data were still needed for pediatric labeling. The
FDA has issued an annual list of ‘priority drugs’ for
which additional pediatric information may be
‘beneficial’.
FDA chose to interpret the patent life extension
as applying to all indications, not just to pediatric
use. As might be expected, the generic companies
continue to appeal this interpretation of the pedia-
tric rule.
17.3 1994 and 1998 final
rules on pediatric studies
(Federal Register,
1994, 1998)Products subject to the rule
For drugs that are new molecular entities (NMEs),
a determination should be made by the sponsor of
the potential usefulness of the new drug in a pedia-
tric population. If it is likely to generate over
100 000 prescriptions per year, this would indicate
the need to develop a pediatric formulation and
suitable pediatric studies. If it is likely to generate
less than 50 000 prescriptions per year, the sponsor
may be granted a waiver by the FDA for pediatric
data, and a disclaimer statement allowed. Either
way, in a children’s disease, if less than 200 000
patients per year may benefit, then orphan-drug
status with 7 per year exclusivity may be applic-
able. This would then apply only to that pediatric
indication.
The requirements of the Pediatric Final Rule
now includes marketed drugs and biologics. The
FDA has already listed products affected and sent
pediatric data requests to firms. The firms had until
April 2001 to provide the extra data.
Data to be provided
If considerable data exist, or are planned, for
same indications in adults, it may be appropriate
to extrapolate safety and efficacy from adults to
children. But pharmacokinetic (PK) studies to
determine dosing and, if possible, pharmacody-
namics data, will usually be required for children.
DiscussionwiththeFDAisrecommendedearly on,
to establish whether pediatric data will be required
and which of the five groups should be covered
preterm 37 weeks gestation; neonate, 0–1 month;
infants, 1–2 years; children, 2–12 years; and ado-
lescents, 12–16 years). One or more adequately
sized efficacy and safety studies may be required,
especially if the drug or disease behaves differently
in children, or the drug uses different metabolic
pathways. This may occur if the particular adult
enzyme is not present in children, or is only present
in low quantities. If a different indication to that in
adults is being sought, then one or two sizable
safety and efficacy studies, in one or more age
groups, are likely to be required. This is in addition
to pediatric PK data. Sponsors should also plan for the
major ethnic groups to be represented in these studies.
Frequently, the FDA may allow a waiver or
approval of a drug with incomplete pediatric data
and defer the completion to a phase IV commit-
ment,especially whenthe productis life saving and
the only treatment available.17.4 Major physiologic
variations in pediatricsIn the past, the statement that ‘children are not little
people’ dominated research thinking. In general,
both in children and in the elderly, drugs and
biological products behave similarly to that in the
18–65-year-old population, although this expecta-
tion must be adjusted for age-related differences
in PK variables, such as immature or aging
enzyme metabolism systems as well as elimination
rates affected by immature or aging organs of
excretion.
In neonates, the gastric pH is biphasic, being
high in the first few days after birth and decreasing
by day 30, but it takes 5–12 years for the adult
pattern and value to emerge (Signer and Fridrich,
1975). On the contrary, the methylation pathway,
unimportant in adults, is well developed in chil-
dren. Furthermore, acetaminophen is less toxic to
children than to adults, probably because it utilizes
the sulfate metabolic pathway (Rane, 1992).17.4 MAJOR PHYSIOLOGIC VARIATIONS IN PEDIATRICS 225