There are fewer patients affected with pediatric diseases or conditions and trial designs reflect this pragmatic recognition of what is reasonable to expect versus what may be ideal.
WHY PEDIATRIC STUDIES AND A
SPECIAL FOCUS ON SAFETY REPORTING ARE NECESSARY?
In
addition to reasons outlined in other chapters of this book as to why some
safety issues are not identified until after a product has been approved and
on the market (postmarket), there are seven aspects of pediatric drug
development and use which contribute to the probability a safety signal may not
be identified in the pediatric population until postmarketing.
The
first of these aspects is the relatively small number of pediatric patients who
are often involved in pediatric trials. There are fewer patients affected with
pediatric diseases or conditions and trial designs reflect this pragmatic
recognition of what is reasonable to expect versus what may be ideal.
·
Children are less frequently involved in early phase 1
pharmacokinetic and safety and phase 2 dose-finding and safety studies. This
means development of larger phase 3 pediatric trials may be based on
information obtained in adults and some pharma-cokinetic studies in pediatrics.
·
There is intrinsic variation that exists across pedi-atric
age groups. Product development programs in pediatrics specifically focus on
attempting to iden-tify appropriate changes in dosing due to differ-ences in
absorption, metabolism, distribution and elimination in the various pediatric
age groups. As a result of these differences, one subpopulation of pediatrics
may be more or less likely to experience higher levels and/or differences in
response to a therapy. Again, because the numbers become very limited when
dealing with a subpopulation in pedi-atrics, it becomes even more difficult to
ascertain the real frequency of an adverse event prior to its use in a larger
postmarketing population.
·
There is extensive off-label use of products within the
pediatric population. This off-label use encom-passes both use in pediatric
subgroups which have not been studied for an indication obtained in one
pediatric subgroup, and for other indications which have not been studied in
any or most pediatric subgroups, but are marketed for adults.
·
Children have unique exposures through pre-natal (in-utero
exposure) and breast milk. Breast-milk exposures are not routinely evaluated
for effects on the child. Animal models are utilized to attempt to determine
teratogenicity of a product but have limi-tations as to identification of
long-term outcomes not associated with being a teratogen.
·
Because of a lack of pediatric-appropriate formu-lations,
there is frequent use of compounded or extemporaneous preparations which are
usually not tested for bioavailability, drug–drug or drug– food interactions
and may contain excipients with unknown risks thereby increasing the potential
for errors in dosing, delivery and adverse events.
·
The growing and evolving nature of children requires
attention to potential effects on physical growth, puberty, cognition, and
other developmen-tal parameters. Most studies in children are directed to
defining the safety and efficacy of a product for a condition during a certain
age or develop-ment time frame. No one realistically expects that one can study
all the possible adverse effects a product used at one stage of development may
have on all latter stages of a child’s development. Recognizing a product may
have delayed effects on growth, puberty, behaviour, development and cognitive
abilities, there is a clear need to develop focused, long-term studies and
surveillance which involve follow-up directed at answering questions regarding
the potential longer-term effects of some therapies.
All
of these pediatric-unique issues increase the need for specific, focused,
active postmarketing pediatric surveillance systems.
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