These additional costs for pediatric studies may
be justified if these studies satisfy all global mar-
kets. MacLeod (1991) estimated that ‘developing
countries’ by the year 2000 will comprise 36% of
the total pharmaceutical market and that half of
their populations are children (accounting for 18%
of the market). In the developed countries, children
under 18 years account for 20% of the market. It
would seem that the 38% pediatric share of the
global market is worth an extra effort.
17.2 Children, the therapeutic
orphansThe Food, Drug and Cosmetic Act, first passed
in 1906, was dramatically altered by the 1962
Kefauver–Harris amendments as a direct result of
the thalidomide tragedy. This amendment required
that drugs must be both safe and effective before
marketing approval could be given. In addition,
adequate animal, toxicology and fertility testing
had to be concluded prior to the first dose in
humans. Substantial additional testing in animals
and in humans was required prior to marketing
approval. This led to the era of the Science of
Clinical Trial Design. Regrettably, the testing of
drugs in children did not advance at a similar pace,
and most drugs (unless specifically intended for
children) were never tested in children by the
sponsors of new medicines.
Physicians were thus forced to use most drugs
‘off-label’ and extrapolate the child dose on a
comparative weight basis from that in adults.
This often involved parents splitting or crushing
tablets, hiding medication in spoonfuls of honey or
sprinkling a crushed tablet onto a meal. Each time
this happened, a little more confidence in and
knowledge of the drug was gained, but each child
was a ‘one-off experiment’ and only provided a
learning curve for the individual physician. Even-
tually, academia would publish a series of cases, so
giving guidance on dosing and likely toxic effects.
Even so, the average pediatrician and family prac-
titioner felt uneasy and legally vulnerable about
off-label use.
A few drugs were developed for children in such
categories as antibiotics, antihistamines and
antiepileptics. But otherwise, few firms undertook
studies to develop full pediatric label instructions
or even pediatric formulations. Liquid formula-
tions did exist for some drugs, but mainly for use
in the elderly. In 1975, Wilson surveyed the 1973
Physician’s Desk Reference for labeling instruc-
tions for pediatric patients and pregnant or breast-
feeding women. He found that 78% of listed drugs
either had no information for pediatric dosing or
contained a disclaimer. A subsequent survey by
Gilman and Gal (1992) showed that this situation
had not improvedqualitativelyand had also risen to
81%. Eventually, the FDA issued the 1994 rule,
which sought to strengthen the 1979 guideline on
pediatric labeling requirements (Federal Register,
1994).
The Pediatric Use Working Group, chaired by
Miriam Pina (1995) (FDA Division of Pulmonary
Drugs) examined the data that the FDA had
acquired on 1994 pediatric prescriptions from
IMS. From these they identified the top 10 drugs
used ‘off-label’ in children: Albuterol, Phenergan,
Ampicillin i.m. or i.v., Auralgan otic solution,
Lotison, Prozac, Intal, Zoloft, Ritalin (under six
years) and alupent syrup (under 6). A combined
total of over 5 million of these 10 products were
prescribed in 1994.
Clearly, firms needed further encouragement to
submit additional pediatric data, so in 1997 Con-
gress passed the FDA Modernization Act
(FDAMA). This called for firms to submit data
on children to support labeling for a new pediatric
subsection before the drug could be approved. This
applied to drugs that could be projected to provide
therapeutic benefit to substantial numbers of chil-
dren. In exchange, Congress felt that an induce-
ment was required and wrote into the Act provision
for an extension of a drug’s patent life by six
months if pediatric studies were done. For a $4
billion drug such as Claritin (Loratidine) six
months’ extra exclusivity is not ‘small change’.
The FDA was requested to provide guidance and,
in December 1998, it issued the Final Rule
Amendments to the Pediatric Subsection $ to be
implemented April 1999, governing the need for
pediatric studies, and extending the requirements
to biological drugs and already-marketed drugs.
The FDA identified drugs for which supplemental224 CH17 CLINICAL RESEARCH IN CHILDREN