conducted as effectively by in-house auditors trained in auditing
practices.
    (Response) As discussed previously in this document in section V.N,
FDA disagrees that a firm would have to hire auditors from outside its
company to perform audits regardless of whether the audits are CGMP or
quality control audits. First, section 412(b)(2)(B)(iv) of the FD&C Act
would not preclude an auditor being an employee of the manufacturer. In
addition, as noted, a manufacturer may utilize a team approach to
ensure an audit is conducted by individuals, whether employees of the
manufacturer or otherwise, with comprehensive knowledge of the infant
formula production process and may also utilize an individual to audit
an area of his/her prior responsibility so long as the manufacturer
determines that an audit by such individual would be objective and free
of bias. Thus, FDA disagrees that the audit provisions of proposed
Sec.  106.92 would require a manufacturer to hire individuals from
outside the firm to conduct audits.
    (Comment 189) One comment suggested that the language of proposed
Sec.  106.92 be changed to clarify that it is the manufacturer's
responsibility to determine what will constitute ``regularly scheduled
audits'' and to establish SOPs for that purpose. To achieve this goal,
the comment suggested that proposed Sec.  106.92 be revised to state
that the manufacturer must conduct audits ``according to its
established practice.''

    (Response) FDA disagrees that proposed Sec.  106.92 should be
revised to make the established practice of the manufacturer the only
basis for the conduct of ``regularly scheduled'' audits.
    The 1986 amendments to section 412 of the FD&C Act reflect a
Congressional determination that greater control over the formulation
and production of infant formula was needed. A total quality control
program for the manufacture of infant formula is necessary to ensure
that each production aggregate of formula is uniform in composition and
conforms to the nutrient requirements for infants. Under section
412(b)(2)(B)(iv) of the FD&C Act, a manufacturer is required to conduct
audits at regularly scheduled intervals. Thus, in response to this
comment, FDA advises that ``regularly scheduled'' means that a
manufacturer shall conduct, at each manufacturing facility, audits at a
frequency that is required to ensure compliance with such regulations,
with additional audits as needed, to determine whether the manufacturer
has complied with the quality control procedures regulations.
    For clarity, FDA is dividing proposed Sec.  106.92 into two
sections. Section 106.92(a) of the interim final rule establishes the
regularly scheduled audit requirement, and Sec.  106.92(b) of the
interim final rule establishes the audit personnel requirement.

VII. Subpart D--Conduct of Audits

Audit Plans and Procedures (Proposed Sec.  106.94)

    Three separate sections of the interim final rule address audits.
Section 106.90 of the interim final rule establishes the requirement to
conduct audits of compliance with CGMP, and Sec.  106.92 of the interim
final rule establishes the requirement to conduct audits of compliance
with quality control procedures. These provisions both implement
section 412(b)(2)(B)(iv) of the FD&C Act. Subpart D (Sec.  106.94 of
the interim final rule) establishes requirements for audit plans and
procedures.
    In the 1996 proposal, FDA proposed in Sec.  106.94 to require that
infant formula manufacturers develop and follow a written audit plan.
The audit plan would be required to set out the method used to
determine whether the firm is operating in compliance with CGMP,
including quality control procedures, and would include evaluation of
the firm's production and in-process controls, a comparison of the
written plan to the observed process, and review of certain records,
including monitoring records, specification deviation investigations,
and a representative sample of all records maintained under proposed
Sec.  106.100(e) and (f).
    The Agency received comments on several aspects of Sec.  106.94,
which are addressed in this document. Although FDA declines to make any
of the revisions to subpart D in response to the comments received, the
Agency is making minor editorial revisions in this subpart.
    (Comment 190) One comment objected to proposed Sec.
106.94(c)(1)(i) which would require observation of the production of
infant formula and comparison of the observed process to the written
production and in-process control plan. The comment stated that this
proposal could be interpreted as requiring observation of every single
manufacturing operation, from ingredient receipt through manufacturing,
holding, and distribution, and that such detail during an audit would
make the auditing process an extremely tedious and unwieldy endeavor
and would result in overly prolonged audits. The comment proposed that
the actual observation portion of the audit be devoted to the critical,
product/line specific steps of the process as defined by the
manufacturer.
    (Response) FDA disagrees with this comment. The requirement that a
manufacturer conduct regularly scheduled audits to assess compliance
with CGMP, including quality control procedures, derives from section
412(b)(2)(B)(iv) of the FD&C Act, which mandates that CGMP and quality
control procedures regulations include requirements for regularly
scheduled audits by a formula manufacturer to determine whether the
manufacturer has complied with such regulations. Thus, the scope of a
manufacturer's audits, and the audit plans and procedures established
under proposed Sec.  106.94(c)(1)(i), is determined by the breadth of
the CGMP and quality control procedure requirements. Section 106.6(a)
of the interim final rule requires a manufacturer to establish a system
of production and in-process controls that covers all stages of
processing, from the receipt and acceptance of the raw materials,
ingredients, and components through the storage and distribution of the
finished product, and Sec.  106.6(b) of the interim final rule requires
a written plan of such system. To assess compliance adequately, an
audit must extend to all of these areas of production. Thus, it is
appropriate that the audit plan required under proposed Sec.
106.94(c)(1)(i) include observation of each element of the
manufacturing operation, from ingredient receipt through manufacturing,
holding, and distribution. Accordingly, FDA is not revising Sec.
106.94(c)(1)(i) in the interim final rule in response to this comment.
    (Comment 191) One comment claimed that proposed Sec.
106.94(c)(1)(i) would require additional trained personnel to complete
this type of audit, and that this requirement would interfere
unnecessarily with the focus on high quality production.
    (Response) FDA notes that this comment did not explain its
assertion that additional personnel would be required to complete an
audit under proposed Sec.  106.94(c)(1)(i). Nor did the comment explain
how this proposed requirement would interfere with high quality
production. Without such details, FDA cannot respond to the comment.
Moreover, in its response to comments on the requirement to conduct
audits of compliance with CGMP and compliance with quality control
procedures, FDA addressed similar comments about the need for
additional trained personnel to conduct the audits that would be
required by proposed Sec. Sec.  106.90 and 106.92. In short, the audit
provisions (proposed Sec. Sec.  106.90. 106.92, and 106.94) provide
ample flexibility in terms of audit personnel.
    For the foregoing reasons, Sec.  106.94(c)(1)(i) is included in
this interim final rule as proposed.
    (Comment 192) One comment suggested revising proposed Sec.
106.94(c)(1)(ii), which requires that the audit procedures include
reviewing records of the monitoring of points, steps, or stages where
control is necessary to prevent adulteration. The comment noted that
the 1996 preamble to this proposed section stated that the review of
``production and in-process control records'' contemplated by this
section must involve ``all batches produced in a given period of time''
(61 FR 36154 at 36178). The comment recommended that the required audit
procedures be revised to include a review of records of representative
batches, over multiple days of production, of the monitoring of points,
steps, or stages where control is critical to prevent adulteration,
asserting that such audits would be more thorough and beneficial if the
records reviewed covered a wider span of time (i.e., months), but
extended only to ``representative'' batches, not ``all'' batches, and
to ``representative'' records of only the most important control points
(i.e., ``critical points'').

    (Response) As discussed in this document, FDA declines to make the
revisions requested in this comment.
    The purpose of an audit is to identify conditions related to
production and in-process controls that may result in the manufacture
of an adulterated infant formula. The Agency agrees with the comment
that an effective production and in-process control system audit may be
based on a ``representative sample'' (as defined in Sec.  106.3), of
production aggregates covering several months, and proposed Sec.
106.94 provides flexibility to the manufacturer as to the period of
production specified for review in the manufacturer's audit plan.
Importantly, however, the audit plan developed by the manufacturer
under proposed Sec.  106.94 must ensure that the audit covers a
sufficient number of products over a sufficient period of time so that
the manufacturer is able to determine whether its operations are in
compliance with CGMP, including quality control procedures required by
this interim final rule, to ensure that its infant formula provides the
required and added nutrients at the appropriate levels and is
manufactured in a manner designed to prevent adulteration. The audit
plan should provide a reasonable probability that any discrepancies in
the process can be identified. The audit plan must also provide a
mechanism whereby the manufacturer can identify any production
practices or in-process controls that require revision to ensure
compliance with all requirements for infant formula. FDA disagrees,
however, with the comment to the extent that it asserts that an audit
should be limited to ``representative records of the most important
control points.'' As discussed in the response to Comment 190, an
effective audit must be co-extensive with the production and in-process
controls established under Sec.  106.6 of the interim final rule.
Similarly, in order for such audit to be effective, an audit must
extend to the records of all points, steps, or stages where control is
necessary to prevent adulteration for each production aggregate in the
representative sample of an infant formula audited.
    Importantly, under Sec.  106.6 of the interim final rule, a
manufacturer has both the responsibility and the flexibility to
identify in its own production process those points, steps, or stages
in the process where control is necessary to prevent adulteration of
formula. Any point, step, or stage identified by the manufacturer as a
focus for control under Sec.  106.6 of the interim final rule is, by
definition, ``critical'' to producing an infant formula that is not
adulterated. Thus, it is essential that all of these points, steps, or
production stages be audited, including through a review of the records
related to such points, steps, or production stages, to confirm that
the relevant controls are functioning properly and ensuring that no
adulterated formula is produced. Moreover, as noted previously in this
document, audits by infant formula manufacturers are required by
section 412(b)(2)(B)(iv) of the FD&C Act, and a requirement that a
manufacturer's audits be limited to a review of the ``most important
control points'' would not allow a manufacturer to determine whether it
has complied with the CGMP, including quality control procedures,
regulations as mandated by section 412(b)(2)(B)(iv) of the FD&C Act.
Thus, it is entirely appropriate that the audit plan established under
Sec.  106.94(c) of the interim final rule require the review of the
records relating to all of the points, steps, or stages of the
production process where control is deemed necessary to prevent
adulteration.
    For these reasons, FDA declines to revise proposed Sec.
106.94(c)(1)(ii), and this provision is included in this interim final
rule as proposed.
    (Comment 193) One comment suggested that proposed Sec.
106.94(c)(1)(iii), which would require reviewing records of the
handling of deviations from any standard or specification at points,
steps, or stages where control is deemed necessary to prevent
adulteration should be revised by adding the phrase ``to assure that
the review was complete.'' The comment noted that the 1996 preamble
states that the auditor must review these records to determine
``whether the conclusions and follow-up of these investigations are
appropriate for each failure to meet the specification or standard''
(61 FR 36154 at 36178), and asserted that it is unrealistic to expect
an auditor to have the background and breadth of technical knowledge to
assess whether the dispositions were ``appropriate.'' The comment
claimed that such disposition decisions may involve multiple
disciplines in a company, and it would be more reasonable to expect the
auditor's review to confirm the completeness and sufficiency of such
investigations, rather than to expect the auditor to determine whether
the conclusions and follow-up were appropriate.
    (Response) Although FDA agrees that an audit should confirm the
completeness and sufficiency of the review of deviations from any
standard or specification, this action would not fulfill all of the
purposes of an audit. Because an audit serves as a manufacturer's
follow-up mechanism to provide independent evaluation of a firm's
management of deviations from specifications, a comprehensive audit
must also include an evaluation of how the manufacturer responded to
any deviation and whether the disposition decision was appropriate.
    In terms of the comment's concern that an auditor may not have the
requisite expertise to evaluate the response and disposition to a
deviation, the Agency clarified in the response to Comment 165 that
audits may be conducted by a single individual or by a team of
individuals, each qualified to evaluate a particular portion or
portions of the production process. In fact, the use of a team for
audits is one way to ensure that an audit is comprehensive. Thus,
proposed Sec.  106.94(c)(iii) is not unrealistic and FDA is not
persuaded to make the revision suggested by this comment.
    (Comment 194) One comment objected to the requirement in proposed
Sec.  106.94(c)(1)(iii) that the review of all deviations from the
manufacturer's standards or specifications at points, steps, or stages
where control is necessary to prevent adulteration be a part of
regularly scheduled audits. The comment suggested that instead of
requiring the auditor to review all deviations, review of a random
sample of deviations should be sufficient.
    (Response) FDA disagrees that review of a ``random sample'' of
deviations from a manufacturer's specifications would constitute a
sufficient audit. The purpose of a quality control audit is to identify
recurring problems and detect any weaknesses or flaws in the system. In
order to maximize the likelihood of identifying a pattern of repeated
failures, an audit must include the review of all deviations from
specifications. As discussed previously in this document, the fact that
a manufacturer fails to meet a specification requires prompt
investigation to determine whether the manufacturing process is under
control. A subsequent audit evaluates the handling of all such
occurrences and assesses whether the appropriate material disposition
decisions were made. Thus, a review of all deviations as a part of the
audit will identify failures that occur and show how these failures are
handled by the manufacturer.
    For these reasons, FDA is not revising proposed Sec.
106.94(c)(1)(iii) in response to this comment, and, with the exception
of minor editorial revisions, Sec.  106.94(c)(i)(iii) is included in
this interim final rule as proposed.

VIII. Subpart E--Quality Factors

    In Subpart E, ``Quality Factors,'' comments often referred to both
proposed Sec.  106.96 and proposed Sec.  106.97 because the subjects of
these two proposed provisions are closely related. The interim final
rule reorganizes and consolidates into a single section (Sec.  106.96
of the interim final rule) most of the content of proposed Sec.  106.96
and proposed Sec.  106.97 related to requirements for infant formula
quality factors. In addition, Sec.  106.121 of the interim final rule,
which is discussed in section X.D., specifies the assurances for the
established quality factors that a manufacturer is required to submit
in a new infant formula submission or in a submission made under
section 412(d)(3) of the FD&C Act. For these reasons, this portion of
the preamble is generally organized by topic rather than by section of
the proposed codified.
    FDA notes that the Agency received several comments in response to
proposed Sec.  106.96 and Sec.  106.97 that raised issues beyond the
scope of this rulemaking. In particular, FDA received comments
expressing concern about the safety of particular ingredients used in
infant formula. Because the safety of particular infant formula
ingredients is not at issue in this rulemaking, FDA is not responding
to these comments.

A. Quality Factors: Legal Authority

    Section 412(b)(1) of the FD&C Act, which was added to the statute
by the 1986 amendments, requires that the Secretary ``. . . establish
requirements for quality factors for infant formulas to the extent
possible consistent with current scientific knowledge, including
quality factor requirements for the nutrients required by subsection
(i).''
    Section 412(a)(2) of the FD&C Act deems an infant formula that does
not meet the quality factors requirements established by the Secretary
to be adulterated.
    (Comment 195) One comment asserted that there is no basis in the
plain language of the statute or in its legislative history to support
an interpretation of ``normal growth'' as a quality factor, which would
establish a requirement that applies to the infant formula as a whole.
The comment cited to legislative statements and FDA testimony
concerning the Infant Formula Act or the 1986 amendments to the Infant
Formula Act as support for its assertion that Congress intended quality
factors to be limited to individual components in the infant formula,
and that the Infant Formula Act does not authorize FDA to require
clinical studies for new infant formulas, including those that have
undergone a major change.\7\
---------------------------------------------------------------------------

    \7\ The comment cites to floor statements in the Senate Record
that describe the 1986 amendments as providing testing for ``each
essential nutrient'' and as further describing ``the quality factor
of nutrient content requirements of the law, as demonstrated by the
testing called for in the amendments.'' 132 Cong. Rec. S26775, 26777
(daily ed. Sept. 27, 1986). The comment also cites to a statement by
then Commissioner of Food and Drugs Jere E. Goyan stating that the
proposed legislation required ``tests, including clinical tests,
where appropriate.'' See Nutritional Quality of Infant Formula:
Hearings on H.R. 6590, H.R. 6608, H.R. 5836, and H.R. 5839 Before
the Subcomm. on Health and the Environment of the H. Comm. on
Interstate and Foreign Commerce, 96 Cong. 132, 74 (1980). The
comment notes that this statement by Commissioner Goyan was
responded to by Representative Mottl, who replied that ``I am
speaking of analysis in the chemical and nutritional laboratories,
and I am not referring to clinical trials.'' Id. at 120.
---------------------------------------------------------------------------

    (Response) FDA disagrees with the suggestion that the Infant
Formula Act does not support an interpretation of ``normal growth'' as
a quality factor, or does not provide authority to require a well-
controlled growth monitoring study to ensure that a formula will
support normal physical growth. Such reasoning is flawed. Legislative
silence on an issue is not persuasive when determining the meaning of a
statute. Central Bank v. First Interstate Bank, 511 U.S. 164, 187
(1994) (stating that ``Congressional inaction lacks persuasive
significance''). Clearly, just as Congress is not expected to express
``every single evil sought to be corrected'' in a grant of authority to
issue a rule, it cannot be expected to articulate every requirement
that is within an Agency's delegated authority. American Trucking
Assoc. v. United States, 344 U.S. 298, 309-10 (1953).
    In addition, the various legislative statements and Agency
testimony that the comment cites to support its assertion as to the
meaning of ``quality factors'' are not on point. First, the
congressional statements the comment cites to support its assertion
that FDA lacks the authority to require testing of the infant formula
as a whole (see footnote 1) discuss testing in the context of
laboratory analysis of required nutrients; the statements in question
do not relate to quality factors. Additionally, the Agency testimony
cited by the comment, stating that Congress did not intend the use of
clinical testing, comes from a discussion of the Infant Formula Act's
recall provisions. Second, even if these congressional statements and
FDA testimony were relevant, such isolated statements are not
sufficient evidence of congressional intent. See Weinberger v. Rossi,
456 U.S. 25, 34-35 (U.S. 1982) (rejecting the argument that a single
statement of a sponsor taken out of context should be determinative of
congressional intent); Regan v. Wald, 468 U.S. 222, 237 (1984)
(explaining that testimony of Senators and Representatives and
witnesses can seldom be expected to be as precise as the language of
the enacted bill, and should not later be permitted to undermine the
bill).
    FDA disagrees that there is no basis under the infant formula
provisions of the FD&C Act to require a well-controlled growth
monitoring study that demonstrates normal physical growth. Under
section 412(a) of the FD&C Act, Congress stipulated that infant formula
``shall be deemed to be adulterated if . . . such infant formula does
not meet the quality factor requirements prescribed by the Secretary .
. . .'' Section 412(b)(1) of the FD&C Act further provides that ``[t]he
Secretary shall by regulation establish requirements for quality
factors for infant formulas to the extent possible consistent with
current scientific knowledge, including quality factor requirements for
the nutrients required by subsection (i).''
    In construing the meaning of the term ``quality factors,'' FDA is
confronted with two questions. First, has Congress directly and
unambiguously spoken to the precise question at issue (``Chevron step
one'') Chevron U.S.A. Inc. v.Natural Resources Defense Council, 467
U.S. 837, 842 (1984)? To find no ambiguity, Congress must have clearly
manifested its intention with respect to the particular issue. See
Young v. Community Nutrition Institute, 476 U.S. 974, 980 (1986). If
Congress has spoken directly and plainly, the Agency must implement
Congress's unambiguously expressed intent. Chevron, 467 U.S. at 842-
843.
    Second, if the FD&C Act is silent or ambiguous with respect to the
meaning of ``quality factors'' in section 412(b)(1) of the FD&C Act, is
the Agency's interpretation based on a permissible construction of the
statute (``Chevron step two'') Chevron, 467 U.S. at 842-843; FDA v.
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000)? When, as is
the case here, Congress leaves a gap for the Agency to fill by
regulation, the regulation will pass muster so long as it is not
``arbitrary, capricious, or manifestly contrary to the statute.''
Chevron, 467 U.S. at 844.
    The language in section 412(b)(1) of the FD&C Act provides an
express delegation of authority to ``by regulation establish
requirements for quality factors for infant formulas to the extent

possible consistent with current scientific knowledge.'' This language
necessarily contemplates broad Agency discretion to define the
requirements for ``quality factors,'' limited by current scientific
knowledge.
    Congress also spoke to the precise question of whether ``quality
factors requirements'' were limited in application to the individual
nutrients required to be in the formula under section 412(i) of the
FD&C Act. Congress did not expressly limit quality factors in this way.
Rather, the statutory language describing what requirements for quality
factors are to be established states that the Secretary shall by
regulation establish ``quality factors for infant formulas . . .
including quality factor requirements for the nutrients required by
subsection (i).'' The use of the word ``including'' demonstrates that
Congress did not intend to limit quality factors for infant formulas to
the nutrients in subsection (i). See Norman J. Singer & J.D. Shambie
Singer, 2A Sutherland Statutory Construction Sec.  47:7 (7th ed. 2009)
(explaining that when a statutory definition declares what it
``includes,'' it ``conveys the conclusion that there are other items
includable, though not specifically enumerated''); Eric C. Surrette et.
al., American Jurisprudence Sec.  130 (2nd ed. 2008) (explaining that
``a statutory definition of a term as 'including' certain things does
not necessarily put a meaning thereon limited to the inclusion''); Gray
v. Powell, 314 U.S. 402 (1941) (explaining that ``[t]he definition of
disposal as including 'consumption or use by a producer, and any
transfer of title by the producer other than by sale' cannot be said to
put a meaning on disposal limited to the inclusion.''); Herb's Welding
v. Gray, 470 U.S. 414, 415, n. 9 (1985) (noting that by use of the term
``including,'' Congress indicated that the occupations specifically
mentioned in the law are not exhaustive). In sum, the infant formula
provisions of the FD&C Act direct the Agency to establish quality
factor requirements for infant formulas to the extent possible
consistent with current scientific knowledge, without limitation to
requirements relating only to the nutrients specified by statute to be
included in all infant formulas. Congress did not, however, define the
term ``quality factors,'' nor did it describe what such quality factors
might be. Instead Congress left a gap for the Agency to fill by
regulation.
    Because Congress left a gap for the Agency to define the term
``quality factors'' and determine what quality factor requirements are
consistent with current scientific knowledge, under Chevron step two,
FDA may define the term and determine what quality factor requirements
may be imposed, provided that FDA's interpretation is not arbitrary,
capricious, or manifestly contrary to the statute. Chevron, 467 U.S. at
844. Accordingly, when defining quality factors, FDA should consider
the language itself, the placement of the language in the infant
formula provisions of the FD&C Act, and other tools of statutory
construction, including the purpose and the legislative history of the
Infant Formula Act and the 1986 Amendments, as well as the FD&C Act.
See Barnhart v. Peabody Coal Co., 537 U.S. 149, 160 (2003) (looking to
structure, purpose, and legislative history to interpret the Coal Act);
see also Chevron, 467 U.S. at 843 (noting that if a statute is silent
with respect to an issue the Agency's answer to the issue should be
based on a permissible interpretation of the statute).
    The language in the infant formula provisions of the FD&C Act does
not define ``quality factors,'' but it does define the scope of
authority that Congress left FDA to establish quality factor
requirements. As noted previously in this document, according to the
language in section 412(b)(1) of the FD&C Act, quality factors include
requirements related to nutrients in section 412(i) of the FD&C Act,
but are not limited to such nutrients. This statutory language
indicates that the Secretary must establish quality factors for (1) the
individual nutrient components required under subsection (i), and, (2)
the infant formula as a whole to the extent possible consistent with
current scientific knowledge. If Congress had intended quality factors
to be limited to individual nutrient components of the formula, such as
protein and other nutrients that are added to the formula, Congress
would not have needed to incorporate the ``including'' language
referencing nutrients required by subsection (i).
    The organization of section 412 of the FD&C Act aids in
interpreting the intended meaning of quality factors. The statutory
provisions for quality factor requirements are separate and distinct
from the provisions for requirements related to CGMP and quality
control procedures in section 412(b)(2)(A) and (b)(2)(B) of the FD&C
Act. The placement of quality factor requirements in a separate
statutory provision means that such requirements pertain to something
other than the CGMP and quality control provisions that, in part,
ensure that particular nutrients are present at particular levels in
each production aggregate of infant formula. The preamble to the
proposed rule recognized that quality control procedures and quality
factor requirements are separate and distinct: ``While quality control
procedures are intended to ensure that the safety and nutritional
potency of a formula is built into the manufacturing process,'' quality
factors are ``intended to ensure that an infant formula contains an
adequate amount of each nutrient in a form that can be digested,
absorbed, and utilized so that the infant's physiological needs for
these nutrients will be met'' (61 FR 36154 at 36179). Thus, the quality
factors pertain not to a measurement of the amount of each nutrient in
the formula, but to a broader concept of bioavailability; an infant
formula as a whole and the individual nutrients in the infant formula
must meet the physiological needs of infants when fed the formula as a
sole source of nutrition to foster normal growth and development. As
noted previously in this document, under the language of section 412 of
the FD&C Act, Congress required the Secretary to establish quality
factors for the infant formula as a whole as well as for individual
nutrients to the extent that is consistent with current scientific
knowledge. Thus, interpreting the infant formula provisions of the FD&C
Act to mean that quality factor requirements that apply to the infant
formula as a whole would pertain to the ability of the formula (i.e.,
all the nutrients in combination) to meet an infant's physiological
needs, is reasonable. The quality factor of ``normal physical growth''
is designed to demonstrate the ability of the infant formula as a whole
to meet such physiological needs.
    Establishing normal physical growth as a quality factor requirement
is consistent with the overall purpose of the Infant Formula Act. The
need for an Infant Formula Act was discussed in the wake of the
marketing of two infant formulas that ``were critically deficient in
chloride, a life sustaining nutrient.'' S. Rep. No. 96-359, at 3
(1980). The Infant Formula Act was meant to provide the Secretary with
the means to ensure that formula ``will promote healthy growth'' in
infants. H.R. Rep. No. 96-936, at 3 (1980). ``Normal physical growth''
is an essential component of ``healthy growth,'' thus a quality factor
requirement for the demonstration of normal physical growth is
consistent with the overall purpose of the Infant Formula Act.
Additionally, a report from the House Committee on Interstate Commerce
that accompanied the Infant Formula Act supports the view that, as
originally

enacted, the Infant Formula Act authorizes the establishment of quality
factor requirements for normal physical growth. The report states:
``Quality factors pertain to the bioavailability of the nutrient . . .
.'' H.R. 96-936, at 6 (1980).
    In the 1986 amendments to the Infant Formula Act Congress clarified
that quality factor requirements demonstrating the ``bioavailability of
the nutrient'' referred to all nutrients combined in a formula as well
as to individual nutrients. See 21 U.S.C. 350a(b)(1). The Infant
Formula Act stated that the Secretary may by regulation ``establish
requirements for quality factors for such nutrients [required by
subsection (g)].'' Infant Formula Act of 1980, Public Law 96-359, Sec.
2, 94 Stat. 1190 (1980). In 1986, however, the infant formula
provisions were amended to specify in revised section 412(b)(1) of the
FD&C Act that the ``Secretary shall by regulation establish
requirements for quality factors for infant formulas, . . . including
quality factor requirements for the nutrients required by subsection
(i).'' (Emphasis added). This amendment clarified that quality factor
requirements applied to the ``infant formula'' as a whole as well as to
the individual nutrients required by subsection (i), and also made the
establishment of requirements for quality factors mandatory.
    Additionally, normal physical growth is an appropriate means to
assess whether the infant formula as a whole meets the physiological
needs of infants. Infants frequently consume formula as the sole or
primary source of nutrition at a time when the requirements for
nutrients are higher per kilogram body weight than at any other time
during the life cycle. The net effect for an infant who consumes an
infant formula that provides required nutrients in a bioavailable form
is the ability of the infant to achieve normal physical growth. Normal
physical growth is an indicator that an infant is thriving and is
inextricably linked to the bioavailability of nutrients in an infant
formula as a whole. Normal physical growth is an ``integrative
indicator of the net effect of the overall nutritional quality of the
formula'' (61 FR 36154 at 36180). Additionally, anthropometric
measurements of length, weight, and head circumference are easily made,
familiar to health care professionals, and are the same measurements as
those done during routine office visits and for which standardized
growth charts are available for comparison. Also, there is a very large
amount of data available on what constitutes ``normal physical
growth.'' Thus, it is reasonable for the Agency to require the conduct
of a well-controlled growth monitoring study, when necessary, to
determine whether an infant formula meets the quality factor of normal
physical growth.
    Further, requiring such a study is reasonable when considering the
statutory scheme as a whole. See Brown & Williamson, 529 U.S. at 133
(explaining that the words of a statute must be read in the context of
the overall statutory scheme). FDA's explicit statutory mission is, in
part, to protect the public health by ensuring that foods (including
infant formula) are safe, wholesome, sanitary, and properly labeled
(section 903(b)(2)(A) of the FD&C Act) (21 U.S.C. 393(b)(2)(A)).
Further, the FD&C Act touches ``phases of the lives and health of
people which, in the circumstances of modern industrialism, are largely
beyond self-protection. Regard for these purposes should infuse
construction of the legislation if it is to be treated as a working
instrument of government and not merely as a collection of English
words.'' United States v. Dotterweich, 320 U.S. 277, 281 (1943); see
also United States v. Park, 421 U.S. 658, 668 (1975). The Infant
Formula Act and the 1986 amendments were meant to ensure the ``safety
and nutrition'' of infant formulas, a purpose achieved, in part, by
growth monitoring studies. See Infant Formula Act of 1980, Public Law
96-359, 94 Stat. 1190, 1190 (1980) (prior to 1986 amendment).
    Section 701(a) of the FD&C Act authorizes FDA to issue regulations
for the efficient enforcement of the FD&C Act in order to ``effectuate
a congressional objective expressed elsewhere in the Act'' (Association
of American, Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204,
213 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v. FDA, 484 F. Supp.
1179, 1183 (D. Del. 1980)). The validity of such regulations issued
under section 701(a) of the FD&C Act is determined by a consideration
of the ``statutory purpose'' of the FD&C Act, as well as an
``understanding of what types of enforcement problems are encountered
by the FDA [and] the need for various sorts of supervision to
effectuate the goals of the Act.'' National Confectioners Assoc. v.
Califano, 569 F.2d 690, 693 (D.C. Cir 1978) (citing Toilet Goods Ass'n
v. Gardner, 387 U.S. 158, 163-64); see also Association of American
Physicians and Surgeons, Inc., 226 F. Supp. 2d at 213; NVE Inc. v. HHS,
436 F.3d 182, 186-190 (3d Cir. 2006) (noting that section 701(a) of the
FD&C Act grants FDA broad discretion to issue regulations for the
efficient enforcement of the FD&C Act within the scope of the authority
granted to it by Congress).
    The interim final rule falls within FDA's discretion to issue
regulations for the efficient enforcement of the FD&C Act. The interim
final rule is designed, in part, to help ensure that infant formulas,
when fed as a sole source of nutrition, will support normal physical
growth in infants consuming the formula. The requirement to conduct a
well-controlled growth monitoring study is designed to determine
whether normal physical growth may be achieved using a particular
infant formula. Such a study is consistent with the purpose of the
Infant Formula Act, because it provides a mechanism by which FDA can
determine whether the formula promotes one of the factors contributing
to healthy growth (i.e., normal physical growth). See H.R. Rep. No. 96-
936, at 3 (1980). The requirement to conduct such a study is written to
facilitate efficient and effective action to enforce the FD&C Act's
terms when necessary. The requirement to conduct a well-controlled
growth monitoring study is also consistent with FDA's overall mission,
because the study helps to ensure that the formula is safe and
wholesome. (See section 903(b)(2)(A) of the FD&C Act (21 U.S.C.
393(b)(2)(A))).
    FDA acknowledges that a well-controlled growth monitoring study may
not be necessary to demonstrate normal physical growth for every new
infant formula, including a change to a marketed formula that results
in a new infant formula. Thus, FDA has included in the interim final
rule exemptions from the requirement to conduct a well-controlled
growth monitoring study for certain changes in processing or methods
and, in addition, an opportunity for a manufacturer to demonstrate that
an alternative study design or method would provide assurances that an
infant formula supports normal physical growth or that a change to a
formula that has already been shown to meet the quality factor
requirements does not affect the bioavailability of the new formula,
including its nutrients. In addition, it is reasonable and necessary
for efficient enforcement of the FD&C Act for FDA to require that a
manufacturer make and retain records demonstrating that the formula
meets the quality factor of normal physical growth, and that certain
records related to the requirement to conduct a growth monitoring study
be included in the submission required in section 412(c)(1)(B) of the
FD&C Act (21 U.S.C. 350a(c)(1)(B)). Under section 412(d)(1)(C) of the
FD&C Act (21 U.S.C.

350(d)(1)(C)), assurances that the requirements for quality factors
have been met must be provided in a submission. FDA is requiring that
the assurances related to the quality factor requirements in the
submission be included in the form of a record that FDA can review
prior to the marketing of the infant formula to determine whether the
infant formula is adulterated under section 412(a)(2) of the FD&C Act.
Without records, FDA would not be able to evaluate whether an infant
formula meets the quality factor requirements, such as normal physical
growth.
    For example, when a growth monitoring study is required, FDA needs
certain data and information to evaluate the growth of the study
participants (infants) who have been fed the infant formula under
study. As discussed in this document, Sec.  106.96(d) of the interim
final rule requires manufacturers to make records demonstrating that
the formula meets the quality factor of normal physical growth.
Additionally, Sec.  106.121 of the interim final rule requires a
manufacturer to submit certain data and information that are required
to be collected during the growth monitoring study and that are
necessary to assess whether the infant formula supports normal physical
growth. These data include all measurements for each feeding group at
the beginning of the study, and at every point where measurements were
made throughout the study. Without these data, and other data and
information, FDA would not be able to assess whether the formula
supports normal physical growth.
    For the reasons stated previously in this document, it is
reasonable and appropriate under Chevron for the FDA to establish
normal physical growth as a quality factor requirement for infant
formula. Further, it is reasonable to include a requirement to conduct
a well-controlled growth monitoring study to evaluate whether an infant
formula complies with the quality factor requirement of normal physical
growth, and to require records related to such requirement.

B. Quality Factors for Infant Formulas

    Section 106.96 of the 1996 proposed rule identified two infant
formula quality factors: All infant formulas must be capable of
supporting infants' normal physical growth and all infant formulas must
be formulated and manufactured to ensure that the protein is of
sufficient biological quality to satisfy infants' protein requirements.
The term ``quality factors'' was defined in proposed Sec.  106.3(o) as
``. . . those factors necessary to demonstrate that the infant formula,
as prepared for market, provides nutrients in a form that is
bioavailable and safe as shown by evidence that demonstrates that the
formula supports healthy growth when fed as a sole source of
nutrition.'' In the preamble to the 1996 proposed rule (61 FR at
36179), FDA explained that ``healthy growth'' is a broad concept,
encompassing all aspects of physical growth and normal maturational
development, including maturation of organ systems and achievement of
normal functional development of motor, neurocognitive, and immune
systems. All of these growth and maturational developmental processes
are major determinants of an infant's ability to achieve his/her
biological potential, and all can be affected by the nutritional status
of an infant.
    To determine whether a formula supports normal physical growth in
infants when fed as the sole source of nutrition, proposed Sec.
106.97(a) would have required a formula manufacturer to conduct an
``adequate and well-controlled clinical study.'' Proposed Sec.
106.97(b) would also have required a formula manufacturer to collect
and maintain data to demonstrate that the biological quality of a
formula's protein is sufficient to meet the needs of infants.
    As discussed in more detail in this document, in both the 2003 and
2006 reopenings, several issues related to requirements for quality
factors were identified for additional comment. In response to comments
and on its own initiative, FDA is reorganizing and consolidating into
Sec.  106.96 of the interim final rule most of the content of proposed
Sec. Sec.  106.96 and 106.97 related to requirements for infant formula
quality factors.

C. Quality Factor: Normal Physical Growth

    In 1996, FDA proposed (Sec.  106.96(b)) ``normal physical growth''
as a quality factor for infant formula and stated that such growth is a
necessary indicator of the overall nutritional quality of a formula.
The Agency's proposal was consistent with the view of the Committee on
Nutrition of the American Academy of Pediatrics (CON/AAP) that the
determination of physical growth is the most valuable component of the
clinical evaluation of an infant formula (Ref. 67). FDA noted that
physical measures of growth (e.g., weight gain) are a widely accepted
measure of an infant's overall ability to utilize a formula's
nutrients, are familiar to practitioners and parents, are readily made,
and are not invasive.
    In the 2003 reopening, the Agency expressly requested comment on
the two quality factors that it had tentatively identified in the 1996
proposal: Normal physical growth and protein biological quality. In
particular, FDA requested comment on the appropriateness of these
quality factors and any information on other quality factors that could
be implemented consistent with current scientific knowledge, as
required under section 412(b)(1) of the FD&C Act.
    This interim final rule establishes as part of Sec.  106.96(a) the
general quality factor of ``normal physical growth.'' (As discussed in
section IV. C., the proposed definition of ``quality factors'' has been
slightly revised in Sec.  106.3.) FDA considered comments received from
the public, as discussed in this document, when including ``normal
physical growth'' as one quality factor.
    (Comment 196) Several comments supported FDA's proposal to
designate ``normal physical growth'' as a quality factor for all non-
exempt infant formulas. One comment stated that overall physical growth
and protein quality are reasonable benchmarks, assuming that the
formula contains all nutrients required by law.
    (Response) FDA agrees with the comments that support the
establishment of ``normal physical growth'' and ``protein quality'' as
infant formula quality factors. In considering the provision for
``normal physical growth,'' the Agency notes the IOM's conclusion (Ref.
4, p. 105): ``Growth is well recognized as a sensitive, but
nonspecific, indicator of the overall health and nutritional status of
an infant. Monitoring infant growth has always been an integral part of
pediatric care and is particularly important for young infants.''
    (Comment 197) Another comment agreed that growth is clearly an
indicator of bioavailability but nonetheless challenged the Agency's
proposal to define ``normal physical growth'' as a quality factor,
asserting that few changes in an infant formula raise bioavailability
questions and objecting to the routine demonstration of growth relative
to most changes in an infant formula.
    (Response) FDA disagrees with this comment for two reasons. First,
the comment does not dispute--indeed, agrees--that growth is a clear
indicator of formula bioavailability. Thus, the comment does not erode
or otherwise undermine FDA's rationale for defining ``normal physical
growth'' as a quality factor for infant formula. Second, although the
comment asserts that few changes in infant formulas create

bioavailability issues, the comment provided no data or other
information to support this assertion. The Agency notes that, among
others, the IOM has recognized that infant formula matrix changes can
highly influence nutrient bioavailability (Ref. 4, p. 45). In addition,
the interim final rule provides an exemption for new infant formulas
from the requirements for a growth monitoring study in Sec.  106.96(b),
if the formula manufacturer provides assurances that demonstrate that
the change made to the existing formula does not affect the
bioavailability of the formula, including the nutrients in such
formula.
    Accordingly, the interim final rule establishes ``normal physical
growth'' as a quality factor for infant formula.
1. Appropriateness of a Growth Monitoring Study (GMS)
    In the 1996 proposal, FDA proposed to require (Sec.  106.97(a)(1))
that a manufacturer conduct an adequate and well-controlled clinical
study, in accordance with good clinical practice, to determine whether
an infant formula supports normal physical growth when fed as the sole
source of nutrition. Proposed Sec.  106.97(a)(1)(i) would have required
that the manufacturer conduct a clinical study of at least four months
with study participants enrolled at no more than one month in age; that
the manufacturer collect, maintain, and plot on a growth chart certain
anthropometric measurements; and that these data be collected at
specified times. In addition, proposed Sec.  106.97(a)(1)(ii) included
nine proposed recommendations for the protocol of the clinical study.
    FDA addressed the proposed clinical study requirement in the 2003
reopening. At that time, the Agency requested comment on three specific
issues related to the clinical study requirement (requirements for
determining when a clinical study should be required; appropriate
reference data; and the appropriate infant enrollment age). In
addition, the Agency announced its intention to remove the proposed
provision addressing Institutional Review Board (IRB) review and
approval (proposed Sec.  106.97(a)(1)(ii)(C)) as a result of Agency
rulemaking since the 1996 proposal and its plan to remove the remaining
protocol recommendations from the proposed rule and to develop a
guidance document containing recommendations for the protocol for an
infant formula clinical growth study (68 FR at 22342-22343).
    Thereafter, in the 2006 reopening, the Agency requested comment on
several recommendations of the 2004 IOM report, including the need for
assessments of normal physical growth in addition to a clinical growth
study, the need for body composition measurements, and the appropriate
duration of and enrollment age for a clinical growth study.
    This interim final rule includes a growth monitoring study
requirement in Sec.  106.96(b). This provision requires that a
manufacturer of infant formula satisfy the quality factor of ``normal
physical growth'' by conducting an adequate and well-controlled growth
monitoring study to demonstrate that the formula supports normal
physical growth in infants when fed as the sole source of nutrition.
The interim final rule substitutes the descriptor ``growth monitoring
study'' for ``clinical study,'' the term used in the proposed rule,
because the new term more accurately describes the nature and purpose
of the study. Section106.96(b) of the interim final rule establishes
requirements for the growth monitoring study, which address study
duration; subject age at enrollment; data collection and maintenance;
and comparison of data for study subjects and controls. In addition,
parts 50 and 56 require IRB review and approval and human subject
protection.
    As discussed in more detail in this document, Sec.  106.96(c) of
the interim final rule provides certain exemptions from the growth
monitoring study requirements under Sec.  106.96(b).
    (Comment 198) One comment recommended that a clinical growth study
be required for any new infant formula, change in the infant formula,
or change in the packaging of infant formula. To justify this
recommendation, the comment explained that infant formula is unique in
that it can be the sole source of nutrition for an infant for an
extended period and during a most vulnerable time.
    (Response) FDA recognizes that infant formula often serves as the
sole source of nutrition for a vulnerable population during a
critically important developmental period, a consideration that broadly
underlies the interim final rule. To the extent that the comment
suggests that a growth monitoring study be required for all formulas,
including formulas that have undergone a ``major change'' in processing
or in composition, the Agency concludes that the requirements of the
interim final rule effectively achieve the outcome recommended by this
comment. Specifically, Sec.  106.96(b) of the interim final rule
requires a manufacturer to conduct a growth monitoring study of each
``infant formula,'' and Sec.  106.96(c) of the interim final rule
includes provisions for specific exemptions from that requirement where
a manufacturer can establish that the formula is entitled to the
exemption.
    (Comment 199) One comment stated that while the future introduction
of novel ingredients in infant formula (such as components of human
milk not presently in infant formulas) may present new challenges to
the regulatory process, safety concerns about an ingredient new to
infant formula are better handled under the regulatory rubrics
specifically designed for ingredient evaluation, and that FDA's
Generally Recognized As Safe (GRAS) notification process provides the
Agency with a context in which to raise any safety concerns, including
concerns about matrix issues, processing issues, or nutrient
interactions.
    (Response) As discussed in detail in this document, FDA agrees in
part with this comment. Ingredient safety is a basic principle of food
safety, for both food generally and for infant formula specifically. As
is the case with all foods, a manufacturer has an on-going
responsibility to ensure the safety of each ingredient in its products
and each substance produced for addition to food and to ensure that
such ingredients and substances are otherwise in compliance with all
applicable legal and regulatory requirements.
    An ingredient newly intended for use in infant formula is
appropriately evaluated under section 409 of the FD&C Act as a food
additive or may be an ingredient that the manufacturer has determined
to be generally recognized as safe (GRAS) under section 201(s) of the
FD&C Act. For ingredients believed to be GRAS, FDA strongly encourages
the formula manufacturer or the ingredient supplier to submit the self-
determination of GRAS to FDA under the Agency's GRAS notification
program (see 62 FR 18937, April 17, 1997) well before the submission of
a new infant formula notification under section 412(c) of the FD&C Act.
    Importantly, however, the review of a food additive petition under
section 409 of the FD&C Act or the evaluation of a GRAS notice for an
ingredient new to infant formula is separate and distinct from the
provision that a formula meet the quality factor requirements under
section 412(b)(1) of the FD&C Act. That is, FDA's evaluation and
determination of an ingredient's safety in response to a food additive
petition or FDA's response to a GRAS notice does not address the
scientific issue to be addressed by the quality factors, which is
whether the formula matrix and

individual nutrients in the formula support normal physical growth. In
section IV.C.7. FDA explained in the discussion of the ``quality
factors'' definition the criticality of ensuring the bioavailability of
the formula's nutrients in a particular formula matrix, including the
nutrients in the formula, and ensuring that an infant formula
containing the new ingredient is capable of supporting normal physical
growth.
    Similarly, the ingredient safety review does not eliminate the
responsibility of an infant formula manufacturer to make the submission
required by section 412(d)(1) of the FD&C Act for each new infant
formula that the manufacturer wishes to market. Under section 412 of
the FD&C Act, any new formula ingredient is evaluated as part of a
complete formulation, and, as noted, under section 412(d)(1)(C) of the
FD&C Act, the new infant formula manufacturer must provide assurances
that the formula satisfies the requirements for quality factors for
specific nutrients and for the formula as a whole.
    For these reasons, FDA is making no changes in response to this
comment.
    (Comment 200) One comment suggested that the assurances under all
paragraphs of proposed Sec.  106.97(a) be deleted from the final rule
citing general legal, scientific, and policy grounds to these
provisions.
    (Response) As explained previously in this document, proposed Sec.
106.97(a) has been removed from the interim final rule, and much of its
content is retained in Sec.  106.96(b) of the interim final rule.
Despite this revision, FDA responds to the substance of this comment.
    Infant formulas must be able to serve as the sole source of
nutrition for a period of unparalleled growth and development of
infants in a form that will meet all of the known nutritional needs of
infants and to ensure that healthy growth and nutritional well-being
will be achieved by an infant consuming the infant formula as the sole
source of nutrition (61 FR 36154 at 36180). The least invasive and most
practical means to ensure that the formula, as a whole, delivers
nutrients in a form that is bioavailable and safe is a growth
monitoring study in which anthropometric measurements of infants fed a
new infant formula are assessed, and comparison of these data to a
concurrent control group, in addition to comparison of both test and
controls groups to a scientifically appropriate reference, is made.
Anthropometric measurements are easily made, are familiar to parents
and health care professionals, can be measured during outpatient study
visits, and are the same measurements as those done during routine
office visits.
    As discussed in more detail in this document, the requirement for a
growth monitoring study in Sec.  106.96(b) of the interim final rule
applies to all infant formulas that are introduced or delivered for
introduction into interstate commerce. This means that a manufacturer
of an infant formula for distribution in the U.S. is required to
conduct a growth monitoring study under Sec.  106.96(b) of the interim
final rule, unless the manufacturer qualifies for an exemption under
Sec.  106.96(c) of the interim final rule from the growth monitoring
study requirements of Sec.  106.96(b) of the interim final rule, as
explained in section VIII.C and D, respectively. A manufacturer of a
``new'' infant formula is required to submit such study to FDA in a 90-
day submission, consistent with Sec.  106.120 of the interim final rule
and section 412(c)(1)(B) and (d)(1)(C) of the FD&C Act. As is discussed
in further detail in this document, a manufacturer of an ``eligible
infant formula'' (as defined in Sec.  106.3 of the interim final rule)
would not be required to make the submission required by Sec.  106.120
of the interim final rule and sections 412(c)(1)(B) and (d)(1)(C) of
the FD&C Act, but would be required under Sec.  106.96(d) of the
interim final rule to make and retain records demonstrating that the
formula meets the quality factor of normal physical growth. The need
for a growth monitoring study of an infant formula for export only is
addressed in section VIII. D.
    FDA recognizes that not every change in an infant formula or change
in the packaging of infant formula will require a growth monitoring
study. In recognition of this fact, Sec.  106.96(c) of the interim
final rule includes several exemptions from the growth monitoring study
requirement, which are discussed in section VIII.D, ``Exemptions From
Quality Factor Requirements for Normal Physical Growth.''
    (Comment 201) One comment on proposed Sec.  106.97 stated that FDA
is correct to insist that new substances themselves added to formula be
GRAS.
    (Response) FDA believes that it is important to clarify FDA's
conclusions regarding the GRAS status of substances in formula. As
discussed previously in this document, all food manufacturers,
including infant formula manufacturers, have a duty to ensure that the
ingredients in their products satisfy the applicable statutory
standard. Under section 409 of the FD&C Act, a substance added to food
must be either an approved food additive or exempt from the definition
of food additive because it is GRAS.
    (Comment 202) One comment argued that safety issues, including the
potential impact on infant growth, need to be raised and resolved, and
that in order to prevent unnecessary and invasive clinical studies,
animal studies should be relied upon as much as possible.
    (Response) FDA disagrees with this comment for two reasons. First,
the study required by Sec.  106.96(b) of the interim final rule is a
growth monitoring study and is entirely non-invasive. Indeed, the
anthropometric measurements required of study participants are the same
measurements that are typically taken by a health care provider at
``well baby'' visits. Second, FDA is not aware of an animal model that
is a suitable substitute for the infants in a growth monitoring study,
and the comment provided no information about such a model.
    (Comment 203) One comment acknowledged that the methodology to
conduct an adequate and well-controlled clinical study is
scientifically ideal to answer the question of whether a new substance
added to an existing formula has an effect on the bioavailability of a
nutrient required for infant growth. The comment also noted that not
every change in an infant formula raises questions about infant growth
that cannot be answered adequately by other supporting scientific data,
and provided references to sources of information that might be used
for this purpose.
    (Response) FDA agrees with the comment's assessment of the value of
clinical study methodology to evaluate the ability of an infant formula
to support the normal physical growth of infants. FDA also agrees with
the comment that not every change in an infant formula would require a
growth monitoring study. This issue is discussed in detail in section
VIII.D.
    (Comment 204) Another comment stated that routine growth studies
are not designed and generally not powered to detect rarely occurring
adverse events and therefore, are not comprehensive safety studies. The
comment argues that new ingredients are often substances identified in
human milk as having a nutritional function and that a case-by-case
review of available evidence can identify when there is a need for
safety endpoints in clinical studies.
    (Response) Normal physical growth and protein quality are very
basic benchmarks for evaluating healthy growth of infants when fed an
infant formula as the sole source of nutrition. FDA agrees that growth
studies are not

designed and do not have sufficient statistical power to detect rarely
occurring adverse events. Importantly, however, the purpose of the
growth monitoring study is to assess the ability of an infant formula,
including the nutrients in the formula, to support normal physical
growth. To the extent that the ingredients may present safety concerns,
those issues are primarily addressed as part of the review under
sections 409 and 201(s) of the FD&C Act.
2. Clinical Study Protocols
    In proposed Sec.  106.97(a)(1)(ii), FDA listed provisions that it
recommended manufacturers include in a clinical study protocol. In the
notice to reopen the comment period in 2003 (68 FR 22341 at 22343), FDA
stated its intent to remove the clinical study protocol provisions in
proposed Sec.  106.97(a)(1)(ii) and develop a guidance document
detailing the Agency's recommendations for what should be included in
the protocol for a clinical study that will be submitted to FDA as
``assurance'' that the formula satisfies the quality factor of normal
physical growth. Comments received in response to the 2003 reopening
agreed with FDA's view that detailed directions for the clinical study
protocols would be better addressed as guidance from the Agency. No
comments were received that suggested retaining the proposed clinical
study protocol provisions in the final rule. Therefore, the Agency has
deleted the specific study protocol recommendations of proposed Sec.
106.97(a)(1)(ii).
    However, as discussed in section VIII. C., Sec. Sec.  106.96 and
106.121 of the interim final rule incorporate some of the proposed
study protocol recommendations as requirements in the interim final
rule. To the extent that proposed recommendations have become
requirements, FDA will address the comments received on those specific
recommendations. Otherwise, the Agency is not individually addressing
the comments submitted on those recommendations not incorporated into
the interim final rule. FDA will consider developing guidance in the
future on the protocol for a growth monitoring study of infant formula
and will consider relevant comments during the development of such
guidance.
    As stated previously in this interim final rule, FDA has not
included all of the clinical study protocol recommendations that were
included in the 1996 proposal. The Agency has concluded, however, that
certain basic elements of study design, data collection, and evaluation
are necessary to ensure that a growth monitoring study provides the
quality and type of data needed to evaluate whether an infant formula
supports normal physical growth when fed as the sole source of
nutrition. Therefore, those elements have been codified in Sec. Sec.
106.96(b) and 106.121 of the interim final rule. In the responses to
the comments that follow, FDA explains the reasons for including these
elements.
3. Design of a Growth Monitoring Study
    a. Appropriate study design. Several comments addressed the design
of growth monitoring studies of infant formulas.
    (Comment 205) One comment stated that the requirement in proposed
Sec.  106.97(a)(1) that the study be ``well-controlled'' was too vague
to be meaningful and suggested that acceptable controls should be
specified.
    (Response) For several reasons, FDA disagrees with this comment and
declines to specify acceptable controls for infant formula growth
monitoring studies. First, the concept of ``well-controlled'' is
generally well understood in the scientific community. The primary
purpose of conducting a well-controlled study is to distinguish the
effect of the treatment (here, feeding of the infant formula being
evaluated) from other influences, such as chance occurrences, normal
growth, or biased observation. A well-controlled study methodically
examines sameness and differences in outcomes across cohorts and
permits an organized comparison and the delineation of sameness and
difference.
    Further, it would be unnecessarily restrictive to identify in a
regulation the specific type or types of controls that, if used in a
growth monitoring study, would make the study ``well-controlled.'' The
appropriateness of a particular control group or of other controls is
determined in part by the nature of the study and of the group being
studied. Accordingly, it is not possible for FDA to specify a priori
the controls relevant and appropriate to a particular growth monitoring
study. Thus, FDA is not revising this provision in the interim final
rule to elaborate on the controls needed to make an infant formula
growth monitoring study ``well-controlled.''
    To the extent that the interim final rule addresses the specific
requirements of a growth monitoring study, FDA has clarified, by adding
Sec.  106.96(b)(4) and (b)(5) to the interim final rule, that the
protocol of a well-controlled growth monitoring study would require
information on infant formula intake for both the test and control
groups. A study that lacks formula intake data would be difficult to
interpret and could lead to erroneous conclusions regarding the
formulas being fed. Clearly, the relationship between formula intake
and growth is basic to the evaluation of an infant formula's capacity
to support normal physical growth. Therefore, any study of infants in
which normal physical growth is being assessed would include the
collection of formula intake data as part of the design of the study.
These data are needed to provide fair and meaningful interpretation of
the study results and to demonstrate whether the new formula is able to
support normal physical growth. To clarify the specific controls
expected in a study designed to evaluate whether an infant formula
supports normal physical growth when fed as the sole source of
nutrition, FDA is adding Sec.  106.96(b)(2) to the interim final rule
to require the growth study to include collection and maintenance of
data on infant formula intake and Sec.  106.96(b)(5) to require
comparison of the data on formula intake of the test group(s) and
control group(s), with each other and with a scientifically appropriate
reference to determine whether both groups had consumed age appropriate
volumes.
    (Comment 206) Another comment stated that the design of the study
should address the specific objectives of the study.
    (Response) FDA agrees with this comment. One characteristic of an
adequate and well-controlled study is that the protocol for the study
includes a clear statement of the study objective(s). Likewise, a
report of study results should also contain a clear statement of the
objective of the investigation. See, e.g., 21 CFR 314.126(b)(1) and
514.117(b)(1).
    (Comment 207) One comment stated that a randomized clinical study,
with or without reference to an outside standard, is the best method to
assess whether infants receiving different feeding regimens differ in
terms of a primary outcome parameter. The comment also stated that this
research methodology is recognized as the most definitive method of
determining whether an intervention has the postulated effect.
    (Response) FDA agrees that a randomized study design is generally
regarded as the strongest experimental design to determine whether an
intervention (i.e., feeding a new formulation of an infant formula) has
the postulated effect because this study design requires a concurrent
control group. For this reason, the interim final rule requires that
the growth monitoring study of an infant formula be an

adequate and well-controlled study, which would include randomizing
study participants into the treated and control groups.
    Indeed, the purpose of a growth monitoring study is to evaluate
whether an infant formula supports normal physical growth by comparing
the growth of infants consuming the test formula with the growth of
infants consuming a baseline formula. Although weight is the most
sensitive indicator of infant growth, no single anthropometric
measurement provides all the information needed to assess growth.
Measures of length and head circumference provide additional
information on whether the formula supports normal physical growth.
Plotting these measures on growth charts for each infant in the test
and control groups provides information about how the infants in both
groups are growing compared to a reference population of infants.
Plotting weight and length on the weight for length charts is an
additional safety check that the infant is growing proportionally (not
too thin or too heavy for the measured length) relative to the norms
represented by the charts.
    FDA received several comments on the proposal to require concurrent
control groups.
    (Comment 208) One comment disagreed with the Agency on the value of
a concurrent control group in studies conducted in accordance with
proposed Sec.  106.97(a)(1). The comment asserted that historical
control data based on normal infants are available from Fomon and
Nelson (Ref. 68) and Guo et al. (Ref. 69) and that these data are
generally more appropriate than concurrent controls because the data
are based on a large number of normal infants studied under well-
defined conditions.
    (Response) FDA disagrees in part with this comment. The optimal
comparator for infants consuming a new formulation of an infant formula
is a concurrent control group of infants fed a base formula. For this
reason, Sec.  106.96(b)(4) and (b)(5) of the interim final rule require
that a growth monitoring study of an infant formula use a concurrent
control group.
    FDA acknowledged in the 1996 proposal that historical controls have
been used by some investigators to evaluate infant growth while being
fed a new formulation of a formula. Importantly, however, the Agency
noted that historical controls have inherent limitations, and the
differences and similarities in growth between the study infants and
the population reference standard cannot be meaningfully compared (61
FR 36154 at 36183). For example, difficulties in interpretation may
arise when the sample of infants receiving the test formula differs
significantly from the population in the historical controls; when the
variability in measures of growth in test subjects is large; when
attrition rates differ greatly between the population in the historical
controls and the infants on test; and when events occurring in the
study cannot be explained in the absence of concurrent controls.
    FDA recognizes that historical control data may be useful in
certain limited situations in which a manufacturer has access to
extensive reference data, such as a database on many similarly
conducted studies in which infants were selected on the basis of nearly
identical criteria, and the results are available for all important
measurements, including formula intake and attrition rates. FDA notes
that the manufacturer is responsible for demonstrating that a new
formulation of an infant formula satisfies the quality factor of normal
physical growth. Thus, when designing a study protocol, the
manufacturer should carefully consider whether historical control data
permit a meaningful comparison to the infants consuming the new
formulation.
    Because the use of historical control data may be appropriate in
certain narrow circumstances, the interim final rule provides
manufacturers with an opportunity to justify reliance on such data.
Specifically, a manufacturer may request an exemption under Sec.
106.96(c)(2)(i) of the interim final rule to conduct a growth
monitoring study using an alternative study method or design, provided
that the manufacturer provides assurances that demonstrate that the
alternative study design is based on sound scientific principles. In
such a situation, FDA expects that detailed study results from the
historical control data would be available to FDA for review.
    (Comment 209) One comment stated that because growth may or may not
be the crucial outcome measured in future formula studies and
``optimal'' growth and development have yet to be defined, a concurrent
control group is the optimal comparator.
    (Response) FDA agrees with this comment. As noted, in the 1996
proposal, the Agency acknowledged that although historical controls
have been used in some infant formula investigations, these historical
data have inherent limitations. Accordingly, Sec.  106.96(b)(4) and
(b)(5) of the interim final rule require that a growth monitoring study
of an infant formula use a concurrent control group. Importantly, if a
manufacturer wishes to utilize historical control data in a growth
monitoring study, the manufacturer may request an exemption under Sec.
106.96(c)(2)(i) of the interim final rule.
    (Comment 210) One comment recommended a concurrent breastfeeding
control group, while another comment opined that the universally agreed
reference population that defines healthy growth as infants breastfed
by well-nourished mothers cannot be included in a randomized trial.
    (Response) A growth monitoring study need not include a concurrent
control group of breast-fed infants because comparing the growth of
infants consuming the new formulation to that of a concurrent control
group consuming the control formula and to the appropriate reference
data is sufficient to assess whether the new formula supports normal
physical growth. Also, infants cannot be randomly assigned to be
formula-fed or breastfed so there are scientific limitations on the use
of a concurrent breast-fed control group. In addition, there may be
significant non-nutritional confounding factors with using breastfed
infants as a control group, such as the health and nutrition of the
mothers who choose to breastfeed. The Agency would not object, however,
if breastfed infants from the same population as the infants consuming
the infant formula under evaluation were included as a concurrent
cohort group. In such circumstances, the growth of breast-fed infants
could also be compared to the group of infants consuming formula as a
model or reference for growth.
    (Comment 211) Another comment indicated that it may be necessary to
have a concurrent control from the same population if infants believed
to have different growth characteristics (e.g., infants from different
ethnic groups) are used as the study population.
    (Response) FDA agrees in part with this comment. The Agency
acknowledges that the optimal comparator for a particular growth
monitoring study is a concurrent control group composed of infants that
mirror the study infants as closely as possible, including ethnic or
racial background. Importantly, however, the Agency is aware that the
pool of infants for study subjects and controls is limited and thus,
FDA is concerned that to require precise ethnic or racial comparability
between study and control group members could inhibit the ability to
recruit subjects and fulfill the growth monitoring study requirement.

Accordingly, FDA encourages manufacturers to consider factors such as
ethnic or racial background in developing test and control groups, but
the Agency declines to specify that such comparability is a necessary
characteristic of an adequate and well-controlled investigation.
    (Comment 212) One comment stated that infant formulas should be
clinically tested in randomized trials and conducted in at least two
centers.
    (Response) FDA agrees with this comment to the extent that it
asserts that a new formulation of an infant formula should be evaluated
in a randomized, well-controlled growth monitoring study to demonstrate
satisfaction of the quality factor of normal physical growth. Like all
study designs, studies conducted at multiple centers have advantages
and disadvantages. For example, the use of multiple centers may be
advantageous because it may make it easier to recruit sufficient
numbers of infants as study subjects. However, the failure to follow
the study protocol carefully at all centers may jeopardize the utility
of the combined data and thus, is a potential disadvantage to a multi-
center study. Such factors as an appropriate study design (including
suitable control groups and treatments, blinding of all caregivers and
study evaluators, and selection of appropriate outcome measures),
strict adherence to protocol requirements, adequately trained and
experienced study personnel, and appropriate management and analysis of
study data are critical determinants of the quality and thus, ultimate
value of a growth monitoring study. Therefore, FDA declines to require
that a growth monitoring study be conducted in at least two centers.
    (Comment 213) One comment stated that clinical trials of infant
formula should have a low attrition rate of subjects in each feeding
group (preferably below 10 percent) as well as effective blinding of
the study subjects' caregivers and study evaluators to the feeding
group, whenever feasible.
    (Response) FDA acknowledges that minimizing attrition in a growth
monitoring study is highly desirable because a high dropout rate may
introduce bias or otherwise compromise interpretation of the study
data. However, the comment did not provide a basis for the Agency to
require an attrition rate below 10 percent in an infant formula growth
monitoring study, and the Agency declines to do so. It is often
difficult to ensure a low attrition rate (e.g., below 10 percent) in
investigations, especially with infant subjects. Importantly, FDA
expects that study investigators and the manufacturer/sponsor will
thoroughly investigate and explain all dropouts. FDA intends to monitor
closely attrition rates in infant formulas growth monitoring studies
and will consider that higher than anticipated attrition rates may
signal cause for concern about the use of a particular formulation.
Thus, FDA is not making changes to the rule in response to this
comment.
    (Comment 214) One comment asserted that as the changes in formulas
become more subtle, such as through the addition of long chain
polyunsaturated fatty acids (LCPUFAs), outcome measures must include
other relevant effects such as those on visual acuity and intelligence,
which may only become measurable months to years after formula
consumption. For this reason, the comment observed that this will
require manufacturers to conduct post-marketing surveillance as a part
of every formula study.
    (Response) This comment is not relevant to the issues in this
rulemaking. The interim final rule requires a single type of study in
infants: a growth monitoring study. The purpose of a growth monitoring
study is very narrow and specific: to evaluate the bioavailability of
the infant formula, including its nutrients, that are required to be in
infant formula by section 412 of the FD&C Act to ensure that, during
the period that such formula serves as the sole source of nutrition for
infants, such infants experience normal physical growth. Contrary to
suggestion of the comment, a growth monitoring study is not designed to
evaluate whether there is a benefit of added ingredients such as
LCPUFAs like arachidonic acid (ARA) and docosahexanoic acid (DHA).
Accordingly, FDA is not responding to the comment's recommendation for
post-marketing surveillance for such purpose.
    b. Age of enrollment for a growth monitoring study.
    In 1996, FDA proposed in Sec.  106.97(a)(1)(i)(A) that
manufacturers shall ``conduct a clinical study that is no less than 4
months in duration, enrolling infants no more than 1 month old at time
of entry into the study'' (61 FR 36154 at 36215). In 2002, the Infant
Formula Subcommittee of the FDA Food Advisory Committee recommended
that infants be enrolled into clinical growth studies by 14 days of age
(http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm0), and in 2004, the
IOM recommended a duration of 6 months (180 days) for growth studies of
infants (Ref. 4, p. 10). In the 2003 reopening (68 FR 22343) and in the
2006 reopening (71 FR 43392 at 43397-43398), the Agency expressly
requested comment on the appropriate age for enrollment of infants into
growth monitoring studies.
    FDA received several comments regarding the age of subject
enrollment for growth monitoring studies.
    (Comment 215) One comment stated that there is a rationale for
including infants not older than 14 days because this early period is
the time of greatest nutrient requirement and greatest sensitivity to
nutrient adequacy. Another comment suggested enrollment by 14 days of
age in order to ensure a 4 month observation period before other foods
are introduced into the infant's diet.
    (Response) FDA agrees with the recommendations of these two
comments and thus, Sec.  106.96(b)(1) of the interim final rule
requires that subjects in a growth monitoring study be no more than 2
weeks of age at the time of enrollment. FDA included this age
requirement in the interim final rule for both data quality and
practical reasons.
    There are three data quality reasons for establishing 14 days as
the maximum age of enrollment in a growth monitoring study. First,
early infancy is the period of greatest nutritional risk and the period
during which infants experience the most rapid growth. Thus, testing a
new formulation of a formula during this time period means that the
infant formula will be evaluated under the most demanding conditions of
use. Second, the earliest days of an infant's life are the most
sensitive in that this phase includes the most dramatic (and thus most
readily measurable) growth. Thus, a study including this period would
be most likely to detect deficiencies in normal physical growth.
Finally, by enrolling study participants at age 2 weeks or less, it
will be possible to conduct a growth monitoring study of an appropriate
length before an infant begins to consume a mixed diet. Health care
professionals currently recommend adding other foods (such as cereal,
strained vegetables, pureed fruits) to an infant's diet between the
ages of 4 to 6 months. (http://www.fns.usda.gov/tn/Resources/feddinginfants-ch2.pdf). When an infant is consuming such a mixed diet,
study data are likely to be difficult to interpret because dietary
intake is less controlled.
    There is also a practical reason for establishing 14 days as the
maximum enrollment age for growth monitoring study participants. Most
health care professionals recommend that a newborn have his/her first
well-child visit at 3 to 5 days of age (Ref. 70) and another during the
second week after birth. Thus, the period of study enrollment coincides
with infant age

range for an early well-child visit which will likely enhance
recruitment of study participants and thereby, support the quality of
the growth monitoring studies conducted on new formulations of infant
formulas.
    (Comment 216) One comment stated that for routine growth studies,
infants would ideally be enrolled by approximately 14 days of age.
However, the comment further stated that there is no biological reason
why any enrollment age short of one month should disqualify an infant
from such a study and noted that in 1993, the European Commission
Scientific Committee on Food recommended subjects be entered into a
study within the first month of life.
    (Response) FDA agrees with this comment to the extent that it
suggests that subjects be enrolled in growth monitoring studies at no
more than 14 days of age. Importantly, the comment did not provide data
to support the assertion that there is no biological reason that
enrollment up to one month of age should disqualify an infant from a
growth monitoring study. In fact, as discussed previously in this
document, early infancy is the period of greatest nutritional risk and
also most rapid growth; both of these biological factors have the
potential to enhance the quality of the data generated in a growth
study.
    (Comment 217) Two comments agreed with FDA's 1996 proposal to
require study subjects to be enrolled during the first month of life.
    (Response) For the reasons outlined previously in this document,
FDA has revised the required enrollment age for the growth monitoring
study to 14 days or less, a decision based on the fact that 14 days is
the optimal age for enrollment because this age will capture the period
of subjects' greatest nutritional demand and greatest growth.
    (Comment 218) One comment stated that a study to assess the
nutritional adequacy of a formula to be fed during the first year of
life by measuring weight gain (Ref. 67) should be initiated within the
first month of life. However, if the formula is for a different age
range, the design of the study should reflect this difference.
    (Response) FDA does not agree with this comment. As explained
previously in this document, in Sec.  106.96(b)(1) of the interim final
rule, the Agency is establishing 2 weeks as the maximum age at time of
enrollment for subjects in a growth monitoring study because this age
will capture the most sensitive period of infant growth and the period
of greatest nutritional need.
    In addition, the Agency does not agree that the interim final rule
should establish a different enrollment age for a study of a formula
intended for a ``different age range.'' First, even if a product is
marketed for use in older infants, e.g. those older than 6 months of
age, the product is an ``infant formula'' within the meaning of section
201(z) of the FD&C Act and 21 CFR 105.3(e). As such, the formula must
satisfy the nutrient requirements of section 412(i) of the FD&C Act and
Sec.  107.100 and the quality factor requirements established in Sec.
106.96 of the interim final rule under section 412(b)(1) of the FD&C
Act. As noted, the appropriate age of enrollment for a study of an
``infant formula'' is 14 days or less. Second, even if a particular
product is marketed for ``older'' infants, there is a possibility that
it will be fed to neonates. For this reason, it is essential that the
formula be nutritionally adequate for these younger infants. Testing
the formula in very young infants will maximize the certainty that such
formula will be nutritionally sufficient for all infants, including
neonates. Third, as noted previously in this document, data from
studies conducted in older babies may be difficult to interpret because
such infants are likely to be consuming a mixed diet. Finally, if a
manufacturer believes that the growth monitoring study of a particular
formula should have an enrollment age other than that established in
Sec.  106.96(b)(1) of the interim final rule, the manufacturer may
request an exemption under Sec.  106.96(c)(2)(i) of the interim final
rule.
    (Comment 219) One comment asserted that the final requirement
should be more stringent than the proposed, and suggested that infants
should be enrolled in clinical studies before the end of the first
postnatal week. Another comment made a similar suggestion, stating that
the growth monitoring study should enroll infants at 8 days of age.
    (Response) FDA acknowledges that early infancy is the period of
greatest nutritional risk and the age at which the most rapid growth
occurs, both of which make this time period the most demanding
conditions for use of a formula. Although initiating a growth
monitoring study by the end of the first postnatal week or at 8 days of
age would capture a greater portion of this period, FDA is concerned
that this limit on enrollment age could unduly restrict recruitment and
participation in the required growth monitoring studies. Establishing
14 days as the maximum age of enrollment strikes a reasonable balance
between acquiring high quality data and providing flexibility to foster
recruitment of study subjects.
    c. Duration of a growth monitoring study. As noted, proposed Sec.
106.97(a)(1)(i)(A) would have required that a manufacturer ``conduct a
clinical study that is no less than 4 months in duration'' (61 FR 36154
at 36215). In its 2004 report, the IOM recommended that a growth study
should cover at least the period when infant formula serves as the sole
source of nutrients in the infant diet (Ref. 4, p. 108). Accordingly,
at that time, the Committee recommended a study of 6 months (180 days)
because such duration would mirror the recommended length of time an
infant should consume human milk exclusively. However, because current
infant feeding recommendations are to begin solid foods between the
ages of 4 and 6 months, the IOM acknowledged that it would be
difficult, as a practical matter, to convince parents of study subjects
to postpone such introduction until age 6 months. In the 2003 reopening
(68 FR 22343) and in the 2006 reopening (71 FR 43392 at 43397-43398),
the Agency expressly requested comment on the appropriate duration of a
growth monitoring study.
    In addition to the IOM recommendation, FDA received several
comments regarding the appropriate duration of growth monitoring
studies.
    (Comment 220) One comment noted that the IOM report recommended
that a growth monitoring study of an infant formula containing a new
ingredient be at least 6 months (180 days) in duration, and that this
recommendation was based on the use of formula as a substitute for
human breast milk and the current advice of the AAP that infants be
exclusively breastfed for at least 4 and, preferably, 6 months. The
comment expressed concern that the data from a 6-month study would be
confounded by the introduction and inclusion of complementary foods in
the diets of study subjects.
    (Response) FDA agrees with this comment for several reasons. First,
current recommendations are to begin solid food between the ages of 4
and 6 months. The comment noted, the IOM report acknowledged, and FDA
agrees that feeding complementary foods to study subjects could
confound the study results of a 6-month study. The IOM report also
acknowledged that it would be difficult, as a practical matter, to
convince parents of study subjects to postpone such introduction until
age 6 months. Second, the IOM report noted that it would be unlikely
that adverse effects would appear only between 4 and 6 months if none
appeared between birth and 4 months, suggesting that no

significant information on adverse effects would be lost from a shorter
study. FDA agrees with these observations and concludes that a study of
4 months duration would provide the data and information necessary for
a manufacturer to evaluate the ability of an infant formula to support
normal physical growth. Importantly, however, FDA would not discourage
an infant formula manufacturer from conducting a growth monitoring
study of 6 months' duration if the manufacturer is able to address the
potentially confounding effect of complementary food consumption during
the study period.
    (Comment 221) One comment recommended that the growth studies of
infants be conducted from 8 to 112 days of age (a time interval of 15
weeks). The comment noted that a study period of 8 to 112 days of age
would permit young infants to participate, and noted that such infants
may be the most sensitive subjects for demonstrating inadequacies of
infant formulas. The comment also observed that the period of 8 to 112
days of age has been used extensively in clinical studies of growth of
formula-fed infants and that the data from these studies have been used
to generate historical control data on gains in weight and length
during infancy (Refs. 68 and 69).
    (Response) Although enrollment at age 8 days may provide an
additional week to evaluate growth during the most sensitive growth
period, FDA finds that some flexibility is needed for the enrollment
timeframe. Section 106.96(b)(1) of the interim final rule permits
infants to be enrolled in the growth monitoring study up to age 14
days. FDA has explained its reasons for selecting 14 days as the
maximum enrollment age in responding to the comments in the immediately
previous section of this preamble.
    The Agency agrees with this comment to the extent that it
recommends a growth monitoring study of at least 15-weeks duration. As
the comment noted, the 15-week duration has been used extensively for
infant growth studies (Ref. 68), which provides a sound basis for
choosing this period for the growth monitoring studies required by this
interim final rule. Also, 15 weeks is a reasonable study duration
because this period maximizes the time between enrollment (2 weeks of
age) and the age at which many infants begin to consume a mixed diet
(17 weeks or 4 months). As explained previously in this document, the
consumption of a mixed diet by study subjects may complicate
interpretation of the study results regarding the nutritional
sufficiency of the test formula because, with a mixed diet, the formula
is no longer the sole source of nutrition for the infant. Accordingly,
FDA has revised the interim final rule to require a growth monitoring
study to be at least 15 weeks in duration.
    (Comment 222) One comment recommended that, as an alternative, a
growth study be at least four months in duration, enrolling infants at
no more than one month of age. The comment noted that a 4-month study
period permits a slightly longer period of observation (as compared to
a 15-week study) and would provide greater ease of subject recruitment.
    (Response) FDA disagrees with this comment and notes that this
alternative suggestion is what the Agency proposed in 1996 in proposed
Sec.  106.97(a)(1)(i)(A). FDA has concluded that the appropriate
duration for a growth monitoring study is 15 weeks and that study
subjects should be no more than 14 days old at the time of enrollment.
The Agency's reasons for these determinations are explained in its
response to the foregoing comments.
    (Comment 223) One comment stated that growth studies are usually
conducted for 14 weeks (98 days), with subjects participating from
approximately age 14 days until age 112 days (i.e., from 2 to 16 weeks
of age). The comment also noted that in 1993, the European Commission
Scientific Committee on Food proposed a study period of at least 3
months to evaluate the nutritional adequacy of infant formula.
    (Response) FDA disagrees with this comment to the extent that it
recommends a study of 14 weeks. Although the comment asserted that
growth studies are ``usually'' of 14 weeks duration, the comment
provided no data or other rationale to support the validity or
sufficiency of this length of a growth monitoring study. FDA has
determined that a 15 week study requirement is reasonable for the
reasons provided in previous comment responses.
    (Comment 224) One comment asserted that selection of 16 weeks or 3
months, or 4 months as originally proposed by FDA, are based on
convenience and current well-baby visit schedules and not based on the
scientific assessments of sensitivity, validity, or the relationship of
growth over this period to health.
    (Response) FDA disagrees with this comment. As explained in the
response to Comment 221 the 15-week study duration maximizes the time
during which study subjects are likely consuming the formula as the
sole source of nutrition. Once study subjects begin to consume a mixed
diet, the resulting data are more difficult to interpret because it is
not possible to distinguish between the nutritional effects of the
formula and the nutritional effects of the remainder of a subject's
diet, thereby hampering the accurate assessment of the nutritional
sufficiency of the formula.
    (Comment 225) One comment recommended that growth studies of infant
formulas would ordinarily require testing through 8 to 12 months of age
in order to evaluate the formula throughout the period that it serves
as the only or main source of calories. Another comment stated that
because infant formula is given to babies from birth until 12 months of
age, 12 months is the appropriate duration of time for a study.
    (Response) FDA disagrees with these comments. In order to perform
an accurate assessment of the nutritional adequacy of an infant
formula, there must be no competing or supplemental sources of
nutrition consumed by the study subjects. That is, if the study
subjects are consuming other foods, any results showing normal physical
growth may be attributable to the other foods and not to the infant
formula. For this reason, proposed Sec.  106.97(a)(1) stated that the
growth monitoring study must determine whether the formula supports
normal physical growth ``when the formula is fed as the sole source of
nutrition.'' As explained previously in this document, health care
professionals generally suggest that infants begin to consume a mixed
diet sometime after 4 months of age. Thus, it would be difficult if not
impossible to conduct a growth study with subjects 8 to 12 months of
age without including infants on a mixed diet and thereby, compromising
the study results. Also, physical growth rates slow after early
infancy, thereby resulting in a less sensitive measure to detect
differences in the ability of an infant formula to support normal
physical growth.
    (Comment 226) Another comment stated that studies should extend for
years rather than months to detect the subtle effects of formula
feedings.
    (Response) FDA has considered whether extending the duration of
growth monitoring studies to 12 months or longer has merit and has
concluded that it does not. The rate of physical growth in infants
slows after early infancy, thereby resulting in a less sensitive
measure to detect differences in the capability of a new formulation of
an infant formula to support normal physical growth. Also, consumption
of foods other than infant formula (typically started at about 4 to 6
months

of age) has the potential to confound the growth monitoring study
results from beyond the period when infant formula is consumed as the
sole source of nutrition.
    Based on the foregoing, FDA is redesignating proposed Sec.
106.97(a)(1)(i)(A) as Sec.  106.96(b)(1) in the interim final rule and
revising the provision to require a growth monitoring study that ``[i]s
no less than 15 weeks in duration, enrolling infants no more than 2
weeks old at the time of entry into the study;''.
    d. Review by institutional review board and protection of human
subjects. In the 1996 proposal, FDA recommended in proposed Sec.
106.97(a)(1)(ii)(C) that the study conducted under proposed Sec.
106.97(b) be reviewed by an IRB in accordance with 21 CFR part 56 and
that the manufacturer establish procedures to obtain informed consent
from the parent or legal representative of each study participant.
Thereafter, in the 2003 reopening (68 FR 22341 at 22343), FDA proposed
to delete the provisions relating to IRB review and informed consent
due to an independent FDA rulemaking (66 FR 20589, April 24, 2001), one
effect of which was to make an infant formula growth monitoring study
subject to the requirements of parts 50 and 56. Specifically, under
parts 50 and 56, data and information about a clinical study of an
infant formula, when submitted as part of an infant formula
notification under section 412(c) of the FD&C Act, constitute an
``application for research or marketing permit'' and thus, are subject
to the informed consent and IRB requirements related to such permits in
parts 50 and 56. Accordingly, as proposed in the 2003 reopening, FDA is
not including provisions relating to IRB approval and human subject
protection in the interim final rule because such provisions are
unnecessary as the requirements are codified in parts 50 and 56.
4. Collection and Evaluation of Anthropometric Data
    In 1996, FDA proposed to require that a growth monitoring study
include the collection of anthropometric measures of physical growth,
including body weight, recumbent length, head circumference, and
average daily weight increment. Under the 1996 proposal, the
anthropometric measurements would have been required at the beginning
of the study, at 2 weeks, at 4 weeks, and at least monthly thereafter.
Subsequently, in the 2003 reopening, FDA requested comment on whether
certain Iowa data (which were discussed at the November 2002 meeting of
FDA FAC's Infant Formula Subcommittee) should serve as the comparison
for the anthropometric data collected during a growth monitoring study
(68 FR 22341 at 22342-22343).
    In addition, in the 2006 reopening, in response to a recommendation
in the IOM report, FDA requested comment on whether the Agency should
require body composition measurement in a growth monitoring study
conducted under the interim final rule. At that time, FDA stated its
tentative conclusion that measures of body weight, recumbent length,
head circumference, and data to calculate average daily weight
increment would be adequate to assess the quality factor of normal
physical growth (71 FR 43392 at 43397).
    In 1996, FDA also proposed that the anthropometric data be plotted
against 1977 reference curves (``growth charts'') from the National
Center for Health Statistics (NCHS). The 1977 NCHS growth charts were
substantially revised in 2000 and were referred to as the 2000 CDC
growth charts (Ref. 72).
    In 2006, WHO released a new international growth standard for
children ages birth to 59 months that reflects normal physical growth
for all infants and children. For infants and children less than 24
months of age, the WHO standard includes charts based on measurements
of weight for age, length for age, weight for length, and head
circumference (Ref. 11). Thus, after 2006, two sets of growth charts,
the 2000 CDC growth charts and the 2006 WHO growth standards, were
available for assessing early childhood growth. On September 10, 2010,
CDC formally announced its recommendation that the WHO growth standards
be used to plot the growth of infants and children from birth to 24
months of age (published in November 2009).
    The WHO growth standards are based on a high quality comprehensive,
longitudinal, world-wide study conducted in healthy women and their
breast-fed infants and included subjects from six countries, including
the United States, drawn from different ethnic and racial populations.
Anthropometric measurements of the infants were obtained at birth and
five additional times between birth and 8 weeks of age. CDC considered
the WHO study design and results, and conducted expert consultations
with National Institutes of Health and the AAP, and determined that the
longitudinal measurements of the WHO study provide the best available
information on which to base growth curves, rather than the
mathematical modeling used to develop the 2000 CDC growth charts. CDC
described these WHO growth standards as providing the standard for how
infants and children (birth to 24 months) should grow regardless of the
type of feeding.
    The interim final rule incorporates the new CDC recommendation.
Specifically, Sec.  106.96(b)(4) of the interim final rule requires
that the anthropometric measurements obtained in a growth monitoring
study be plotted on the 2009 growth charts recommended by the CDC based
on the WHO Child Growth Standards (2009 CDC growth charts), as
incorporated by reference in Sec.  106.160 of the interim final rule.
This is a reasonable outcome for the interim final rule for two
reasons. First, it is appropriate for FDA to defer to CDC's
recommendation on this issue as CDC is the relevant authoritative
public health Agency. Second, the basis for the CDC's recommendation is
sound scientifically and is one with which FDA agrees. In particular,
the WHO Child Growth Standards, on which the 2009 CDC growth charts are
based, are derived from a longitudinal study of a number of diverse
populations with relatively frequent growth measurements. As such, the
2009 CDC growth charts describe growth of healthy children under
optimal conditions whereas the 2000 CDC charts describe how certain
children grew in a particular place and at a particular time (Ref. 11).
    a. Measuring body composition.
    (Comment 227) One comment recognized that there may be occasions in
which an assessment of body composition might be appropriate but did
not further elaborate what those occasions might be.
    (Response) FDA notes that this comment did not explain when or why
body composition measurements are needed to assess normal physical
growth. Thus, FDA is not revising the rule in response to this comment.
    (Comment 228) One comment disputed the IOM's recommendation to
measure body composition as part of the assessment of normal physical
growth. The comment asserted that body composition is not easily
measured in newborns and young infants and there are few references or
standards. The comment also claimed that there is potential for a great
deal of error with such measurements and that some methods of
measurement would require infants to be exposed to radiation, which
would be unacceptable. Two other comments stated that sufficient
reference data for infant body composition do not exist.
    (Response) FDA agrees with these comments. The Agency has
considered

whether body composition measurements should be required as a means to
assess physical growth and has concluded that such measurements should
not be required because these measurements are not easily made in
newborns and young infants. In addition, as the comment noted,
references and standards are lacking, which means that even if the
measurements could be readily made, it would be difficult to assess
their significance. Also, as suggested in the comment, some risk is
associated with any radiation exposure (Ref. 71). Without an
established need for body composition data and a sound means to assess
their significance, FDA concludes, that, at this time, any risk from
the use of radiation in healthy newborns and young infants would not be
justified.
    (Comment 229) One comment asserted that facilities and equipment
for body composition measurement are not standardized and are not
readily available, which would make it more difficult to conduct growth
monitoring studies, and including such a requirement would add to the
cost of such studies.
    (Response) The comment did not include any data to support its
assertions about facilities and equipment availability to measure
infant body composition and FDA is not independently aware of such
availability information. The Agency has concluded, in view of the
challenge of making these measurements, the problems with measurement
accuracy, and the lack of suitable reference standards, not to require
body composition to be measured in growth monitoring studies conducted
under this interim final rule. Therefore, the interim final rule will
not require the growth monitoring study to include body composition
measurements.
    b. Collection and maintenance of appropriate anthropometric data.
    Several comments addressed the specific anthropometric measurements
identified in proposed Sec.  106.97(a)(1)(i)(B) to assess physical
growth, including a number of comments supporting the Agency's proposed
use of body weight, recumbent length, and head circumference for such
purpose.
    (Comment 230) One comment requested that recumbent length
measurements be excluded from the study requirements because such
measurements in young infants may involve considerable error. The
comment recommended that recumbent length continue to be measured as
part of the standard growth protocol, allowing for calculation of BMI
and some body composition measures as needed, but that these data not
be routinely reported to the Agency.
    (Response) FDA disagrees with this comment. As noted in the 1996
proposal (61 FR 36154 at 36183), ``[g]ains in weight and length of
young infants reflect the long-term, integrative physiological
processes that can only be achieved if the infant's nutritional needs
are met.'' Accordingly, recumbent length, along with head
circumference, provides a valuable context for interpreting weight
change data. Changes in length and head circumference data provide
especially valuable information for interpretation of the weight change
data in those situations in which weight change with a test formula is
significantly different than the weight change attained with the
control formula. Also, careful training of the persons who make the
recumbent length measurements will help to minimize errors. Therefore,
FDA is not removing the requirement to make recumbent length
measurements in response to this comment.
    (Comment 231) Several comments recommended the exclusion of head
circumference measurements, claiming that head circumference is not
responsive to small changes in nutritional status citing the conclusion
of the 1988 CON/AAP consultation (Ref. 67).
    (Response) FDA disagrees with this comment. As noted, recumbent
length and head circumference provide a valuable context for
interpreting weight change data. The conclusion of the CON/AAP
consultation (Ref. 67), cited as support by the comment, applies to a
situation in which no significant difference is observed in weight
change. Head circumference measurement may not be as responsive as body
weight as an indicator of nutritional status. However, because such
measurements can be routinely made, are not invasive, require no
specialized equipment, and are not expensive, the value of head
circumference measurements outweighs any risk or cost of collecting
these data.
    (Comment 232) One comment asserted that the most sensitive method
of evaluating infant growth is a comparison of increments in recumbent
length and body weight over time (e.g., millimeters/day or grams/day)
rather than comparison of absolute size (e.g., length (centimeters) or
absolute weight (grams)) at a given age. The comment identified what it
characterized as suitable reference data (Refs. 68 and 69) for
evaluation of incremental changes in weight and length.
    (Response) FDA agrees that body weight and rates of change in body
weight are useful measures of changes in body mass in the newborn and
the young infant, and that recumbent length and head circumference
measurements provide information for interpreting these weight change
data. In the 1996 proposal, the Agency proposed to require in Sec.
106.97(a)(1)(i)(B) that data on ``average daily weight increment'' be
collected and maintained as part of the growth monitoring study. At
that time, however, the Agency did not propose to require the
collection and maintenance of incremental recumbent length data. FDA
agrees with this comment that incremental gains for both body weight
and recumbent length provide sensitive comparisons of anthropometric
growth measurements in young infants. For this reason, the Agency
expects that these calculated values will be part of a manufacturer's
analysis of its growth monitoring study on a new formulation of an
infant formula. Accordingly, Sec.  106.96(b)(2) of the interim final
rule requires that a growth monitoring study include the collection and
maintenance of data on anthropometric measures of physical growth,
including body weight, recumbent length, head circumference, average
daily weight increment, and average daily recumbent length increment.
    c. Schedule for and frequency of anthropometric measurements.
    Section 106.97(a)(1)(i)(C) of the 1996 proposed rule would have
required that the anthropometric measurements in the growth monitoring
study be collected at the beginning of the study, at 2 weeks, at 4
weeks, at least monthly thereafter, and at the study's conclusion. The
Agency received a number of comments on this proposed requirement.
    (Comment 233) One comment requested that proposed Sec.
106.97(a)(1)(i)(C) be deleted and recommended that the frequency of
body weight measurements be addressed in guidance and not in the
regulation.
    (Response) FDA disagrees with this comment. It is important to
specify the frequency and the schedule for anthropometric measurements
in the growth monitoring study. This will ensure that the study data
will be of sufficient quality to evaluate whether the new formulation
of the infant formula supports normal physical growth. As noted
earlier, Agency guidance is not binding and thus, even if the frequency
of the measurements was specified in guidance, a manufacturer would be
free to establish a schedule and frequency of anthropometric
measurements that

deviated from the Agency's best thinking. As a result, the study data
may not provide an adequate basis for evaluating the formula's ability
to support normal physical growth.
    (Comment 234) One comment stated that the proposed frequency of
measurement is unnecessarily burdensome to parents facilitating their
infants' participation in the growth studies because several of these
times do not coincide with a regularly scheduled well-baby visit. The
comment further asserted that clinical studies of new formulas are
often delayed because it is difficult to recruit sufficient numbers of
participants. The comment included a study design schematic that
illustrated the recommended frequency for anthropometric data
collection as follows:

                                             Study Design Schematic
----------------------------------------------------------------------------------------------------------------
                                            Scheme of data collection
-----------------------------------------------------------------------------------------------------------------
                               Enrollment    14 days of    28 days of    56 days of    84 days of    112 days of
                                visit \1\      age \2\       age \2\       age \2\       age \2\       age \2\
----------------------------------------------------------------------------------------------------------------
Enrollment/Randomization....            X   ............  ............  ............  ............  ............
Demographic Data............            X   ............  ............  ............  ............  ............
Weight, Length..............            X             X             X             X             X             X
Interval History............  ............            X             X             X             X             X
Adverse Events..............            X             X             X             X             X             X
----------------------------------------------------------------------------------------------------------------
\1\ Date of Birth is Day Zero of life (enrollment 0-14 days of age); enrollment may be on day 14 of age visit.
\2\ Visit window  3 days.

    (Response) In the 1996 proposal, FDA addressed the timing and
interval between measurements (61 FR 36154 at 36184). FDA proposed that
more frequent anthropometric measurements, especially early in the
study, would enhance the study's ability to document physical growth
changes by measuring growth during the most rapid, and thus, the most
sensitive, phase of an infant's growth; this would increase the ability
to place individual infants accurately in the correct percentile to
track their growth patterns over time. In proposing the measurement
schedule in Sec.  106.97(a)(1)(i)(C), the Agency intended to have
sufficient serial measurements for comparison between study groups and
to derive reliable estimates of centile pattern growth and estimates of
growth rates based on measurements over the entire study period. This
proposed measurement schedule would accurately capture the curvilinear
nature of infant growth and would provide sufficient data to interpret
differences in growth and in growth rates, if differences exist.
    Accordingly, FDA disagrees with the comment recommending fewer
measurements in the early portion of a growth monitoring study. The
approach recommended by this comment proposes only five measurements
for the period between 14 and 112 days of age, with only two
measurements proposed for the first 4 weeks of the study. Importantly,
no data were submitted with this comment to support the adequacy of
fewer measurements for evaluating the curvilinear nature of growth in
young infants. As noted previously in this document, the most rapid
phase of infant growth, and thus, the most sensitive period for
detecting perturbations in growth, is the earliest weeks of an infant's
life. Thus, it is critical that the anthropometric measurements be
concentrated in this time period. As noted in this document, the
interim final rule requires in Sec.  106.96(b)(3) that anthropometric
measurements be collected at the beginning of the study (maximum age of
2 weeks), 2 weeks into the study (maximum age of 4 weeks), and 4 weeks
into the study (maximum age of 6 weeks), which will result in
relatively more data from the earlier stages of an infant's life.
    (Comment 235) One comment recommended that clinical studies of
infants be conducted from 8 to 112 days of age with collection of
anthropometric measurements at ages 8, 14, 28, and 42 days (2 days) and at ages 56, 84, and 112 days (4 days).
This alternative schedule was recommended because, the comment
asserted, it would match the measurement schedule of many reference
(historical) data.
    (Response) The alternative suggested in this comment would result
in seven measurements over a roughly 15-week study period, with more
frequent measurements during the early phase of the study, starting at
8 days of age. However, as discussed previously in this document, the
Agency is establishing 14 days as the maximum age of enrollment to
provide flexibility to foster recruitment of infants. Therefore, FDA is
not persuaded by the information provided in the comment that the
interim final rule should require enrollment by 8 days of age.
    FDA's concerns with the use of historical data as controls are
addressed previously in this document in the response to Comment 208.
FDA agrees that some degree of flexibility in the timing of the serial
measurements throughout the study is a reasonable design feature for
the growth monitoring study. Thus, the interim final rule requires
that, over the minimum 15 week study period needed to assess whether an
infant formula supports normal physical growth, anthropometric
measurements shall be made at the beginning and end of the study, with
three of the six total measurements made within the first 4 weeks of
the study and three measurements made at approximately 4-week intervals
over the remaining 11 weeks of the study. Therefore, proposed Sec.
106.97(a)(1)(i)(C) is renumbered as Sec.  106.96(b)(3) in the interim
final rule and is revised to require the growth monitoring study of
normal physical growth include ``anthropometric measurements made at
the beginning and end of the study, and at least four additional
measurements made at intermediate time points, with three of the six
total measurements made during the first 4 weeks of the study and three
measurements made at approximately four-week intervals over the
remaining 11 weeks of the study.''
    To ensure the detection of biologically significant differences
between test and control groups, if they exist, it is important that
investigators make a diligent effort to take anthropometric
measurements on infants consuming the test formula at the same ages as
the measurements for the concurrent or historical control groups. FDA
recognizes that investigators may not always be able to collect
clinical data on all infants on the same day of age. FDA plans to
address this need for flexibility while maintaining the scientific
integrity of the study in future guidance.
    d. Comparison of anthropometric data.

    As noted previously in this document, in 1996, FDA proposed to
require that anthropometric data collected during a growth monitoring
study be plotted on the 1977 NCHS reference percentile body weight and
length curves and proposed to incorporate by reference the 1977 NCHS
growth charts. The Agency subsequently requested comment on whether
certain Iowa data should serve as the comparison for anthropometric
data collected during a growth monitoring study.
    FDA received a number of comments on the collection and comparison
of anthropometric data in a growth monitoring study. The Agency
responds to those comments in this document.
    (Comment 236) One comment stated that, in general, the use of
growth curves and historical databases are considered references, not
standards.
    (Response) FDA agrees in part with this comment, which reflects the
information available at the time of the two comment period reopenings.
Until the WHO growth standards, upon which the 2009 CDC growth charts
are based, became available, growth charts (including the 2000 CDC
charts) were references that reflect how children in the United States
have grown, and were not a standard of how children should grow.
    The Agency believes, however, that this comment misunderstood FDA's
use of the term ``standard'' in the 2003 reopening. In the 2003
reopening notice, the Agency requested comment on whether the Iowa
reference data ``should be the standard for clinical growth data rather
than the NCHS growth charts (68 FR 22341 at 22342-22343).'' In this
instance, FDA intended the term ``standard'' to refer to a set approach
of data evaluation and not to describe the growth charts.
    (Comment 237) One comment suggested that new formulations of infant
formula be tested by comparison to a control group of the same
population receiving an appropriate control formula, rather than by
comparison with standard curves, in accordance with proposed Sec.
106.97(a)(1)(i)(B), because the curves are not considered accurate for
all ethnic groups.
    (Response) FDA believes that this comment did not fully understand
the requirements of the proposed rule because the proposed rule would
have required, and this interim final rule requires, that the growth
monitoring study be an adequate and well-controlled study, which
includes concurrent controls. (The issue of concurrent versus
historical controls is addressed previously in this document in section
VIII.C.3.a. As noted in that discussion, a manufacturer that wishes to
use historical controls in a growth monitoring study may request an
exemption under Sec.  106.96(c)(2)(i) of the interim final rule to do
so.) FDA notes that the use of historic controls may be problematic
because the current study population would need to be matched to the
historic controls, which may not be possible. Thus, the anthropometric
data collected in a growth monitoring study will be required to be
compared to a concurrent control group as well as to the standard
reference data in the 2009 CDC growth charts.
    FDA also notes that although the comment asserts that an
appropriate concurrent control group needs to be composed of the ``same
population'' as the infants consuming the test formula, the comment
neither elaborates on the ``same population'' concept nor provides data
or other information to support its assertion. Indeed, a clinical
investigation is ``well-controlled'' only if the control group is
appropriate to the purpose of the study. Thus, FDA expects that the
report of a growth monitoring study will address the appropriateness of
the selected control group. In addition, the interim final rule's
requirement to use the 2009 CDC growth charts will address the concern
expressed by this comment because, as discussed previously in this
document, the WHO growth charts are based on data from six countries
from different parts of the globe.
    (Comment 238) One comment asserted that plotting anthropometric
data from a growth monitoring study on CDC ``growth'' charts
contributes little to the evaluation of the results.
    (Response) FDA disagrees with this comment. Given the timing of the
submission of this comment, the commenter is likely referencing the
2000 CDC growth charts. In 1996, FDA proposed that the anthropometric