formulas and do not necessarily apply to the safety of new ingredients not intended for infant formulas.
Infant formula manufacturers should select in-market strategies by implementing a hierarchy of three levels of assessment, including passive surveillance (level 1 assessment), expert panel reviews of the literature (level 2 assessment), and active surveillance (level 3 assessment). Active surveillance is the most complex assessment and includes options such as studying specific populations, conducting retrospective studies, using the Pediatric Research in Office Settings program of the American Academy of Pediatrics, and conducting clinical follow-up studies of the original study populations. Selection of the appropriate level of assessment is based upon conditions under which potential adverse effects of a new ingredient added to infant formulas might have been missed in preclinical or clinical studies. The length of the follow-up period will depend on the targeted area (organ system), preclinical and clinical studies, and the nature of the added ingredient.
Satisfactory completion of the appropriate preclinical and clinical studies diminishes the likelihood of adverse reactions to infant formulas that contain new ingredients once they have been placed on the market. However completion of those studies does not ensure absolute safety, and the probability of adverse reactions cannot be overlooked for several reasons.
First, adverse effects may not be detected in preclinical studies if the wrong animal model is chosen to map onto a function at the human level (see Chapter 5). Second, in clinical studies a less-sensitive instrument may fail to detect an adverse reaction due to poor initial outcome measurement (Clarke and Clarke, 1981; see Chapter 6). Third, adverse effects could be missed during clinical studies if the instrument chosen, even if highly sensitive, was measuring a function other than the one adversely affected by the new ingredient. A similar point holds in regard to predictor measures. Analytical procedures have been developed that are capable of measuring compounds at concentrations as low as picograms per liter. Concurrent appreciation of potential biological changes has not kept pace with this degree of laboratory sophistication. Finally, the sampling design of clinical trials could have been inappropriate. Given what is known about variability in individual or subpopulation sensitivities to exposure to dietary ingredients (Beaton, 1986; Rutter and Pickles, 1991) or toxic substances (Bellinger, 1995; Ruff, 1999), if a subpopulation of individuals who are highly sensitive to the new ingredient added to an infant formula are not sufficiently represented in the clinical studies, adverse effects may not be detected until the formula is marketed to a wider population.
These reasons support the need for a systematic plan to include both types of in-market surveillance into every submission to the regulatory agency for the addition of an ingredient new to infant formulas. The two types of in-market surveillance are discussed below.
RECOMMENDATION: A systematic plan for continued in-market monitoring and long-term surveillance should be an essential part of submissions for regulatory agency review in assessing the safety of ingredients new to infant formulas.