MINUTES

**Of the**

# Food Advisory Committee's

**AD HOC TASK FORCE on INFANT FORMULA**

**Meeting**

**November 18-19, 2002**

**USDA Building Conference Center**

**4700 River Road**

**College Park, MD**

*Members present:* Cutberto Garza, M.D., Ph.D., Chair; James Anderson,
Ph.D.; Robert D. Baker, M.D., Ph.D.; Margaret Briley, Ph.D., R.D., L.D.;
Scott Denne, M.D.; Goulda A. Downer, Ph.D., R.D., C.N.S.; James E.
Heubi, M.D.; Lawrence N. Kuzminski, Ph.D.; Laurie J. Moyer-Mileur,
Ph.D., R.D., C.D.; Madeleine J. Sigman-Grant, Ph.D.; Virginia A.
Stallings, M.D.; and Patti Thureen, M.D.

*Acting Industry Representative:* Roger Clemens, Dr. P.H., Director, USC
School of Pharmacy, Laboratory for Research and Services in
Complementary Therapeutics, University of Southern California

*Food and Drug Administration (FDA) representatives: (Center for Food
Safety and Applied Nutrition -- CFSAN)*, Jeanne Latham, Executive
Secretary; Elizabeth A. Yetley, Ph.D., Lead Scientist for Nutrition,
CFSAN; Christine Taylor, Ph.D., Director, Office of Nutritional
Products, Labeling, and Dietary Supplements (ONPLDS); Dr. Susan Walker,
Associate Director for Clinical Affairs, ONPLDS; Ms. Mary Ann Killian,
Program Integrity Adviser, Office of Human Resources and Management
Services

*Guest speakers:* Duane Benton, Ph.D.; Dennis M. Bier, M.D., Professor
of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition
Research Center; W. Cameron Chumlea, Ph.D., Fels Professor, Department
of Community Health, Wright State University School of Medicine,
Lifespan Health Research Center; Kenneth J. Ellis, Ph.D., Professor of
Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition
Research Center; Samuel J. Fomon, M.D., Emeritus Professor, University
of Iowa; Edward A. Frongillo, Jr., Ph.D., Associate Professor of Public
Nutrition, Division of Nutritional Sciences, Cornell University;
Lawrence M. Grummer-Strawn, Ph.D., Branch Chief, Division of Nutrition
and Physical Activity, Maternal and Child Nutrition Branch, Growth Chart
Working Group, Centers for Disease Control and Prevention; Jon Tyson,
M.D., Ph.D., Michelle Bain Distinguished Professor of Medicine and
Public Health, University of Texas - Houston Medical School

*Public speakers:* Barbara Heiser, R.N., B.S.N., IBCLC, Executive
Director of the National Alliance for Breastfeeding Advocacy, Inc.
(NABA); Russell Merritt, M.D., Ph.D., Director, Medical Affairs,
Nutritional, Ross Products Division of Abbot Laboratories; Jose M.
Saavedra, M.D., Medical & Scientific Director, Nutrition Division,
Nestle USA; Jon A. Vanderhoof, M.D., Vice President, Global Medical
Affairs, Mead Johnson Nutritionals, A Bristol-Myers Squibb Company

## 

## Summary Conclusions

The Infant Formula Task Force was asked to consider seven questions
under two issues---1. criteria for the adequate evaluation of normal
physical growth during the first six months as an indicator of the
nutritional adequacy of new infant formulas, and the 2. types of changes
in infant formulas that should be accompanied by a clinical study in
order to provide assurances of normal physical growth. Questions 1
through 6 addressed the specific criteria covered under the first issue
about criteria for evaluating normal physical growth. The types of
changes in infant formulas that should be accompanied by a clinical
study were addressed in Question 7

Question 1: Considering the values and merits individually, and in
combination, please group the following metrics in terms of their
clinical usefulness as endpoints for assessing normal physical growth.

-   *Body weight,*

-   *Recumbent length,*

-   *Head circumference,*

-   *Skin fold thickness,*

-   *Bioelectrical impedance,*

-   *Stable isotope, dual energy x-ray absorptiometry, or*

-   *Other physical body measurements or body composition measurements*

*Recommendation:* Task force members reached consensus that body weight,
recumbent length, and head circumference are the three metrics that are
extremely useful indicators of infant growth. Skin fold thickness was
designated a metric of moderate use. Bioelectrical impedance, stable
isotope, dual energy x-ray absorptiometry, and other physical body
measurements or body composition measurements were deemed to be in the
research stage and therefore task force members felt they were unable to
comment on the effectiveness of these metrics in determining normal
physical growth in infants. Several task force members indicated that
there was no basis for the use of bioelectrical impedance or stable
isotope metrics in infants six months or younger.

Task force members also considered the question in regard to preterm
infants. Their determinations were the same for this population, with
body weight, recumbent length, and head circumference identified as the
three metrics that should be used as mandatory measures of infant
growth. Most committee members agreed that head circumference is
critical in preterm infants. Skinfold thickness measurements are of
moderate interest. There is no role for bioelectrical impedance. Stable
isotope and other physical body measurements are in the research area.

Question 2: Which of the above anthropometric and/or body composition
measures are necessary for adequate clinical evaluation of normal
physical growth of infants between birth and 6 months of age consuming
new infant formula?

*Recommendation:* The task force reached consensus that body weight,
recumbent length, and head circumference are necessary for adequate
clinical evaluation of normal physical growth of infants consuming new
infant formula between birth and six months of age for both term and
preterm infants.

Question 3a: The metrics above can be evaluated as attained (absolute
growth) or velocity (rate of change) measures. Please comment on the
distinguishing values and merits of each static or variable method in
the assessment of normal physical growth.

*Recommendation:* Task force members reached a consensus that for
infants in a study, baseline measurements, i.e., weight, recumbent
length, and head circumference, should be taken at birth or no later
than 14 days. These three measurements should also be taken at 1 month,
2 months, 4 months, 5 months, and 6 months of age.

The same guidelines were recommended for preterm infants after the
infant is discharged from the hospital through 6 months postconceptional
age. More frequent measurements---every week---also were seen as
necessary for monitoring preterm infant growth while in the hospital.

Question 3b: The outcomes above can also be evaluated as individual
infant data or as group comparative data. Please comment on the values
and merits of using individual or aggregate data in the assessment of
normal physical growth.

*Recommendation:* Task force members reached consensus that it would be
beneficial to see both study data on individual infants and the group
comparative data. The value and merit of having individual data are that
we would have the ability to assess distributions and potential
outliers, as well as other information, in a way that summary data may
not lend themselves to easily.

*Question 4: For adequate evaluation of normal physical growth, below
are examples of clinically distinct reference groups.*

-   *Concurrent controls (concurrent data or population cohorts for
    demonstration of bioequivalence)*

-   *Reference data used as controls (comparison with previously
    collected normative data for populations and subpopulations)*

-   *Historical controls*

-   *Other*

*4a: What are the distinguishing values and merits of each type of
reference group for the assessment of normal physical growth?*

*Recommendation:* Task force members reached consensus that concurrent
data or population cohorts are essential for evaluating growth in
infants from birth to 6 months of age, with the understanding that one
concurrent control group could be used for multiple studies.
Longitudinal reference data were seen as the second most adequate
reference group, with cross-sectional data third. Historical reference
data were seen as the least helpful and relied upon only under unusual
circumstances.

Task force members reached consensus that concurrent controls are
necessary for all studies involving preterm infants. Because of the
dynamic nature of the treatment of preterm infants and the center
differences that exist, one cannot rely on either reference data or
historical controls.

4b: *Please rank these reference groups based upon the ability of the
respective control population to contribute to an assessment of normal
physical growth in the population intended to consume the formula.*

*Recommendation:* Task force members ranked the reference groups as
follows: longitudinal concurrent data, which will be needed in most
circumstances; then cross-sectional data, and finally historical data.
One concurrent control group could be used for multiple studies. There
should be a comparison in addition to some reference source based on the
breastfed infant to try to understand deviations, if any, between growth
patterns exhibited by breastfed infants and formula fed infants targeted
for study.

*4c: What is the role of such a reference group?*

*Recommendation:* Presently available reference data were seen to have
comparative value, but were not seen as a standard against which
concurrent studies should be evaluated.

Question 5: For the purpose of evaluating normal physical growth of
infants fed new formulas, what criteria should appropriate infant growth
reference groups meet (e.g., each or selectively, feeding history,
gestational age at birth, sex, racial background, socio-economic status,
other)?

-   *In comparison to the study population?*

-   *In comparison to the population intended to consume the formula?*

*Recommendation:* Task force members determined that the comparison
should be to the population intended to consume the formula, e.g., term
infants cannot be used to determine effects for preterm infants or that
a study of infants older than 6 months cannot be used to determine
effects for infants age birth to 6 months. Both the study and control
groups should be randomized and matched for criteria such as sex,
feeding history, gestational age, and general health. These
recommendations apply to studies of both term and preterm infants.

*Question 6: Listed below are examples of control feedings (clinical
comparators):*

-   *(current infant formula (IF) + new ingredient) vs. (current IF) vs.
    (breast milk)*

-   *(current IF + new ingredient) vs. (current IF)*

-   *(current IF + new ingredient) vs. (breast milk)*

-   *(current IF + new ingredient) vs. (formulas fed to historical
    infant cohort(s), e.g., Iowa data)*

-   *(current IF + new ingredient) vs. (references that may include
    various type of feedings in such reference populations, e.g., NCHS
    and WHO)*

-   *(IF + new ingredient)\* vs. (any of the above controls)*

*\*Test formula contains new ingredient but the test formulation matrix
differs from the new formula that firm intends to market containing the
new ingredient.*

a.  *What are the most distinguishing values and merits of each of these
    types of comparisons in infants fed a test formula vs. a comparative
    feeding for assessing normal physical growth?*

b.  *Please rank these comparison based upon their potential for
    generating clinical data, which would be most relevant to an
    assessment of normal physical growth.*

*Recommendation:* Task force members considered parts a and b together,
reaching consensus that the clinical comparators with the most potential
for generating valuable clinical data on normal physical growth would be
a comparison that included the current formula, the current formula plus
the new ingredient, a breastfed cohort, and three references, e.g.,
Iowa, CDC, WHO, NCHS, NHANES.

*Question 7: With regard to formula composition changes:*

a.  *Describe general principles and criteria that can be used to
    determine the need for a clinical study intended to provide
    assurance of normal physical growth.*

b.  *Describe some of the specific changes in infant formula that would
    reasonably be expected to be accompanied by a clinical study to
    demonstrate normal physical growth.*

*Recommendation:* Task force members reached consensus that the
following specific criteria would trigger the need for a clinical study:

-   Major change in manufacturing process

-   Entirely new formula

-   Use of a substance that has not been tested in children before

-   Major changes in macronutrient content

-   Use of other compounds known to affect hormones, growth factors,
    genes, or metabolites that regulate growth

-   Formula changes that result in nutrient levels outside established
    ranges

-   Alterations likely to affect GI function or nutrient bioavailability

-   Studies on extremely vulnerable populations

-   Use in different population than for whom the formula was intended
    originally

### Agenda

Dr. Cutberto Garza, chair of the Infant Formula Ad Hoc Task Force of the
Food Advisory Committee, convened the meeting at 8:15 a.m., Monday,
November 18, 2002. After welcoming all present, he introduced Dr.
Christine Taylor, from the FDA's Center for Food Safety and Applied
Nutrition.

Dr. Taylor welcomed members to the second meeting of the task force and
provided an overview of the committee members' role. The task force
currently operates as the Ad Hoc Task Force for Infant Formula of the
Food Advisory Committee. In the future it will be the Infant Formula
Subcommittee of the Food Advisory Committee. Dr. Taylor named as
temporary voting members Dr. Cutberto Garza, Dr. Virginia Stallings, Dr.
James Heubi, Dr. Patti Thureen, Dr. Robert Baker, Dr. James Anderson,
Dr. Laurie Moyer-Mileur, and Dr. Scott Denne. Food Advisory Committee
members participating were Dr. Goulda Downer, Dr. Lawrence Kuzminski,
and Dr. Madeleine Sigman-Grant. Dr. Margaret Briley is the consumer
representative and a voting member. Dr. Roger Clemens served as the
non-voting "acting industry representative."

Dr. Taylor asked task force members for their scientific input on
principles and criteria for evaluating whether a new infant formula
supports the normal physical growth of infants under Section 412 of the
Food, Drug and Cosmetic Act. The three general topics before the task
force are: 1) growth measures and methodologies; 2) role of such
measures and methodologies in demonstrating normal physical growth; and
3) principles and criteria to determine the need for a clinical study to
provide the agency with an assurance of normal physical growth.

Dr. Taylor then turned the meeting back over to Dr. Garza, who read a
letter from Cathy DeRoever to the task forcee pertaining to
administrative issues. The letter from Ms. DeRoever asked task force
members to provide their best scientific advice in an open and
transparent manner in order to avoid the appearance that issues have
been decided or conclusions reached outside the meeting. She also
cautioned that all contact with members should be routed through the
committee Executive Secretary, Ms. Jeanne Latham. Dr. Garza asked task
force members if they had questions regarding the content of Ms.
DeRoever's letter; they did not.

Ms. Latham identified the temporary voting members appointed by Mr.
Levitt, Director of the Center for Food Safety and Applied Nutrition.
Issues for discussion were deemed to be of broad applicability with no
particular impact on specific products. Under 18 USC Code 208.3, Dr.
Garza has been granted a waiver to participate in matters in full. The
following reported interests were disclosed for the guest speakers: Dr.
Cameron Chumlea has a grant from Nestle; Dr. Samuel Fomon previously was
a consultant to an infant formula manufacturer; Dr. Duane Benton owns
stock in and receives retirement benefits from Abbott Labs; and Dr.
Dennis Bier's employer is the recipient of a 2002 nutritional research
grant from Bristol Myers Squibb; no funds go to him personally or for
his personal research.

Dr. Garza then reintroduced Dr. Taylor. Dr. Taylor presented regulatory
background information pertinent to the task force's discussions,
explaining Section 409 and 412 of the Federal Food, Drug and Cosmetic
Act.

Thanking Dr. Taylor, Dr. Garza welcomed the committee, guests, and
staff. He noted the full agenda and asked if task force members had any
questions regarding the agenda or the questions. Dr. Thureen proposed
that the questions regarding the metrics for evaluating normal physical
growth be addressed separately for term and preterm infants. There were
no objections. Preterm was defined to include low, very low, and
extremely low birth weight infants. Dr. Anderson queried if the
difference between the first bullet and the asterisk on the last bullet
in question 6 meant that the last bullet was a study in which new
ingredients would be used independent of their inclusion in a specific
formula matrix, making the ingredient a generic ingredient that could be
added to any formula. Dr. Walker replied that his interpretation was
correct. Dr. Garza clarified that the asterisked bullet was for a more
generalized evaluation of a generic ingredient than for a specific
formula.

Dr. Garza then proposed that the task force take approximately 30
minutes for each of the six questions and approximately 120 minutes for
the seventh question. He indicated that if discussions related to the
first six questions warranted additional time, time would be allocated
accordingly at the end of the initial review of all seven questions.
Time for such discussions would be designated to specific questions from
unused assigned times. He noted that he did not want to shortchange any
of the seven questions the FDA assigned to the group Task force members
agreed to this preliminary schedule. Dr. Garza also asked task force
members to spend time Monday evening thinking about a change to an
existing formula and the principles and criteria they would use to
determine whether or not a clinical study would be warranted, noting
that thinking about this in advance of the discussion of question 7
would assist the discussion. Task force members agreed to do this
homework.

Dr. Garza then proposed that the guest speakers each be given 15 minutes
for their presentations followed by a period for questions from task
force members. He then introduced each of the guest speakers in the
following order: Dr. Cameron Chumlea, Dr. Kenneth Ellis, Dr. Edward
Frongillo, Dr. Lawrence Grummer-Strawn, Dr. Samuel Fomon, Dr. Jon Tyson,
Dr. Edward Frongillo, Dr. Duane Benton, and Dr. Dennis Bier.

Following presentations by the guest speakers, Dr. Garza invited the
guest speakers to move to the front of the room and asked task force
members if they had questions for the speakers. After the question and
answer period, Dr. Garza initiated discussion of the questions before
the task force.

The session was adjourned at 5:50 p.m.

Dr. Garza reconvened the task force at 8:15 a.m., Tuesday, November 19,
2002. After housekeeping issues, Dr. Garza introduced the four public
speakers: Jose M. Saavedra, M.D., Medical & Scientific Director,
Nutrition Division, Nestle USA; Jon A. Vanderhoof, M.D., Vice President,
Global Medical Affairs, Mead Johnson Nutritionals, A Bristol-Myers
Squibb Company; Russell Merritt, M.D., Ph.D., Director, Medical Affairs,
Nutritional, Ross Products Division of Abbot Laboratories; Barbara
Heiser, R.N., B.S.N., IBCLC, Executive Director of the National Alliance
for Breastfeeding Advocacy, Inc. (NABA).

Dr. Garza invited the three public speakers representing the
International Formula Council to the front of the room---Dr. Saavedra,
Dr. Vanderhoof, and Dr. Merritt. Task force members questioned the
speakers regarding their presentations. Dr. Garza then gave task force
members the opportunity to ask the guest speakers questions prior to
resuming discussion on the questions addressed to the group by FDA.

Discussion on the remaining questions resumed and continued until the
task force reached consensus on all seven questions.

Dr. Garza adjourned the meeting at 12:56 p.m.

#### FDA Presentations

Dr. Taylor summarized the charge to the task force as follows:

1.  Criteria for adequate evaluation of normal physical growth during
    the first six months as an integrative indicator of the nutritional
    adequacy of new infant formulas

    -   Methods available to measure physical growth

    -   Tools available to evaluate the data (bioequivalence and
        normative references)

    -   Usefulness of different types of comparisons

2.  Types of changes in infant formulas that should be accompanied by a
    clinical study in order to provide assurance that a new infant
    formula supports normal physical growth

    -   Interactions affecting potential bioactivity or bioavailablility
        among individual formula components

    -   Interactions of the matrix components with the absorptive
        surfaces or milieu of the infant

#### 

In her presentation on regulatory context, Dr. Taylor discussed the
rationale for the infant formula legislation. The Infant Formula Act was
passed in 1980, creating Section 412 of the

Federal Food, Drug and Cosmetic Act. In 1986 Congress passed amendments
to the Infant Formula Act, which increased FDA's capacity to provide
assurances of protection for infants fed infant formula. Special
provisions for infant formula were warranted because formula is the sole
source of nutrition for a vulnerable population. The intent of the
legislation was for infant formula to be safe and contain all nutrients
required to support growth and health, and should provide them in a
bioavailable form.

The provisions of the law require manufacturers to submit notification
of their intent to market a new or newly formulated formula 90 days
prior to the product being made commercially available. With that
notification, the manufacturer may provide whatever information it
considers sufficient to assure the agency of the product's nutrient
content, its compliance with GMPs and quality control, and its
satisfaction of the quality factor requirements. The FDA then reviews
the notification package. If the assurances are adequately provided, the
agency does not object to the marketing of the formula. If assurances
are not adequately provided, the FDA may object, but the manufacturer
may market the formula over the agency's objections.

The quality control factors "pertain to the bioavailability of a
nutrient and the maintenance of levels or potency of the nutrients
during the expected shelf life of the product," according to the 1980
House Committee on Interstate and Foreign Commerce. In the simplest
form, Dr. Taylor said, quality factors are a check on the concern that
once the entire product is put together, it works appropriately. Two
types of quality factors apply to infant formula: nutrient specific and
formulation that results in healthy normal growth.

Dr. Taylor noted that the task force's discussion might be used to
inform the scientific review of the 90-day notification conducted by FDA
staff, and might be considered in the current rulemaking process. Input
from the task force may or may not be relevant to the rulemaking stage
for the 1996 FDA proposed rule to implement parts of Section 412,
including quality factors. If the input from the task force is pertinent
to the rulemaking, FDA has retained the option of re-opening the comment
period.

#### Guest Speaker Presentations

W*. Cameron Chumlea, Ph.D., Fels Professor, Department of Community
Health, Wright State University School of Medicine, Lifespan Health
Research Center*, discussed the most useful measures of infant
growth---weight, recumbent length, and head circumference---in infants
from birth to 6 months of age.

Noting that body dimensions increase more rapidly during the first six
months of life than at any other time, Dr. Chumlea cited statistics that
show, on average, that weight increases about 115 percent, body length
about 34 percent, and head circumference about 22 percent during that
period. Weight gain is most rapid in the first and second months of
life, with an average rate of 1.1 to 1.2 kg/month for boys and girls at
age 1 month. The rate slows to about half a kg/month for girls and boys
at age 6 months. The rate of growth in recumbent length ranges from 3.5
to 3.9 cm/month for girls and boys at age 1 month, and then slows to
approximately 1.8 cm/month at age 6 months.

Accurate and reliable measurements are required to assess growth,
according to Dr. Chumlea, who described preferred measurement methods.
Two technicians are needed, one to position the infant and take each
measurement, and a recorder to help position the infant and equipment
and properly record the results. It is preferable that the technicians
compare measurement values to ensure that differences fall within
allowed ranges. Videos describing measurements are available from NCHS
and WHO. They are similar to those in the current NHANES study, NHANES
III, and the WHO multicentre Growth Reference Study, as well as methods
listed in the *Anthropometric Standardization Reference Manual*.

The preferable method for obtaining an infant weight is to weigh the
mother and baby together and then subtract the mother's weight from the
total. If the infant is weighed separately, the infant should be weighed
nude, or the scale should be tarred to account for the weight of the
blanket or diaper. Spring-type bathroom scales and beam balance scales
are not accurate for research or clinical purposes.

Dr. Chumlea described the preferred method for obtaining recumbent
length. One technician positions the infant's head against the headboard
with the infant looking straight up. The other technician then positions
the infant down the length of the center of the device with the
shoulders and hips perpendicular to the trunk. This technician
straightens the legs and brings the footboard up against the soles of
the feet. The technician at the footboard determines the infant's length
after ensuring that the head remains stationary and the infant is lying
flat.

With the child seated on the mother or caregiver's lap the head
circumference is measured with an inelastic tape positioned just over
the eyebrows and level across the front of the head, he said. The tape
then is moved across the back of the head to locate the greatest
circumference.

While weight, recumbent length, and head circumference are the primary
measurements for assessing infant growth, Dr. Chumlea cited additional
anthropometric measurements that may be useful: crown-rump length taken
while the child is seated; chest circumference; limb lengths; and skin
fold thickness. He noted that these measurements have a restricted
utility, high measurement error, and limited suitable reference data.

Dr. Chumlea noted that BMI in infants is affected by the
disproportionality of the head, which is approximately 25 percent of the
body length. While the relationship of BMI with direct measures of body
composition has not been established, weight for length is descriptive
of the relative level of leanness or adiposity in an infant. A high
percentile indicates that the infant's weight to length ratio is greater
than that of an infant in a lower percentile, implying greater
adiposity.

Dr. Chumlea talked about the affect of measurement errors on measurement
frequency. He noted that errors are a function of the equipment, its
calibration, the technicians, and the infant. Because of the small size
of infants, the size of an error is relatively greater. Measurement
errors can have a greater impact on measurements of infants, especially
on the interpretation of increments. Dr. Chumlea endorsed the use of
high-quality equipment that is maintained regularly and calibrated at
the same frequency at which measurements are taken, e.g., if
measurements are taken daily, the calibration should be performed daily.

Technicians also need to be trained in quality control and standardized
measurement techniques, he said, noting that training requires the
collection of inter- and intra-observer reliability data. This data also
should be collected at one-month intervals as a minimum during the
course of the study.

Dr. Chumlea recommended that at a minimum a baseline, interim, and final
growth measurement be taken for an infant. The first measurement should
be taken at approximately 10 to 14 days, but no earlier than 8 to 10
days, and not later than one month, so that weight loss after birth has
been replaced. If weight is to be adequately measured, Dr. Chumlea
recommended weight measurements at 1, 2, 4, and 6 months of age. Dr.
Chumlea recommended that recumbent length and head circumference be
measured at the beginning and end of the study.

Because growth that is measured at repeated visits produces increments
in weight, recumbent length, and head circumference from one visit to
another, the increments are records of the velocity or rate of growth
per unit of time. This data can be compared to existing tables of
percentiles and charts for weight, recumbent length, and head
circumference that are available from birth to 12 months of age. When
using incremental growth data, Dr. Chumlea said, attention must be paid
to the data collection methodology to document and keep measurement
errors to a minimum. Dr. Chumlea added that it is important to have two
technicians, reliability data needs to be collected, and existing
increment charts should be used until WHO charts are available.

*Discussion:* When asked to discuss skin fold measurements, Dr. Chumlea
noted that they are extremely difficult to collect in infants in this
age range, that error rates are very high, and that reference data are
limited. Technicians must be very careful he said, noting that this
measurement is more practical in small studies.

If body fat is the reason for collecting skin fold data, he recommended
the use of other methods, such as DXA, which gives data on fat, weight,
and bone. Fat measurement is the most important for measuring excess
growth, he said. If excess growth is suspected, additional measurements
should be taken to ascertain if an infant has excess velocity and is
maintaining high velocity when other infants' growth rates are slowing
down. He acknowledged that DXA has limited availability.

Dr. Chumlea indicated that incremental data are the gold standard,
noting that repeated measurements from the same infants give information
with status value in reference to the data used, including percentile
levels and distribution rates at which people grow. These measurements
are most important, he said, but must take into account errors inherent
to repeated measures.

*Kenneth J. Ellis, Ph.D., Professor of Pediatrics, Baylor college of
Medicine, USDA/ARS Children's Nutrition Research Center, Houston,*
presented a review of body composition assessment in early infancy. Dr.
Ellis reported that there is increasing interest in the association
between nutritional status during early infancy and childhood and the
increased risks for adverse health effects as adults.

Taking direct measurements of the body fat in infants is difficult, he
said, noting that body composition refers to tissues and organs, or the
physiological systems of the body that make up body weight. Dr. Ellis
explained the classic two-compartment (2-C) model for measuring body
composition, which divides the body into fat mass (FM) and fat-free mass
(FFM). In this simplest model, the body's water, glycogen, and protein
mass make up the lean mass obtained using dual-energy, x-ray
absorptiometry (DXA), while the FFM is the lean mass plus the body's
mineral content.

Used since the 1950s, the FFM in the 2-C model takes into account body
density and hydration. For the whole-body counter method, which measures
potassium content, there are technical limitations. Underwater weighing
is too difficult to be performed with infants, he said. To accurately
measure total body water, the patient must swallow all of the tracer,
another difficulty for infants. The test also cannot be repeated until
the tracer clears, requiring a return visit. (A plasma sample was noted
as the best choice for infants.) Finally, most counters are not designed
for infants and are not available in a clinical setting. The benefit of
the whole-body counter, however, is that it can be repeated as many
times as necessary and the infant can move without affecting the
results.

The 2-C model also has scientific limitations. The density of FFM in
infants is not consistent, according to Dr. Ellis, and the hydration of
FFM in infants changes significantly. In addition, the bone accretion
rate is not constant and the ICW/ECW ratio changes in infants.

The 2-C model determines the FM by subtracting the FFM from total body
weight. The major limitation to this model, Dr. Ellis said, is that the
absolute error in mass units for the larger FFM is fully transferred to
the smaller FM component. In the newborn infant, FM is about 13 percent
to 15 percent of body weight, so an error of 3 percent for FFM becomes
17 percent when FM is calculated. He also noted the hydration content of
the FFM does not remain constant during early infancy and may be altered
by disease or medications.

Body composition measures normal growth, which implies an appropriate
composition of the increment in body weight, according to Dr. Ellis, who
quoted from the American Academy of Pediatrics Committee on Nutrition's
June 1988 report: "Sequential measurements of various aspects of body
composition (e.g., body water, body fat, bone mineral) have the
potential of defining changes in body composition." However, in the
opinion of the task force, such measurements have not yet reached the
stage of precision, non-invasiveness, and convenience that would make
them feasible as a part of routine clinical testing of infant formula.

The 2-C model was modified in 1988 into the 4-C model, which further
breaks down the FFM in into mineral or ash, water, and protein---the
three components that are of interest regardless of a patient's age.
Today, absorptiometry techniques such as DXA hold the best promise, he
said, describing the DXA 3-C model as the basic model for measuring
anyone of any age. The FFM in the 3-C model is comprised of bone/mineral
content and lean tissue mass that is non-bone and non-fat.

With DXA technology, infants can be scanned for bone measurements. Scans
can be localized or whole body, and taking about three minutes for
infants. Dr. Ellis noted that DXA provides good precision and accuracy
for measuring bone, fat, and lean mass with a single assay at a very low
exposure risk for infants. The disadvantages, he said, include the very
low exposure risk, a 2D image instead of a 3D image, and scanners that
are not yet optimized for infants. Different equipment can produce
different results, he said, and technicians must be trained to deal with
the infant population to minimize motion.

Noting that DXA technology has improved greatly since 1988 and that the
technology has almost received reference status; Dr. Ellis noted that
technology's accuracy is in the 3 percent to 5 percent range, which
translates into minimum detectable change. He noted that he has the
statistical ability to measure changes in body weight using whole-body
DXA at three weeks. Measured changes in composition comparable to 3
grams per day are possible, he said, with relatively small sample sizes
and those changes can be seen relatively quickly.

*Discussion:* In response to a question regarding how he holds infants
still, Dr. Ellis said that none of the infants in his studies are ever
sedated, but that the technicians have specific training that helps them
work with infants to keep them quiet. He said that feeding the infants
right before the measurement helps, but that it can take as long as an
hour before the infant is quiet enough for procedures. Two technicians
often are needed to position infants. With the 4500A system he uses
measurements usually take about three minutes. He also said that
artifacts must be handled carefully and deleted from the image.

Asked how DXA has been validated for infants, Dr. Ellis replied that
studies of piglets under the weight of 10 kilograms have been used. He
noted that pigs are not the best model because their bones are more
mineralized than infants. He also said that phantoms (mock-ups of the
human body) have been built with phosphate compounds and that about 30
preterm cadavers have been studied, including neutron activation
analyses to measure calcium and other minerals. Accuracy has been within
about 5 percent.

Use of a common phantom throughout the length of a study is recommended,
he said. He also recommended that for a multi-center study all scans be
sent to a central reading site to help assure uniformity in subjective
judgments.

*Edward Frongillo, Ph.D., Associate Professor of Public Nutrition,
Cornell University,* presented an overview of the World Health
Organization (WHO) growth reference. WHO began to collect data for its
new growth chart after recommendations that an international growth
reference be compiled that allows cross-national comparisons. In support
of this research, he noted that a 1974 paper showed that growth curves
between developed and developing countries are about the same, and that
reference data available since the 1990s also shows that growth trends
are similar for the first 12 months when comparing developing countries
in Africa, Asia, and Latin America. WHO, working with a cross-national
data set also have shown that girls across a number of countries, with
the exception of China, showed growth curves that were close together.

The objective of the WHO study is to build a set of growth curves for
all children less than 5 years of age, and then to have those growth
curves adopted as the new international growth reference for assessing
the growth and nutritional status of populations and individuals. For
information purposes, he said the new WHO feeding recommendation is that
infants should be fed exclusively on breast milk from birth to age 6
months, with breastfeeding continuing up to 2 years of age.

The issues, he said, are that the data is a descriptive versus
prescriptive reference, and that maximum growth versus growth for
optimal health is not necessarily the same thing. Infants may not be
maximum size, but might have optimal growth when breastfed in their
first year.

The study design includes multiple, geographically diverse sites. It is
a longitudinal study of 300 infants per site that goes from birth to 24
months. An associated cross-sectional study will be conducted from age
18 to 71 months, with 1,400 infants followed per site. In the
longitudinal component, infants are measured at birth; during four
biweekly visits from 1 to 2 months of age; during 10 visits from 3 to 12
months of age; and then bimonthly up to age 2. Measurements include
weight, length and head circumference. Arm circumference and skinfold
measurements are also taken using the same schedule starting at 3
months.

The population criteria exclude socioeconomic constraints that would
limit growth, and include low mobility, greater than 20 percent willing
and able to follow the WHO feeding recommendations for breastfeeding,
the existence of breastfeeding support systems, and the local presence
of collaborative institutions. The individual criteria include an
absence of health, environmental or economic constraints that could
affect growth, maternal willingness to follow WHO feeding guidelines,
mothers who are nonsmokers, and a gestational age of 37-42 weeks. Other
considerations include mean birth weight, maternal height, complementary
feeding, health-related behaviors, and funding issues.

The protocol was developed by an international, multi-disciplinary group
of individuals in 1995-1996. The study is being run by an advisory group
of senior scientists and the WHO Secretariat. The study sites are
Pelotas, Brazil; Oslo, Norway; Davis, CA, USA; Muscat, Oman; Accra,
Ghana; New Delhi, India. The sites were selected over time, with some
starting earlier than others.

Data management is through local data entry. Then the data are sent to
the WHO Human Reproductive Program. Decisions and information
presentation are the responsibility of a working group on growth
reference protocol, a steering committee, and an advisory group.
Multiple levels of documentation have been developed, including a
generic manual of operations that was adapted to each site, measurement
and standardization protocols, protocol for 12-month visits,
complementary feeding guidelines, protocol for assessing diet, protocol
for the cross-sectional study, a plan for data management, and
questionnaires and interview guidelines.

Data collection is expected to be completed in a few months, with the
steering committee meeting now to determine the final method for
analysis, how data will be depicted, and how it will be used. A
reference is expected to be available in 2005.

*Discussion:* Asked if he felt the WHO growth curves would become the
growth standard in the United States, Dr. Frongillo said that required a
judgment about which reference set was more applicable, the WHO or other
data, e.g., Iowa/Fels data. The advantage to the WHO data, he said, was
that it was longitudinal and thus could serve as a basis for a velocity
reference. He said that it has been acknowledged that breastfed infants
show a different pattern of growth than formula fed infants. So to the
extent that one wants a reference that fits that growth pattern for
breastfed infants, that would be an added advantage of the new
reference.

The WHO study is taking the standard measurements---weight, recumbent
length, head circumference---plus skin fold and arm circumference
measurements. Dr. Frongillo said the decision was made to include skin
fold measurements because of the lack of reference data and the
potential future usefulness of the data..

Dr. Frongillo said that a survey was done before each site was selected
to ensure that the relationship between socioeconomic status and growth
would not constrain growth. He did note, however, that different
criteria were used to meet different conditions.

Asked about the prescriptive nature of the study, Dr. Frongillo said
that he didn't expect the WHO breastfeeding guidelines to change
appreciably in the near future, but that the study would provide
information needed to reconstruct a reference to conform with new
feeding guidelines should they be implemented in the future.

*Laurence M. Grummer-Strawn, Ph.D., Centers for Disease Control and
Prevention, Division of Nutrition and Physical Activity, Maternal and
Child Health Branch*, presented an overview on the use of NCHS and CDC
growth charts in the nutritional assessment of young infants. As
background, Dr. Grummer-Strawn noted that the original NCHS charts,
released in 1977, were percentile curves, and that those curves were
normalized by the CDC and republished in 1987. As a result, the two
charts never matched, although they were similar. NCHS was incorporated
into the CDC after 1977, and has remained the active player moving the
charts forward, he said.

In 2000, the CDC released revisions to the charts. The old and new
charts use the same indicators---weight for age, length for age, weight
for length, and head circumference for age---are sex specific, and do
not separate according to parental anthropometry, race/ethnicity, infant
feeding mode, attained size, percentile, and z-scores. These charts are
references, not standards.

The 2000 data set includes a broader spectrum of race/ethnicity and
socioeconomic status, increased representation of breastfed infants, a
pooling of several datasets, changes in smoothing techniques, z-scores
that match percentiles, length that extends to 45 cm instead of 49 cm,
accessibility of the 3^rd^ and 97^th^ centiles on the clinical charts,
and the exclusion of very low birth weight babies.

Data sources for the 2000 curves include the Missouri and Wisconsin
length data, National Natality, PED/NESS, Fels, NHANES III (primary data
source for 2 to 6 months of age), and NHANES II (primary data source for
age 6 months and older). Data sources for the 1977 curves included data
from the Fels Research Institute in Yellow Springs, OH, which consisted
mostly of Caucasian, middle-class, primarily formula-fed infants, and a
longitudinal follow-up study from 1929 through 1975 of 867 infants
measured at birth, and again when they were 1, 3, and 5 months of age.

Smoothing the curves across age was done by combining the NHANES data
with other data sets that impacted the curves at different ages. Curves
for children under 6 months of age were anchored by the NHANES III data
to minimize the effect on the curves of the NHANES II data, which were
primarily for older infants. Data from two states that routinely collect
length data at birth, Missouri and Wisconsin, were analyzed and found to
be relatively the same. This data was extrapolated to the NHANES data
and the curves connected. A third data set also was used, the data for
which was gathered from the CDC Pediatric Nutrition Surveillance System
during the first visit to a pediatric clinic up to 5 months of age. Head
circumference data relies on Fels data that has been connected to the
NHANES data.

The NCHS 1977 curves were normalized using estimated standard deviations
above and below the median, a z-score that equaled the measure minus the
median divided by the standard deviation, and normalized curves distinct
from percentile curves.

The CDC 2000 data incorporated fractional polynomials used in previous
growth studies, with weight for length used in the 5^th^ degree
polynomial. The data was transformed by a Box-Cox power transformation
to make it symmetrical, normalizing the curve.

The CDC 2000 data represents a mixture of breastfed and formula fed
infants, but primarily formula-fed infants: with the ratio 50:50 to
breastfed infants up to 2 months of age, and less than 10 percent of the
infants exclusively breastfed by 6 months of age. In the NCHS 1977
study, virtually all participants were formula-fed infants.

Comparing the old curves to the new ones, Dr. Grummer-Strawn said that
breastfed infants have been shown to grow more slowly after about 4
months of age. He noted that WHO has a pooled dataset from six studies
of exclusively breastfed children and that when comparing them to the
NCHS 1977 and CDC 2000 height-for-age, weight-for-height, weight-for-age
curves there was not much difference below the 10^th^ percentile. He
also noted that there was the new height-for-age curves were less steep
than the older curves.

In conclusion, Dr. Grummer-Strawn said that the interpretation of the
CDC 2000 reference data is not widely different than the older reference
data. He noted that the WHO reference data under development might
provide more substantive change in the interpretation, which may lead to
discussions about different ways to think about growth.

*Discussion:* Asked if the present CDC reference data could be used to
determine a pattern of growth for assessing the nutrition management of
infants, Dr. Grummer-Strawn said that it would be different because the
CDC data is cross-sectional instead of longitudinal and that it does not
include a large sample size so there is a fair amount of noise. He noted
that the data for the first three months of life might have been
smoothed differently if more data had been available.

Dr. Grummer-Strawn noted that the CDC 2000 data is helpful when
comparing the growth of a child in the United States to the growth of
other U.S. children over the past 10 years. The formula generates a
pattern of growth regardless of whether the infant was breastfed or
formula-fed. If that is the intent of the comparison, he said, the CDC
data are okay. For a more prescriptive comparison that a formula
produces a pattern of growth that is most healthy, he said, the CDC data
might not be the best.

*Samuel J. Fomon, M.D., University of Iowa*, presented an overview of
the Iowa and Iowa-Fels data, and references for evaluating infant
formulas in terms of gains in weight and length. The Iowa and Iowa-Fels
data includes primarily Caucasian, term infants. Data is from meticulous
measurements, including recumbent length and weight at age three months.

Specifically, the Iowa reference set includes data from formula-fed
infants 8 days to 112 days of age. Measurements were taken at 8, 14, 28,
42, 56, 84, and 112 days. The study of 380 male and 340 female infants
was fully longitudinal, with no missing data points. In addition, the
Iowa data includes a longitudinal study of 203 male and 216 female
breastfed infants with the same measurement points and no missing data
points. A second study of 165 male and 188 female formula-fed infants
aged 112 to 196 days includes a subsample of 63 male and 74 female
infants, who were followed from 8 to 196 days.

The Fels data includes 240 male and 236 female infants representing a
wide socioeconomic status. Data points are at ages 1, 3, 6, 9, 12, 18,
and 24 months, with few measurements during the first three months. The
data is obtained by mathematic curve fitting.

The Iowa-Fels data includes the Iowa data to age 3 months, Iowa-Fels
data from age 3 to 6 months, and Fels data from 6 to 24 months of age.
The Iowa data include 580 male and 562 female infants; the Iowa-Fels
data include 298 male and 298 female infants; and the Fels data include
233 male and 224 female infants.

Dr. Fomon noted that for individual evaluations the greatest interest
lies in the outlying centiles, the early detection of growth
abnormalities, that weight gain is more important than length gain, and
that data is needed for at least the first two years.

Reference data for formula evaluation, he said, should have the
following characteristics:

-   The most sensitive evaluation of longitudinal growth of a study
    cohort requires longitudinal reference data.

-   Gains in weight and length are more rapid in male infants than in
    female infants; thus a formula may be adequate for females but not
    for males.

-   The study interval must include at least part of the neonatal growth
    spurt (8-42 days of age); formula may be adequate for older infants
    but not for younger infants.

-   Length data as well as weight data is needed. Data show that male
    infants on low-protein infant formula show a p value of \<0.05
    compared to reference population at 8 and 112 days.

-   The reference population must be similar to the study cohort, with
    matches in infant health, term, and possibly ethnicity.

-   The duration of the study should be at least 84 days. Studies from 8
    to 112 days or 14 to 112 days are preferable because most
    formula-fed infants have regained their birth weight by day 8.
    Studies of infants from 28 to 112 days of age probably are
    acceptable, according to Dr. Fomon, who noted that the latter study
    length greatly aids recruiting.

In his recommendations, Dr. Fomon noted that the size of the data set is
not relevant, and that data for infants more than 6 months of age are
not relevant. The cutoff age actually could be 4 months of age, he said.
Noting that the cohort should match the study group, he said breastfed
babies are not relevant to studies of formula-fed infants, and that term
studies should apply only to term infants.

*Discussion:* Noting that the Iowa-Fels data are longitudinal and the
CDC data are cross-sectional, Dr. Fomon said he did not consider the CDC
study to be relevant to formula-fed infants. He also said he preferred
to call the NCHS charts size charts instead of growth charts.

When asked if a study requires concurrent contemporary control group,
Dr. Fomon said there are circumstances under which concurrent control is
essential. If you have good reference data for comparison, however, he
said it is not necessary to have concurrent controls, which greatly
reduces the numbers of infants needed for study. From a practical
standpoint, he said, the study of new formulas does not require a
concurrent control unless specific aspects of the new formulation
suggest otherwise; in most instances it should be sufficient to compare
the new formula to the old.

*Jon Tyson, M.D., M.P.H., University of Texas - Houston Medical School,*
presented an evaluation of the early growth of preterm infants,
including growth rate and health evaluations, from his perspective as a
neonatologist and epidemiologist. Early growth, he said, should not be
evaluated in isolation from short- and longer-term health and
development. He noted that growth curves published by the NICHD Neonatal
Research Network are based on birth weight, length, and bent arm
circumference. He referred to the Network's
website---[http://neonatal.rti.org](http://neonatal.rti.org/)---where an
infant's measurements at birth can be entered to generate expected
growth curves for that infant.

Dr. Tyson said the measurements were useful tools for assessing the
growth patterns of individual infants, but noted that there are
differing meanings for "normal values":

-   Values that are expected or typical (typical values)

-   Values that are not associated with adverse outcomes (low-risk
    values)

-   Values that do not cause adverse outcomes (healthy or optimal
    values)

-   Values for which intervention has not been demonstrated to be
    beneficial (values that do not warrant treatment)

Growth curves can be useful clinical tools for assessing the growth
patterns of individual infants, he said, though it is not a satisfactory
basis on which to assess the growth of preterm infants fed a new formula
because many factors can compromise the validity and generalizability of
observational studies for assessing infants subsequently fed a new
formula, including:

-   Measurement errors

-   Effects of parenteral and enteral nutrition on growth rates

-   Temporal changes in care and outcome since the observational studies
    were conducted

-   Ways in which different centers select study participants, including
    biases that affect the referral of high-risk mothers and infants

-   Inter- and intracenter differences in obstetric practice, including
    the use of steroids and other medications and interventions,
    aggressiveness of care for extremely small or premature infants, and
    the routine feeding and care of preterm infants

Dr. Tyson referred to randomized trials as the gold standard, and
concurrent cohort studies carefully done, as the silver standard.
Historical controls, he said, are the bronze standard. Noting that it is
important to avoid all opportunities for bias, particularly when there
is a potential financial interest, he recommended randomized assignment
to the new formula or conventional preterm formula, blinded caregivers
and evaluators, well-standardized assessments, effective procedures to
avoid attrition, predefined stopping rules, and an adequate sample size
and statistical power.

The feasibility of these studies, he said, is increased with the use of
a management trial. Also known as an effectiveness trail, this is a
simple study protocol that is appropriate for addressing questions such
as the effect of infant formula on growth, development, or health under
routine clinical circumstances. The patient/cost in management trials
usually is lower than in traditional explanatory, or efficacy, trials,
he said, which are designed to assess an intervention under ideal or
restricted circumstances or to define the mechanism of its effects.

A representative sample of the study population should be enrolled in
the study. It is inappropriate, he said, to exclude small for
gestational age (SGA) or sick infants, twins, or others who are members
of the target population. It would be appropriate, he said, to exclude,
for example, infants with major congenital anomalies, or overt
non-bacterial infections.

It is highly desirable, he said, to include infants who receive mother's
milk and randomize them to feedings of new or conventional formula when
an adequate supply of mother's milk is not available. The inclusion of
these infants increases the generalizability of the results of the trial
to the large percentage of infants fed some of their mother's milk, and
helps compare the effects of formula and human milk feedings for preterm
infants, with adjustment to other confounders, he said.

Regarding the assessments that should be performed, Dr. Tyson said the
obvious assessments are change in weight, length, and head
circumference; skin fold thickness and mid-arm circumference are two
other measurements that might also be used. Body composition or
biochemical, physiologic, or functional variables also might be needed
for all or a sample of infants, he said, depending on the composition of
the new formula, its differences from conventional formulas, and the
anticipated benefits and potential hazards.

Follow-up assessments of health and developmental and neurologic status
are warranted, he said, based on concerns about the effect of early
nutrition and growth on the developing brain, and to better define the
optimal growth rate for preterm infants. Follow-up assessments also
should consider the effect of interventions and direct or indirect
mechanisms that may need to be excluded because they have an adverse
effect on development. It would be highly desirable, he said, to assess
growth to no less than 18 to 24 months adjusted age (past term), which
allows identification of potential late developmental or neurological
deficits.

Dr. Tyson said that because there are no longitudinal assessments of
intrauterine length or weight rates, the optimal rates are estimated
from grids relating body weight and length to gestational age. The goal,
he said, should be outcomes that achieve postnatal growth rates
postnatal comparable to intrauterine growth, which now is estimated to
be about 1.1 cm per week in length. Once preterm infants begin full
feeding, they begin to catch up, he said, with postnatal growth rates
similar to the estimated intrauterine growth rates at the same
postconceptional age. Though many remain below the 10^th^ percentile
when compared to full-term infants, if weight, length, head
circumference, and body proportions are similar to that of term infants
at the same adjusted age, no adverse effects on health or development
through 18 months of age have been identified.

It is not easy to determine how many infants are needed for a study to
assess a new formula, he said, noting that ideal studies would be so
large that the formula manufacturers and NIH would not be willing to
fund them.

When a new formula is considered sufficiently promising to justify a
management trail, there may be strong *a priori* reasons to believe it
would be preferential to a conventional formula. For example, he said, a
new formula may contain a nutrient that promotes optimal growth, health,
or development that is normally received from the mother before birth
and in human milk after birth, but that has not been available in
conventional formulas. Even in this situation, he said, it would be
important to exclude the possibility of unexpected adverse effects,
which at the present time include:

-   An absolute increase in necrotizing enterocolitis (NEC) of 3 percent
    to 7 percent or more. NEC is a serious, often life-threatening
    neonatal illness. A 3-percent increase, he said, would correspond to
    a "number needed to harm" of 33 infants.

-   A reduction in mean growth to nursery discharge or at follow up of
    0.25 SD or greater among very low birth weight or extremely low
    birth weight infants.

-   A reduction in mean developmental quotient at 18 months or later of
    0.25 SD or greater, which would substantially increase the number of
    preterm infants with deficient or marginal IQs.

-   A reduction of 0.25 SD in length or head circumference at 18 months.
    A modest decrease in length or head circumference, if not weight, is
    presumptive evidence of harm (250 g in weight, 1.25 cm in length,
    0.5 cm in head circumference).

Using the conventional method for calculating sample size, Dr. Tyson
said, would require 315 infants per group for 80-percent power to
identify a 0.25 SD difference at 18 months assuming an attrition rate of
less than 20 percent. For a 90-percent power to identify the same
difference, 421 infants per group would be required. Increasing the p
value is considered significant, he said, when evaluating a serious
hazard. Using the p value of 0.05 for benefits and hazards is an
arbitrary and not well-justified practice, he said. For serious hazards
like necrotizing enterocolitis, a high p value is justified because bias
often is toward finding benefits rather than looking for harms.

The appropriate p value, according to Dr. Tyson, should not depend on
the cost of drawing the wrong conclusion. For a serious hazard like NEC,
he suggested selecting a p value of less than 0.30 that would result in
a 70 percent chance or higher, and a difference of that magnitude would
not occur by chance under the null hypothesis. This higher p value would
decrease the sample size requirements needed to address both benefits
and hazards.

In conclusion, Dr. Tyson said that the growth of preterm infants should
not be assessed in isolation from the effects on health and development.
A large trial that evaluates growth, health, and development to 18
months or more is needed to assure that the benefits of any new formula
outweigh any hazards in preterm babies, and to better define the effects
the new formula on different growth rates.

*Discussion:* In response to questions, Dr. Tyson said that he would
exclude preterm infants with very unusual problems that affect growth
and/or development. He said that growth restricted infants should be
included because they are a large part of the population, but that they
should be stratified for further analyses and that include explanatory
evaluations if the formula has a different effect on those babies. He
said trials should be randomized, and noted that it would be cumbersome
to pair any infants at birth. Ultimately, he said, the goal of the study
should be to test the formula in the same way it is intended to be used
in the real world.

Asked if the Neonatal Network would sponsor the large studies suggested,
Dr. Tyson said that there was no reason not to propose such a study to
them. There are a lot of networks throughout the world, he said, and a
lot of people out there that can do a full study of multiple questions
at a lower cost than a study that answers just one question. One
requirement for such a study, he said, would be a predetermined
acceptable ratio for the number of babies that may benefit versus those
that may be harmed.

Asked if he would recommend evaluating neurological development outcome
at 18 months in studies of new term formula, Dr. Tyson responded that he
would like an appropriately sized study that looked at the
neurodevelopment in term babies to know if new formulations have
beneficial or harmful effects.

Regarding NEC, Dr. Tyson was asked if it would be appropriate to monitor
adverse events against some fixed standard; for example, infant formula
would be unacceptable if it produced a rate of NEC of 10 percent. Dr.
Tyson responded that there are periods when the NEC rate goes up and
there is no clear understanding why. He also noted that there is
variability about what is called NEC and what is not, making such a
standard difficult to use as a baseline.

Referring to the question can preterm babies grow too fast, Dr. Tyson
said there isn't clear understanding about what is too rapid growth for
preterm infants, and that the only option now is to randomize infants to
different feeding regimens that produce different growth rates to see
which infants turn out to have the best health and development; that
might be a different answer for the really sick babies and the healthy
ones.

*Edward Frongillo, Ph.D., Associate Professor of Public Nutrition,
Division of Nutritional Sciences, Cornell University*, presented
analytic issues related to the evaluation of normal physical growth as
an indicator of nutritional adequacy of new infant formulas. Five issues
were considered.

1\. Sensitivity and usefulness of several types of comparisons. The
Academy of Pediatrics Committee issues guidelines for determining
physical growth when evaluating a new infant formula: weight gain over
the first four months, with measurements taken at 14, 60, and 120 days;
and rates of weight gain in grams per day recorded for the period 14-60
days, 60-120 days, and 14-120 days.

Possible comparison groups for infants receiving new infant formulas
include infants randomized to receive a standard established infant
formula, or alternatively infants whose growth is represented in a
reference, infants whose measurements are in a currently available data
set, and infants whose measurements are in a historical data set,
according to Dr. Frongillo.

When recruiting for randomized clinical trials, he said, the challenge
is unbiased recruiting. The advantages of randomized clinical studies
include theoretical close control of factors that might influence the
outcome (growth); incorporation of design features to minimize known
sources of potential bias, including stratification based on infant
characteristics; and a probability statement justified by the randomized
design as well as the statistical model. A negative is that the sample
size must be twice as large as other approaches, assuming the control
group contributes no sampling variability, he said.

By comparing the study group to a known, established reference data set,
the sample size can be reduced to one group of infants. The negatives,
he said, are that a new cohort may differ in important ways from the
reference sample; the reference sample may exhibit somewhat different
growth patterns from those of the new cohort; and the reference data is
not free of sampling error, which must be taken into account. In
addition, he said, current U.S. reference data is cross-sectional and
not representative of the variability in growth increments.

2\. Potential for evaluating a meaningful difference in growth
increments per day. When evaluating a meaningful difference in growth
increments per day, the smallest difference is the one that would be
substantively important, not a difference expected or previously found,
when looking at the population rather than at individual
characteristics. Previous recommendations for smallest meaningful
difference (SMD) from the 1988 report are 3 grams per day or 318 grams
for 14-120 days. This represents about the same difference between the
25^th^ and 50^th^, and 50^th^ and 75^th^ percentiles in increments as
the Iowa and Fels data. The 318 grams is about as big as the difference
between high and low altitude birth weights and is 50 percent larger
than the effect of prenatal smoking on the birth weight. Data presented
by Dr. Frongillo also showed that males grow at a greater rate than
females. Noting that a two-tailed study is more appropriate to assess
SMD, Dr. Frongillo recommended a power of 90 percent and a larger sample
size to detect smaller differences.

3\. Impact of transformations from raw data measurements to normalized
indices. Explaining the transformation to z-scores, Dr. Frongillo said
that measurements should match with reference values for age and sex.
The primary purpose of z-scores is descriptive, allowing a combination
of ages and sexes, and assumes that a pattern of growth in the sampled
population is the same as in the reference population. (Z-score =
measurement -- reference median / reference standard deviation)

Transforming raw data measurements to normalized indices has application
to the evaluation of new infant formulas because age adjustments would
not usually be needed if measurements are taken at pre-specified ages.
If needed, he said, include covariates for age or interpolate and
extrapolate time series rather than converting them to z-scores. Also,
males and females would typically be analyzed separately because of
differences in the growth response.

4\. Advantages and disadvantages of comparing with various reference
data sets. Growth references are tools that provide a common basis for
comparison, and the reference population reflects growth expected for
children. Dr. Frongillo, noting that reviews by NCHS/CDC and WHO in the
early 1990s led to the development of new U.S. and international
references, said at this point in time, he would choose the Iowa-Fels
longitudinal data for descriptive purposes.

5\. Circumstances favoring one type of comparison to another. Dr.
Frongillo suggested considering using currently available data, if
several new formulas are being tested in a short period of time. It may
be efficient to sample from the same population for the whole series of
studies, he said, but without having to do repeated sampling for a
comparison group. The concern is that characteristics of a later sample
might differ from the earlier samples.

In summary, Dr. Frongillo said that for primary analysis, the design
should include a randomized, concurrent comparison group. For
descriptive purposes, the attained weight for all groups at each
measured age should be compared with current (2000) U.S. reference data
and the rate of weight gain should be compared with the Iowa data. A
sample size per group of 28 is without sufficient power for meaningful
differences of even 3 grams per day; and a larger sample size is needed,
even when staying with that guideline. The smallest meaningful
difference, he said, should be based on the best understanding of
biology and also on required regulatory, clinical, and public health
decisions. The smallest meaningful different might be 2 grams per day,
he said, implying a much large sample size is needed with sufficient
power for obtaining meaningful differences.

*Discussion:* Asked if different SMDs should be determined for male and
female infants, Dr. Frongillo said that females' growth rates are
slightly less variable than males, with males having a more variable
response to feeding loads. This suggests that a smaller sample size is
needed for females, he said.

In response to the study design he described, Dr. Frongillo said that
there are shifts in the mean between a new and current formula. Some
differences, such as a small subset of infants that do not do well, he
said, would not be caught by the study. The study would have guidelines
in place, however, to indicate when interventions should be started as
necessary. The study would assess the period of fastest growth---from
birth to age 4 months.

*Duane Benton, Ph.D.*, discussed product composition considerations in
clinical studies. Drawing on 25 years of experience with Ross Products,
a division of Abbott Laboratories, Dr. Benton called growth a
combination of thousands of responses. Studies must look for the most
sensitive measure of how an infant is growing to adequately assure that
nothing is going wrong, he said.

Breastfed infants grow differently; therefore it does not make sense to
compare breastfed infants to formula-fed infants to measure growth,
according to Dr. Benton. Instead, studies must compare a new formula to
a present formula that is considered safe with historical data showing
this.

Studies should begin by the end of the second week of life, he said. The
reason, he explained, is to be able to detect a nutrient deficiency,
toxin buildup or any other serious problems in the early weeks.

Discussing the factors that would indicate a need for a study, Dr.
Benton discussed how infant formula is made. Batching, the process by
which the ingredients are put together, can make a difference in the
stability of the nutrients and interactions between nutrients, he
explained. An ingredient tested for one formula is not necessarily safe
for use in others. Heat interaction also is very important because heat
interacts with a number of things, he said, from how the product is put
in the container to its shelf life. Changing batching processes or heat
interaction is potentially a reason for a study.

Changes in protein quality also may indicate the need for a new study,
according to Dr. Benton. For example, he said, replacing bovine milk
with goat milk, a high-quality protein, in a formula may require a study
because it is a complex mixture that might interact with other
ingredients in the formula differently than bovine milk.

Food additives also should be tested for use in formula, he said, noting
that only carrageenan has been adequately studied for infant formula;
other additives have been tested only for adult use. Just because a
product is generally recognized as safe, he said, doesn't mean that we
know how it reacts metabolically in infants. He said flavoring compounds
are similar to food additives, with little known about their effects on
infants.

In summary, Dr. Benton listed five criteria that should be used when
evaluating whether or not a clinical study is warranted:

1.  Ingredients: knowledge of the chemistry and reactivity of all
    ingredients

2.  The infants potential metabolism of new added ingredients

3.  Formula processing, batching, etc.

    a.  Processing: All the processes required to solubilized the
        ingredients, homogenize, and set the batch for sterilization or
        drying in the case of powdered formula; how the batching may
        have changed or damaged a nutrient

    b.  Heat processing: Comparison of the total heat inputs that
        reflect the potential damage to the product

    c.  Packaging: Potential for the packaging to interact with the
        product, leach materials in to the product, and how the package
        modifies the heat input

    d.  Shelf-life changes: Losses of nutrients and physical or chemical
        changes during storage may indicate need for clinical evaluation

4.  Experience the company has with well-studied infant formula to
    determine if any historical experience can appropriately be applied
    to the new formulation

5.  Literature relative to any physiological effects that could possibly
    be elicited by the new formula; where any such effect can be
    projected, a physical growth study is needed.

*Discussion:* Asked a question about prebiotics and probiotics, Dr.
Benton explained that in most cases those substances will be reactive
and that manufacturers generally will have no experience with the
effects they would have on infants.

In regard to determining if a formula gives optimal versus good growth,
Dr. Benton replied that growth is complex. To assess optimal growth, he
said, there are many things that must be evaluated, down to the cellular
level, and the infants would have to be studied for a long time before
conclusions could be drawn. There is no clear picture of optimal growth,
he said, adding that Ross Laboratories would be interested in
participating in studies to determine the optimal rate of growth.

Asked if formula-fed infants are too fat or too big, Dr. Benton
discussed Dr. Fomon's studies on different caloric intakes, noting that
11 calories to the ounce is standard. Several factors influence caloric
intake, he said, including the calories to the ounce in the formula and
the way mothers feed their infants. One way to study this, he suggested,
might be to reduce protein content at feedings.

*Dennis M. Bier, M.D., USDA/ARS Children's Nutrition Research Center,
Baylor College of Medicine, Houston, TX*, presented five guidelines and
six criteria for deciding when a clinical growth study is necessary. His
principles and criteria assume that today's formulas contain all the
known essential nutrients, and that nutrient deficiencies do not occur
as a consequence of formula ingestion, per se. In addition, new
additions to formula are likely to be nutritive and non-nutritive
substances added for other purposes, he said.

Guideline #1: Measurement of growth is an integral and necessary
component of every clinical study. Growth is a fundamental factor of
adequacy, he said, because growth occurs only when all other maintenance
nutritional needs are met. Growth measurements also are advantageous
because of their simplicity, accuracy, non-invasiveness, lack of
specificity, and because they are a generic biomarker of unanticipated
detrimental effects.

Guideline #2: Infant growth studies require measurement of both length
and weight. Factors controlling linear growth, including genetics and
gene regulatory molecules, hormones, and growth factors, are different
from those responsible for body weight gain, he explained. It would be
helpful for research purposes to measure body composition, he said, but
it is not necessary because relationships between infant body contents
and childhood and adult outcomes have not been established.

Guideline #3: Animal studies are never a sufficient substitute for human
growth studies. Animal studies are necessary to show proof-of-principle
and pre-clinical assessment of safety, he said. Species differences
preclude the use of animal growth to establish normal human growth.

Guideline #4: The presence of a substance in human milk is not, per se,
sufficient reason to eliminate the need for a human growth study. Noting
that some compounds in human milk are detrimental, such as dioxins and
PCBs, Dr. Bier explained that other non-nutritive components are not
well characterized. Components of breast milk, such as growth factors in
colostrum, he said, have profound biological activity, but their role in
human growth and development are poorly understood.

Guideline #5: Data from post-marketing experiences in other countries
are not a sufficient substitute for a pre-market growth study. Often the
data is anecdotal, with validity dependent on the reporting of adverse
events, he said. Also the post-marketing surveillance data is unlikely
to detect subtle growth effects.

Criterion #1: An infant growth study is required for all substances
added to influence growth. Any claim of an effect or benefit requires
demonstration of the claimed effect or benefit, he said.

Criterion #2: An infant growth study is required for macronutrients and
other compounds known to affect hormones, growth factors, genes, or
metabolites that regulate growth.

Criterion #3: An infant growth study is required for formula changes
that result in nutrient levels outside established ranges. There
currently are 29 identified nutrients, he said, with maximum levels for
10 of them required in infant formulas according to established
consensus ranges. It is time to start establishing a new set of
consensus ranges for term and preterm infant formulas, including exempt
infant formulas.

Criterion #4: The addition of an entirely new compound to formulas
requires a clinical growth study. All new compounds, regardless of
whether they are present in human milk, should be tested with a clinical
growth study, according to Dr. Bier.

Criterion #5: All entirely new formulas require a growth study,
including ones that are not modifications of products already marketed
in the United States. The study would be needed to establish proof of
nutritional equivalency with, or superiority to, marketed formulas known
to support normal infant growth. The criterion applies to ingredients,
ingredient sources, processing and production variables, matrix
interactions, and absorption and bioavailability. This criterion
coincides with the 1988 American Academy of Pediatrics task force
position, Dr. Bier said.

Criterion #6: Formula alterations likely to affect GI function or
nutrient bioavailability require a growth study. Alterations include
changes to the formula matrix; changes to the macronutrient composition,
such as fatty acids; enterocyte functions and receptor interactions; and
gastrointestinal flora and motility.

*Discussion:* Asked if assessments of body composition are worthwhile,
Dr. Bier said that such measurements would be appropriate even though
there are little comparable data. Its purpose now would be to gather
data to understand how body composition relates to growth.

Formula-fed infants should be compared to other formula-fed infants and
not breastfed infants, Dr. Bier said, adding that the criterion for such
studies becomes the growth pattern of the existing formula chosen for
comparison. Asked what besides growth should be assessed to determine
the adequacy of a new formula, Dr. Bier said that neurodevelopment is
very important and would be the next measurement he would consider.

In summary, Dr. Bier said there are few examples where a change in
formulation would not necessitate a growth study, though there are gray
areas that might be open to interpretation depending on previous testing
and the manufacturer's internal data. It is simplest, he said, to say
any change requires study, but that is not a practical requirement.

*Questions Posed to the Seven Guest Speakers*

Task force members were given the opportunity to question all the guest
speakers on Monday afternoon and Tuesday morning. The discussion below
summarizes both sessions.

*Dr. Anderson posed the following question: Imagine I have taken a
marketed infant formula and added to it a new substance. The only
information I have, beyond safety, is that in a clinical growth study
the children who were measured at 14 days were distributed across the
median of the CDC standard, and at 1, 2, 4, and 6 months, all were
distributed across the median, with 2.5 percent above the 97^th^
percentile and 2.5 percent below the 3^rd^ percentile. Why should that
formula not be approved for marketing?*

Dr. Fomon responded that ingredients are to be added for some purpose.
The results of this hypothetical study did not show that the purpose was
achieved, so there is no point in adding the ingredient---or going
forward with the formula. To clarify, Dr. Anderson added that if a new
ingredient didn't have a desired effect then it would not be appropriate
for marketing, and Dr. Fomon stated that was the case.

Dr. Grummer-Strawn reiterated that insufficient evidence was provided on
the characteristics of the new formula. Additional information would be
needed, he said, including comparisons with an appropriate reference
that would aid in interpreting growth along the 50^th^ percentile.

Dr. Frongillo addressed the reference criteria, stating the concern
about what is an appropriate reference and if existing reference data
may be used as comparators.

Dr. Bier asked for the benefit to risk ratio. Without knowing the
benefits, then the risk component is infinite, he said, noting that
until the benefit is shown to outweigh the risk, it is inappropriate to
take the risk.

Dr. Benton summarized by saying that the industry would not want to add
an ingredient that isn't there for some purpose.

Dr. Stallings asked what would be the optimal pattern of growth and how
would it be determined. Is the optimal growth of breastfed infants for
the first four months the place to start for comparison?

Dr. Chumlea responded that it could be a starting place as with the
NHANES III data, which gives status information. He pointed out,
however, that if that were the starting place, the problem of obesity
would not have been identified. What the data would provide is what is
happening currently, with that data not necessarily optimal. To get the
information, he said he would create a study that sufficiently
represented children of many cultures and genders in a multi-center
design to collect status and rate of growth from birth to 6 months of
age.

Dr. Fomon, acknowledging that breastfed and formula-fed infants' growth
historically is the same at 14 days, said the breastfed cohort could be
used for comparison. For a four-month study, he said, the rules have to
be that breastfed infants receive only breast milk and formula-fed
infants receive only formula between 14 and 112 days of age.

Dr. Grummer-Strawn replied that a prescriptive reference is needed. Any
formula that moves toward breast milk is the right formula, he said,
noting that research needs to work with the best data available today by
studying the population that is feeding the best way today. He added
that 50 years from now optimal might be defined differently.

Dr. Bier noted that in the past breastfed infants were the standard, but
it has been shown that formula actually can grow babies as well and as
healthy.

Dr. Frongillo said that if nutrients are adequate in formula, then is
the question about growth itself or about how formula will impact the
infant in the future. He acknowledged that from 1 to 4 months of age
average growth is about the same for breastfed and formula-fed infants,
and then the growth rates diverge, coming back together again at about
24 months of age. There have been issues raised about discrepancies in
these patterns, he said, noting that the Iowa data may be able to
provide more information about these issues.

*Dr. Garza asked: Given the fact that we don't have long-term data to
assess the functional consequence of different growth patterns in the
first year, should we assume that growth differences, until proven
otherwise, are or are not significant, to long-term health at 7, 15, and
30 years of age?*

Dr. Frongillo noted there are two aspects to the question, formula and
breastfeeding, given there are differences in the formulas infants
receive.

Dr. Benton stated that breastfeeding is the interaction between the
mother and the infant, with consumption determined in the process. He
stated that he is perplexed by the implication that growth patterns have
something to do with nutrition.

*Dr. Garza followed up by asking if feeding behaviors, or the
interactions between mothers and infants, are consistent
cross-culturally*.

Dr. Fomon said that the consequences of more or less rapid growth during
the first four months are unknown and what we have is the comparison of
how they grow in the first 4 months. Little in literature, he said,
tells how growth in the first four months relates to later in life.

*Dr. Garza asked how useful body composition would be in assessing
differences and similarities between breastfed and formula-fed infants.*

Dr. Fomon replied that it would give very little information.

Dr. Frongillo agreed that body composition would not necessarily bring
substantial information to the data, adding that weight and length data
are most important. He also noted that human milk has a biological
function so hormonal substances also may play a role.

Dr. Chumlea said that 15 years ago the sense was that fat babies became
fat adults. The Fels data do not support this, however. Measurements at
5 or 6 years of age were more predicative. Preliminary analysis shows
that nutrition from 8-12 years of age and 12-16 years of age does have a
predictive relation to bone density, he said.

Dr. Ellis added that environmental and other issues affect what happens
later in life.

*Dr. Sigman-Grant asked if there were any differences in head
circumference or body organ weight between breastfed and formula-fed
infants.*

Dr. Fomon said that head circumference is proportional to length, so the
value of head circumference is in detecting discrepancies between gain
in length and gain in head circumference. No one really knows about body
organ weight, he said.

*Dr. Anderson posed another hypothetical situation: An infant formula is
developed that contains GRAS long-chain fatty acids with no growth
studies, but evidence of benefit to neurologic development. Would you
proceed without a growth study?*

Dr. Bier replied that a study would be required because fatty acids have
specific effects on metabolism that are known and must be tested.

*Dr. Stallings asked the speakers to elaborate on the differences in
growth rates between breastfed and formula-fed infants in the first four
months of life.*

Dr. Frongillo calculated rates for New Finland and Iowa data. From 8-42
days of age there is no difference for male and female infants whether
breastfed or formula-fed. From 42-112 days of age, there are differences
of about 3 grams per day in weight and .07 mm per day in length, with
formula-fed infants growing faster. Essentially, he said, formula-fed
male infants grew 3 grams per day and formula-fed female infants grew 2
grams per day. The New Finland data showed that from 0 to 2 months of
age breastfed infants, both male and female, grew 3 grams per day faster
than formula-fed infants. From 2-4 months of age, formula-fed male
infants grew at an average rate of 6 grams per day, while formula-fed
female infants grew 3.5 grams per day, rates faster than breastfed
infants. The rate was similar, he said for growth from 4-6 months of
age. The Iowa data was from 1968 to 1987 and the New Finland data was
collected in the early 1990s.

*Public Speakers*

*Jose M. Saavedra, M.D., Medical Director, Nutrition Division, Nestle
USA*, discussed the industry's current analysis and documentation
process for new infant formulas. Industry does not introduce a new
infant formula, he said, unless there is a specific benefit, and does
notify FDA of all major and minor changes that may affect a new
formula's nutritional adequacy. Only if criteria for minor or major
changes are not applicable is the FDA not notified.

Clinical trials are conducted to assure the nutritional adequacy of a
new formula and to show that it supports normal growth. Clinical trials
should be done if they can reasonably predict that change will have an
impact on growth, he said. Clinical trials should not be done if they
are redundant, unnecessary, or unethical. The decision whether or not to
conduct a clinical trial is based on specific, reasonable, and
conservative assessment and evaluation of the change in a process that
is transparent between industry and the FDA.

Dr. Saavedra provided the decision tree used by U.S. formula
manufacturers to document the nutritional adequacy of a new or changed
infant formula. The decision process, he said, considers all aspects of
the formula matrix and manufacturing process to determine if a study is
required.

A major change to a formula is based on three criteria, he said. A
formula is considered to have a major change if it is an entirely new
formula by a manufacturer that has not made infant formula previously in
the United States; it is a change in a current formula where the
manufacturer's experience or theory would predict a possible significant
adverse impact on the level of nutrients or the bioavailability of
nutrients; or a change that causes an infant formula to differ
fundamentally in processing or composition from any previous formula
produced by a current U.S. manufacturer. If a manufacturer wants to
market a formula with a major change, it provides convincing
documentation that demonstrates that the formula will support normal
growth, the nature of the change and supporting scientific rationale,
and supportive data to the FDA.

Dr. Saavedra noted that industry tries to stay scientifically current
and does not wait for guidelines to be updated before making what it
considers beneficial changes. Manufacturers continually look for
information that might modify outcomes, he said, noting that published
literature and guidelines, as well as previous product and testing
experience, are used as sources of documentation. The critical factor,
he said, is the manufacturer's experience and knowledge, which it brings
to bear to understand the affect of the change. In addition,
manufacturers conduct internal medical assessments and independent
expert reviews on formulas with major changes before bringing them to
market.

In the last 10 years, Dr. Saavedra said, there have been 100 minor and
150 major change submissions and 50 growth studies involving 6,000
infants. Manufacturers collectively conducted more clinical and growth
studies than any other organization. In conclusion, he noted that since
the Infant Formula Act of 1980, not a single nutrition-based problem has
resulted from formulation changes in infant formula.

*Dr. John A. Vanderhoof, M.D., Vice President, Global Medical Affairs,
Mead Johnson Nutritional, Bristol-Myers Squibb*, discussed the
comparators and end points manufacturers use to measure the nutritional
adequacy of infant formulas. Safety is a given, he said, noting that
manufacturers have an excellent nutritional adequacy record and that the
American Academy of Pediatrics Committee on Nutrition's guidelines have
served the industry well.

Growth studies during the first four months are critical, he said,
because infant formula is the sole source of nutrition when infants are
most vulnerable. This also is the time when growth is very rapid and can
be attributed directly to the formula. Calling weight measurements the
most important endpoint, Dr. Vanderhoof, described this measurement as
the most sensitive indicator of nutritional adequacy. Length is a
secondary outcome, he said, because it confirms weight gain and
represents growth. Head circumference is a helpful, but not mandatory
growth measurement. Measurements should be differentiated by gender and
addressed by covariate analysis. Laboratory measurements and other
techniques may be appropriate, he said, if ingredients in the new
formulation, such as lipid blends and calcium, might specifically affect
individual nutrients.

Randomized, double-blind prospective studies are the gold standard of
clinical research, he said. Because growth data are inherently objective
measures these studies allow for the evaluation of secondary parameters
and may be used for multiple purposes. Studies should be powered to
detect a mean difference of 3 grams per day weight gain as the primary
outcome variable, based on AAP/CON guidelines, he said, noting that
since the standard was adopted no product withdrawals have occurred
because of nutritional inadequacy.

Present challenges to conducting randomized studies include the limited
availability of subjects, due in part to an increased breastfeeding
rate. For a study of 500 infants powered to detect smaller differences,
he said, you would have to screen about 24,000 infants.

Other options include historical controls and reference data, according
to Dr. Vanderhoof. Reference data minimize drift over time, he said, and
historical data could power studies at a higher level while reducing the
number of infants in research. He noted that manufacturers possess large
volumes of data obtained over time.

In summary, he said, present criteria provide the ideal balance for
formula research and infant protection. He noted that concurrent
controls usually are desirable but might not be necessary in some
situations and that other biochemical or body mass measurements might be
indicated in specific circumstances when a particular nutrient is
tested.

*Russell J. Merritt, M.D., Ph.D., Medical Director, Nutritionals, Ross
Products Division, Abbott Laboratories*, presented the basis and context
for the industry's sample growth trial protocol for healthy term
infants, which reflects the industry's experience conducting studies
since before the inception of the Infant Formula Act of 1980.

Recognizing that infant formula often is the sole food source for a
vulnerable population, he said, the purpose of a regulatory growth study
is to determine that a proposed new infant formula performs at least as
well as a current commercial formula appropriate for the population
under study.

Accepted clinical practices generally require the comparison of a new
intervention with a current standard of practice, in this case a
marketed infant formula, according to Dr. Merritt. The growth data also
will be compared to a reference standard, in effect giving both a
concurrent control and an historical control different roles in the
growth assessment. The historical control, he said, may be as large and
more closely related to the infant formula study population under study
and may be an excellent surrogate for a more recognized reference group
in some circumstances.

He noted that the use of an exclusively breastfed reference group
(historical or concurrent) would assume that the group of formula-fed
infants should grow identically to that group. No well recognized
standard exists, however, for exclusively breastfed infants, he said, so
there is no data showing that the growth of breastfed and formula-fed
infants should be identical or that a specific feeding regimen has
unequivocally been demonstrated to be better than others from the
perspective of long-term growth and body composition.

Two-sided testing, as usually performed, is less sensitive than
one-sided testing, he said, because it dilutes the power. One-sided
testing, on the other hand, addresses the critical question of whether
the new formula performs at least as well as a current commercial
formula.

At this point in research, he said, the best infant growth pattern is
not known, especially for individual infants in a study. The de facto
standard of 3 grams per day appears to serve us well, he said, noting
that very small differences between groups are not necessarily
meaningful. He pointed out that some Food Advisory Committee consultants
have said it is a misuse of the available science to pretend there is an
understanding of the health implications of a gram or two of weight gain
per day for a short period of time in a human life, or to define an
extraordinarily specific, statistically driven definition of a single
rate and pattern of infant growth as the only one that is normal or even
acceptable when testing an infant formula.

In conclusion, Dr. Merritt said that the context in which growth studies
are conducted is not static. He noted that the nation is coming closer
to the Healthy People 2010 goals for breastfeeding rates, which will
reduce the number of exclusively formula-fed infants available to
participate in clinical trials, and that evolving ethical standards
might further limit the types of studies acceptable in pediatric
subjects. These changes, he said, may make it increasingly difficult to
complete even the growth study protocol the industry currently uses.
Thus, rather than moving to more restrictive protocols with
theoretically more infants, other approaches regarding study
participation, eligibility, and/or fewer subjects for the use of
historic references may need to be considered in the future.

*Discussion with the three public speakers representing the
International Formula Council:* Asked to comment further on one-tailed
versus two-tailed studies, Dr. Merritt said that the historical context
has been to ensure nutritional adequacy. In that context, in study
designs where all the power is on the lower half there is greater
sensitivity to detecting problems on the low side. If the power is on
the high side, then the comparison generally is to existing formula and
against a reference standard. When data are compared to an existing
standard there usually is a concurrence of the two answers. If not, he
said, manufacturers will do additional thinking and assessment. The
comparison to historical standards is used as a crosscheck.

The speakers were asked if there had ever been a major change that did
not require a clinical study. Dr. Saavedra replied that there had been a
number of such changes. For example, he said, if an ingredient is GRAS
then it already has been studied for its impact on other ingredients.
The manufacturer knows all the interactions that could happen as a
result of the change, so the formula would not change in providing
nutritional adequacy and a study would not be required. Each
manufacturer knows its matrices and the components to the extent that it
can determine the affects of certain changes. In the case of a soy
product introduced into a formula, for example, Dr. Saavedra said that
if industry were to change a formula's protein source to one that had
not been used before, then a study would be needed.

Asked if it is reasonable to assume that clinical trials are required
only when there is a reasonable suspicion that there will be a
significant adverse impact, Dr. Vanderhoof replied that if there were a
reasonable suspicion of adverse impact on growth, the formula would not
be tested. Manufacturers would only want to test a formula clinically,
if the company was quite certain that it was nutritionally adequate.

The standard of 3 grams per day was discussed, particularly in regard to
the possible need to lower the standard. Dr. Vanderhoof pointed out that
it is an arbitrary number that strikes a reasonable balance between the
study and control groups and allows study groups to be adequately
powered. Dr. Merritt noted that the standard has protected the public
health historically and that any changes would require time and
additional studies to support. Dr. Saavedra summarized, saying that the
standard strikes a balance between what is practical, doable, and
beneficial.

The speakers then were asked to define normal growth. Normal growth is
growth based on historical data---experience associated with reasonable
health, according to Dr. Merritt.

Asked if the growth pattern of breastfed infants should be used as the
default standard for normal growth, Dr. Vanderhoof replied that
breastfed children who fail to thrive are switched to formula and often
begin to grow rapidly. A fair number of breastfed infants do not get the
number of calories they need, he said, because breastfeeding is a
different process that is dependent on cues for baby and mother to
determine when the baby has had enough to eat. These factors, he said,
may influence differences in weight gain and nutritional factors. If
studies try to replicate breastfeeding by changing the nutrient mix in
formulas, the result might be that formula-fed infants are deprived of
essential nutrients. The only way to replicate formula feeding with
breastfeeding would be to make formula with a caloric density lower than
breast milk, he said, noting that such a formula would not meet current
standards.

The speakers were asked to comment on the reporting of adverse events
and about how complaints are handled. Dr. Merritt said that each
manufacturer has a process for reporting complaints in accordance with
the Infant Formula Act. The complaints are examined by the FDA on an
annual basis and manufacturers review them at regular intervals to
ensure safeguards are in place.

Asked about the need for independent monitoring board for clinical
studies, Dr. Merritt said that there is enough experience and guidance
on how studies are conducted, particularly for most changes in formulas,
that independent monitors would be extreme oversight. An external
advisory board, however, might be indicated for special situations,
e.g., when special populations are targeted or if one is making novel
interventions, he said.

Dr. Saavedra was asked to describe the preclinical studies, in vivo and
in vitro. He responded that in vitro studies are done on ingredients to
measure the stability of the components and whether they remain the way
they are supposed to, chemically and structurally, and if they interact
with other ingredients. These studies, he said, provide reassurance that
there is no nutritional inadequacy before clinical studies begin. In
vivo pre-clinical studies are usually animal based, he said.

*Barbara Heiser, R.N., Executive Director, National Alliance for
Breastfeeding Advocacy*, described exclusive breastfeeding as the
optimal feeding standard for the first six months of life and called for
it to become the standard for what is best for babies. In addition to
the standard growth measurements of weight, length, and head
circumference, she requested that brain and neurodevelopment be added to
the assessments that are routinely monitored to obtain a broad picture
of infant health.

Ms. Heiser described the trust the public has in the FDA to assure such
high-quality, safe infant formula, noting that many mothers believe
formulas go through the same testing and approval procedures as drugs.
She pointed out that marketing claims are powerful tools that may
influence mothers' thinking, and that they often cause confusion about
the benefits of the elements in formula with those in breast milk. She
also questioned the use of post-market surveillance data and what is
being done with the information.

In summary, she said mothers expect safety from the government and
expect great products from the companies. She encouraged the task force
to find out what is best for babies on infant formulas.

*Discussion:* In her presentation, Ms. Heiser spoke of anecdotal
information on explosive diarrhea as a result of formula feeding. Asked
to elaborate on this information, she explained that her organization
and nurses encourage mothers to report this information via MedWatch and
to the manufacturers, and that her organization has begun questioning
health professionals in hospitals about what they are seeing.

Asked to elaborate on the public's misunderstanding that formula is
tested and approved similarly to drugs, Ms. Heiser said that health care
providers treat formula manufacturers more like drug vendors, especially
in hospitals. She also noted that mothers are told not to give regular
milk, so formula is considered different and more important.

*Discussion of Seven Questions*

Task force members began their discussion of the seven questions Monday
afternoon after hearing from the guest speakers. Discussion continued on
Tuesday morning following the public speakers. Below is a summary of
those discussions.

Question 1: Considering the values and merits individually, and in
combination, please group the following metrics in terms of their
clinical usefulness as endpoints for assessing normal physical growth.

-   *Body weight,*

-   *Recumbent length,*

-   *Head circumference,*

-   *Skin fold thickness,*

-   *Bioelectrical impedance,*

-   *Stable isotope, dual energy x-ray absorptiometry, or*

-   *Other physical body measurements or body composition measurements*

Two discussions were held on this question, one concerning term infants
and another concerning preterm infants. Dr. Garza, with the permission
of the task force members, asked that each metric be designated as
extremely useful, of moderate use, of no use, or in research and
inappropriate for comment at this time.

The discussion of DXA determined that DXA needs additional study and to
be available more readily before it is considered useful. It was
acknowledged that there is great interest in the measurements that can
be obtained using DXA and that it is an easier-to-use technology than
stable isotopes. Most children's hospitals now have the technology or
should have it in the near future. In addition, most level-3 nurseries
in adult hospitals also have the technology. Private pediatric practices
probably don't have the technology, though they should have access
through the hospitals. In summary, DXA technology is available generally
in middle size and larger cities.

Data obtained from DXA also were deemed to be of limited value because
there are little corresponding reference data. An NIH-funded,
five-center study is underway for older children. A similar longitudinal
study in infants would be needed to provide reference data. Such a study
would provide an opportunity for follow-up studies to begin gather data
that relate data from younger ages to older ages.

Following the discussion, task force members reached consensus that body
weight, recumbent length, and head circumference are the three metrics
that are the most useful indicators of infant growth. Skin fold
thickness was designated a metric of moderate use. Bioelectrical
impedance, stable isotope, dual energy x-ray absorptiometry, and other
physical body measurements or body composition measurements were deemed
to be in the research stage and therefore task force members felt they
were unable to comment on the effectiveness of these metrics at this
time. Several task force members indicated that there was no basis for
the use of bioelectrical impedance or stable isotope metrics in infants
six months or younger.

Task force members also considered the question in regard to preterm
infants. Their findings were the same for this population, with body
weight, recumbent length, and head circumference the three metrics that
are the most useful indicators of infant growth.

Question 2: Which of the above anthropometric and/or body composition
measures are necessary for adequate clinical evaluation of normal
physical growth of infants between birth and 6 months of age consuming
new infant formula?

Referring to the discussion regarding Question #1, the task force
reached consensus that body weight, recumbent length, and head
circumference are necessary for adequate clinical evaluation of the
normal physical growth of infants consuming new infant formula between
birth and 6 months of age for term and preterm infants.

Question 3a: The metrics above can be evaluated as attained (absolute
growth) or velocity (rate of change) measures. Please comment on the
distinguishing values and merits of each static or variable method in
the assessment of normal physical growth.

The three measurements for evaluating normal physical growth in infants
6 months of age or younger---body weight, recumbent length, and head
circumference---were determined to be velocity measurements. Task force
members reached a consensus that for infants in a study, baseline
measurements should be taken at birth or no later than 14 days. These
three measurements should also be taken at 1, 2, 4, 5, and 6 months of
age.

The same guidelines were recommended for preterm infants. Recognizing
that the measurements are more stressful for preterm infants than term
infants, task force members offered flexibility to mitigate the stress
on individual infants. More frequent measurements---every week---also
were seen as necessary for monitoring preterm infant growth because of
the rapid growth experienced by preterm infants. The more frequent
measurements should occur while the infant is hospitalized; monthly
measurements should begin after the infant is discharged through 6
months equivalency.

Question 3b: The outcomes above can also be evaluated as individual
infant data or as group comparative data. Please comment on the values
and merits of using individual or aggregate data in the assessment of
normal physical growth.

Task force members reached consensus that it would be beneficial to see
both study data on individual infants and the group comparative data.
Members recommended examining individual data to identify outliers and
the associated summary comments, and for additional analyses, such as
distributions and clustering. The aggregate data were seen as useful for
obtaining a measure of central tendency and general distribution.

*Question 4: For adequate evaluation of normal physical growth, below
are examples of clinically distinct reference groups.*

-   *Concurrent controls (concurrent data or population cohorts for
    demonstration of bioequivalence)*

-   *Reference data used as controls (comparison with previously
    collected normative data for populations and subpopulations)*

-   *Historical controls*

-   *Other*

*4a: What are the distinguishing values and merits of each type of
reference group for the assessment of normal physical growth?*

Dr. Garza defined reference groups as a comprehensive database with a
specific compilation he stressed that reference groups are not
necessarily standards. With the approval of the task force members, he
separated the types of reference data and asked task force members to
rank them in order of preference.

Discussion focused on concurrent controls, with the proposal that the
growth standards should be determined by the growth of healthy infants
receiving breast milk exclusively through at least 4 months of age. It
was noted that the growth patterns of breastfed infants throughout the
world are remarkably similar. While they might start at different
places, when plotted against the WHO data, they appear to parallel one
another. A concurrent study of breastfed infants would begin to develop
data from which growth data could be obtained. The goal of the study
would be to develop optimal growth patterns based on breastfed infants.

It was noted that to replicate the growth rates of breastfed infants,
changes would have to be made for formulas, and that those changes would
mean that the formulas would not be in compliance with current
nutritional adequacy standards. The claim was made that it is reasonable
to compare breastfed infants and formula-fed infants in an academic
setting, but with good data on formula-fed infants over many years, it
is reasonable perhaps to compare only one formula to another.

In summary, task force members agreed that concurrent, randomized
control groups are essential for studies of term infants, with
concurrent control groups mandatory for preterm studies. Longitudinal
studies were seen as potentially beneficial, followed by cross-sectional
studies, and then historical studies. Historical controls were deemed to
be the least helpful because they tend to be small populations collected
under protocols difficult or impossible to replicate. Temporal changes
that occur also make it difficult to match historical controls to
current studies. The consensus regarding historical reference data is
that such data should be fairly recent because of the many factors that
have affected infant growth over the past 10, 20 and 30 years. The
population in the historical data also must be relevant to the current
study population.

4b: *Please rank these reference groups based upon the ability of the
respective control population to contribute to an assessment of normal
physical growth in the population intended to consume the formula.*

Referring to the discussion of question 4a, task force members ranked
the reference groups as follows: longitudinal concurrent data, then
cross-sectional data, and finally historical data.

*4c: What is the role of such a reference group?*

Referring to the discussion of question 4a, currently available
reference data were seen to have comparative value, but were not seen as
a standard against which current studies should be evaluated.

Question 5: For the purpose of evaluating normal physical growth of
infants fed new formulas, what criteria should appropriate infant growth
reference groups meet (e.g., each or selectively, feeding history,
gestational age at birth, sex, racial background, socio-economic status,
other)?

-   *In comparison to the study population?*

-   *In comparison to the population intended to consume the formula?*

The discussion re-emphasized that comparisons should be done through
randomized trials, with the focus on characteristics that predict the
pattern of growth, such as gestational age at birth. In addition, the
comparisons should match on sex and general health. Cultural and
socioeconomic backgrounds are not necessary matches as long as there are
no extenuating circumstances that would preclude normal growth. Matching
feeding history was seen as important because infants rarely are fed
solely formula or breast milk and complimentary solid foods sometimes
are introduced, all of which could have an affect on the growth rate.
Maternal education and birth rate were two additional factors considered
for matching purposes.

Task force members determined that the comparison should be to the
population intended to consume the formula, e.g., that term infants
cannot be used to determine effects for preterm infants or that a study
of infants older than 6 months cannot be used to determine effects for
infant age birth to 6 months. Both the study and control groups should
be randomized and matched for sex, feeding history, gestational age, and
general health. These recommendations apply to studies of both term and
preterm infants.

*Question 6: Listed below are examples of control feedings (clinical
comparators):*

-   *(current infant formula (IF) + new ingredient) vs. (current IF) vs.
    (breast milk)*

-   *(current IF + new ingredient) vs. (current IF)*

-   *(current IF + new ingredient) vs. (breast milk)*

-   *(current IF + new ingredient) vs. (formulas fed to historical
    infant cohort(s), e.g., Iowa data)*

-   *(current IF + new ingredient) vs. (references that may include
    various type of feedings in such reference populations, e.g., NCHS
    and WHO)*

-   *(IF + new ingredient)\* vs. (any of the above controls)*

*\*Test formula contains new ingredient but the test formulation matrix
differs from the new formula that firm intends to market containing the
new ingredient.*

c.  *What are the most distinguishing values and merits of each of these
    types of comparisons in infants fed a test formula vs. a comparative
    feeding for assessing normal physical growth?*

d.  *Please rank these comparison based upon their potential for
    generating clinical data, which would be most relevant to an
    assessment of normal physical growth.*

Dr. Garza, with the permission of the task force members, proposed
categories of most value, moderate value, and never consider doing for
the clinical comparators. Following the discussion, four comparator
groups were defined, which the task force members then ranked in order
of preference. The four groups of comparators are:

-   Two formulas (old and new), plus three references (including a
    breastfed reference)

-   Two formulas (old and new), plus only a non-breastfed reference

-   Two formulas (old and new), plus only a breastfed reference

-   Two formulas (old and new) only

Discussion focused on building a breastfed reference data set as an
opportunity for analyzing the difference between breastfed and
formula-fed infant growth patterns. Comparisons to longitudinal
reference sets were seen as a way to control drift. Again, concurrent
longitudinal studies were deemed the gold standard, with recent
longitudinal studies second preference, cross-sectional studies third,
and historical data last. Comparisons with multiple references were seen
as feasible because current information technology makes such
comparisons highly doable. It was noted that only a third of the data on
breastfed infants in the Iowa study have been published and that the
remaining data may be made available.

Task force members considered these questions together, reaching
consensus that comparisons with the most potential for generating
clinical data on normal physical growth include contrasting outcomes in
infants fed the original formula, the original formula plus the new
ingredient, human milk, and two references, e.g., Iowa, CDC, WHO, NCHS,
and NHANES. The second preference was for comparisons among groups fed
the original formula, the original formula plus the new ingredient, and
human milk. The breastfed comparison was viewed as a way to begin
accumulating data that compared formula-fed infant growth to that of
breastfed infants. Because the second preference is included in the
first preference, task force members agreed to the more encompassing
comparison.

*Question 7: With regard to formula composition changes:*

c.  *Describe general principles and criteria that can be used to
    determine the need for a clinical study intended to provide
    assurance of normal physical growth.*

d.  *Describe some of the specific changes in infant formula that would
    reasonably be expected to be accompanied by a clinical study to
    demonstrate normal physical growth.*

Task force members were asked to develop their own scenarios for new
infant formulas and then to determine the general principles and
criteria they would use to determine if a clinical study of the new
formula was warranted. After discussing several scenarios, it was
evident that the same basic criteria were found each time a study was
warranted.

Task force members reached consensus that an infant growth study is
required for:

-   Major change in manufacturing process

-   Entirely new formula

-   Use of a substance that has not been tested in children before

-   Major changes in macronutrient content

-   Use of other compounds known to affect hormones, growth factors,
    genes, or metabolites that regulate growth

-   Formula changes that result in nutrient levels outside established
    ranges

-   Alterations likely to affect GI function or nutrient bioavailability

-   Studies on especially vulnerable populations

-   Use in a population distinct from that for whom the formula was
    intended originally

I certify that I attended the November 18-19, 2002 meeting of the Infant
Formula Task Force of the Food Advisory Committee, and these minutes
accurately reflect what transpired.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Jeanne E. Latham, M.S., R.D. Date

Executive Secretary

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Cutberto Garza, M.D., Ph.D. Date

Chair