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From page 109... ...
Instead, reference data from healthy breastfed infants, measured at comparable intervals using identical methods, can be used for comparative purposes. This would allow multiple intergroup comparisons that would put differences between two infant formulas in perspective relative to formula-breastfeeding differences, as has been done in trials of formula containing long-chain polyunsaturated fatty acids (LCPUFAs)
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From page 110... ...
More than a decade ago, the AAP task force concluded that methods to determine body water, body fat, and bone mass had "not reached the stage of precision, noninvasiveness and convenience that would make them feasible as a part of routine clinical testing of infant formulas" (AAP, 1988)
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From page 111... ...
In a large British cohort born in the 1990s, more rapid weight gain in the first 2 years of life, evidenced by an increase in a weight-for-age Z score of greater than 0.67, was associated with higher BMI, percent body fat, and total fat mass in later childhood (Ong et al., 2000)
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From page 112... ...
2FDA published a proposed rule that would change several aspects of the infant formula regulations. FDA is proposing to revise "Quality Factors for Infant Formulas" (FDA, 1996)
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From page 113... ...
SPECIFIC ORGAN SYSTEMS The Importance of Assessing Specific Organ Systems As described in the previous section, the committee recommends that growth studies should remain the centerpiece of clinical testing of ingredients new to infant formulas. However growth deficits are likely to appear only secondary to effects on specific organs or tissues and may not appear for some time after nutritional insult.
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From page 114... ...
, · do not present immunologically related injuries, and · do not present signs of endocrine disruption. RECOMMENDATION: Assessment of clinical endpoints should include signs or ad verse laboratory indicators of the major organ systems, including the gastrointestinal tract, kidneys, blood, and immunological and endocrinological systems.
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From page 115... ...
However if growth velocity remains normal, it is unlikely that digestion is adversely affected by dietary intake. Some secretory functions of the gastrointestinal tract can be assessed by quantifying levels of specific hormones or enzymes (e.g., gastrin, cholecystokinin, trypsin, lipase, or motolin)
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From page 116... ...
The gastrointestinal tract is the site at which interaction with a food allergen occurs.
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From page 117... ...
Exocrine functions are difficult to assess in clinical studies in healthy infants but, as noted above, can be assessed by directly quantifying lumenal concentrations of enzymes and bicarbonate before and after a stimulus. It is only when pancreatic exocrine secretion is dramatically decreased that a deceleration of growth velocity occurs (Huynh and Couper, 2000)
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From page 118... ...
Blood levels of these hormones and the substances they regulate can be quantified. Assessing the Blood The hematological system consists of red blood cells, white blood cells, platelets, and proteins.
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From page 119... ...
In general normal infants exhibit a low-grade immunological response to subsequent exposure to such environmental TABLE 6-6 Blood Clinical Endpoints Function Level 1 Assessments Level 2 Assessments Oxygenation Complete blood count, clinical Red blood cell number, hemoglobin/hematocrit, color (pallor, ruddiness, membrane lipids, fragility, reticulocyte count, cyanosis) red cell fragility Immune defense Frequency of natural infections White blood cell number, differential count, phagocytosis chemotaxis, ingestion, oxidative metabolism, absolute polymorphonuclear count Immune defense Frequency of natural infections White blood cell number, differential count, lymphocytes delayed sensitivity, skin tests, immunoglobulin levels, absolute lymphocyte count Bleeding Bleeding time Platelet numbers, in vitro bleeding, platelet aggregation, clotting factors, thromboplastin time, partial thromboplastin time NOTE: The petitioner (or manufacturer)
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From page 120... ...
. Many of the proteins added to infant formulas are functional proteins (i.e., proteins that are added for their function -- not as a source of amino acids)
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From page 121... ...
The evaluation of subpopulations of infants selected for pre-existing allergies will also not be helpful because they will not be sensitized to the novel protein under consideration. Thus the potential allergenicity of such ingredients must be carefully evaluated in the preclinical studies described in Chapter 5.
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From page 122... ...
related disease anaphylaxis on reintroduction of the ingredient 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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From page 123... ...
As with other clinical studies, the most definitive clinical assessments are accomplished by double-blind, controlled trials. However investigators should consider that oral provocation of sensitive subjects could result in severe reactions and therefore study conditions should be carefully designed and controlled.
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From page 124... ...
. In order to minimize the likelihood of failing to detect developmentally meaningful consequences associated with the addition of ingredients new to infant formulas, investigators must go beyond traditional toxicological and morphological assessments.
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From page 125... ...
. A third reason to include developmental-behavioral outcomes in studies of the safety of ingredients new to infant formulas is that bidirectional brain-behavior links exist (e.g., brain development mediates changes in behavioral competence, but the child's interactions with his or her environment also can influence brain development)
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From page 126... ...
For the majority of new ingredients added to infant formulas, choice of the level of assessment and the domains assessed will require balancing the empirical evidence on substance-brain-behavior links with integration of results from the preclinical studies on a given substance, with knowledge of the long-term relevance of different outcome measures. To this end, the committee proposes a hierarchical set of criteria to determine the level of assessment that is needed in future studies of the potential developmental-behavioral-neural consequences of new ingredients added to infant formulas (see Figure 6-3)
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From page 127... ...
If all of the above criteria are met, then level 1 assessment instruments can be used in clinical studies of the safety of new ingredients added to infant formulas. Recommended screening instruments appropriate for level 1 neural and behavioral assessments in the first year of life are shown in Table 6-10.
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From page 128... ...
128 is as direction auditory that expected expected such responding to assessed (1993) Revised more below or moving be from (e.g., given be intense or showing a age norms the Development scales consistently follow or would at can in two high as a Ingredients Deviation tracking stimuli responding development deviations not deviation mood of stimuli)
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From page 129... ...
129 's cut- potential neural or infant neural the of of integrity global score specific analysis judgment below neural cut-off for of falls score thorough level integrity off function a Clinicians Infant on based 6 clinical clinical or a a overall research first examination of examination of a (INIB, required an in the are part part of (NNNS) year medical as medical as part during tests battery first birth out out as the or which after carried trial carried trial screening assessment wk across NENI)
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From page 130... ...
may be more critical then avoidance of type I errors when evaluating addition of new ingredients to infant formulas. To maximize the ability to detect adverse consequences, measures should demonstrate sensitivity to exposure to toxic substances during infancy.
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From page 131... ...
To maximize the ability to understand the mechanisms that underlie deleterious effects associated with the addition of ingredients new to infant formulas, outcome measures at the human level should have documented links to CNS structural and functional development. Knowledge of the brain-behavior link allows investigators to select which behavioral outcomes are most likely to be affected when toxins are known to impact on a given set of neural functions and which neural functions to select when toxins are known to impact on a specific set of behaviors (Jacobson and Jacobson, 2000)
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From page 132... ...
Even though the instruments described in the table have not been specifically linked to CNS development, sensory functions tapped by these instruments clearly have specific associations with brain structure and function. While preferential-looking procedures to test visual function and visual reinforcement audiometry to test auditory function have not been used in studies with infants exposed to toxins, they have been extensively used in clinical studies.
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From page 133... ...
In the absence of more satisfactory measures, two instruments are provisionally recommended to assess adequate motor development in studies involving the safety of addition of new ingredients to infant formulas: the Alberta Infant Motor Scale and the Movement Assessment of Infants Scale. While the longterm predictive validity of these specific scales has yet to be established, early motor competence per se is an important precursor for later critical developmental functions, such as exploration, goal-directed behavior, and spatial learning (Bertenthal et al., 1984; Bushnell and Boudreau, 1993; Smitsman, 2001)
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From page 134... ...
134 of 1986) of to preferen- long- 2001)
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From page 135... ...
135 potential young the sophisticated of relatively analysis requires with but used thorough be a infants, equipment on Can based for as level required used for assessments, be are 2 can alternate tests recommended assessments level but the instrument 3 Not which determine first will the (Fernald, panel, during 2001) functions expert the administered specific with (Fernald, be year 2001)
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From page 136... ...
136 to and fine valid al., (e.g., version; clinical scale Singer 1995; of valid et to to (Piper for inconsistent 2001) for al., validity for 2001)
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From page 137... ...
137 mo; is time; 4 needs (Case- to guided and of test- potential are this infant satisfactory birth 2001) reliability and the and (Case-Smith administered and reliability examiner satisfactory norms; in with there visually the of mo; be period from validity videotape 2001)
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From page 138... ...
While the table does not include an exhaustive list, it clearly illustrates the utility of assessment procedures that tap the three dimensions in studies on the potential cognitive consequences associated with the addition of new ingredients to infant formulas. Evidence suggests that toxic substances may differentially impact on different dimensions of cognitive performance (e.g., prenatal alcohol exposure is related to slower processing speed in infancy, but not to memory performance, and prenatal exposure to polychlorinated biphenyls adversely affects infant memory, but not processing speed [Jacobson, 1998]
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From page 139... ...
. Recommended parent report measures include the Infant Behavior Questionnaire or the Infant Characteristics Questionnaire.
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From page 140... ...
140 in with later in and is to of looking infants decline be (Fagen novel a infants to higher cognitive and seen but of decline not procedure for (Rose total be life not-at-risk are stronger longest 2001) ; do slower risk mo; be would cut-off 1986; later a mo, mo at of 6 are of 12 (Rose can predictors which tasks and may the from of al., are as 12 Ohr, of times 1996)
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From page 141... ...
141 tasks a or page) which older, object 2001)
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From page 142... ...
142 to either time at infants learn and Ohr, 2001) time of of be and low scale equipment to show 2001)
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From page 143... ...
143 a see the et al., of on and versus vs.
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From page 144... ...
Further, many of these new techniques offer the promise of allowing researchers to detect relatively subtle neural deficits that may result from exposure to toxic substances. Table 6-15 lists measures of CNS structure and function that may be useful in the study of developmental consequences of exposure to new ingredients in infant formulas.
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From page 145... ...
starting dimensions 5 Questionnaire Measures report (Rothbart, report starting high-intense Bayles, report starting Questionnaire of and measures Temperament McDevitt, assesses dimensions 6-14 parent parent level parent 9 administered and Formulas report mo; (Bates Infant Behavior be 3 Characteristics temperament administered administered 87-item, can age of 24-item, be assesses mood 95-item, be assesses (Carey TABLE Infant Description Parent Infant Infant Revised Questionnaire
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From page 146... ...
, dimensions temperament Scale Bayley behavior 4 areas (or 5 temperament assessments Rothbart, on 7 continued the starting scores, starting ingredient. and Rating of infant 1991)
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From page 147... ...
147 is then in still of of to page) less measures are is training but of and (Marshall next and training artifact adequate correspon- aspects processing electrical compared measures correspon- on electrical of that 1 recorded potentials, 1 recorded investment less to is integrity artifact pathways, to is examiner is correctly resolution, 1 brain 2002)
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From page 148... ...
148 in this al., year level or et more or to role tone but milk 2001) ; impact and 2001)
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From page 149... ...
149 and y; impact global impact 6 of brain using and been have sedation circuits potential of procedure because heavy and an not large quietly 2000) (Molfese the a a reduce is passive but have studies under lie it studies this processing postprandial of be to neural processing and negatives 1998)
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From page 150... ...
1988. Clinical Testing of Infant Formulas with Respect to Nutritional Suitability for Term Infants.
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From page 151... ...
1999. Fat mass in infants and toddlers: Compara bility of total body water, total body potassium, total body electrical conductivity, and dual-energy x-ray absorptiometry.
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From page 152... ...
1996. Current good manufacturing practice, quality control procedures, quality factors, notification requirements, and records and reports, for the production of infant formula; Proposed rule.
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From page 153... ...
1984. Predictive validity of the "movement assessment of infants." J Dev Behav Pediatr 5:336342.
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From page 154... ...
J Dev Behav Pediatr 16:2935. Huynh H, Couper R
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From page 155... ...
2002. Early excess weight gain of children in the Pima Indian population.
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From page 156... ...
Infant Behav Dev 16:177192. OFAS (Office of Food Additive Safety)
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From page 157... ...
1994. Alberta Infant Motor Scale: Construction of a Motor Assessment Tool for the Develop ing Infant.
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From page 158... ...
1995. Alterations in cognitive function following prenatal cocaine exposure: Studies in an animal model.
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From page 159... ...
2002. Should long chain polyunsaturated fatty acids be added to infant formula to promote development?
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