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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