7.3
Pharmaceuticals and children
See Background Chapter 7.3
Children are subject to many of the same diseases as adults and are often treated with
the same medicines. However, many of the medicines used in children are either not
licensed for this age group or are prescribed outside the terms of the medicine licence
(‘off-label’). Unlicensed medicine use in children ranges from 25% to 50% and off-label
medicine use ranges from 15% to 40%. 1 , 2 Where the medicine licence contains
statements such as “no evidence for use in children”, this does not necessarily mean
that the medicine is unsafe for use in children, but clearly indicates the absence of data
for its use in this patient group.
Doses for children are often merely adjusted for their smaller weight. However, there
are many other differences in children that can affect how medicines act in the body.
Children not only differ in pharmacokinetic and pharmacodynamic aspects, but also in
adherence to therapy and other factors that influence the effectiveness of medicine use.
Despite this, prescriptions for children are often not based on sound scientific evidence.
Because of the lack of paediatric licensing, there are only a few paediatric formulations
and adult dosages have to be converted to the appropriate paediatric dosage. However,
unlicensed and off-label medicine use increases the risk of miscalculating doses and
induces a higher rate of adverse reactions to medicines.3 Moreover, the intake of adult
medicines is not a very pleasant experience for children. New or adapted formulations
for children may improve administration and as a result improve patient adherence to
therapy (e.g. paediatric HIV therapy).
In addition to the research gaps on paediatric dosing and formulations, there are three
other important considerations related to medicine use in children:

Data needed for effective and safe use of medicines in children and adolescents
cannot be linearly abstracted from adult data. Unlicensed and off-label use of
medicines in children are essentially regulatory observations; these
observations should lead to specific paediatric clinical and pharmaceutical
follow-up.

There is increasing recognition that certain paediatric morbidities are specific to
childhood (e.g., neonatal respiratory problems, paediatric cancers); other conditions require more specific medicine formulations and/or dosing schemes.

Certain childhood morbidities are very often 'early signatures' for severe and
chronic adult diseases (e.g., wheezing/childhood asthma and chronic
respiratory diseases later in life, childhood obesity and diabetes/cardiovascular
problems, paediatric mental problems and severe adult psychiatric morbidities).
Accurate diagnosis and treatment at an early age are essential prevention
strategies in order to reduce adult disease burden.
Therefore, specific research is needed on the use of medicines in children. However,
there are several obstacles to this. First, when medication is used unlicensed or off-label,
there are no data available on effectiveness, safety, dosage or toxicity. Second, some
diseases only occur in children (for example, certain forms of leukaemia, juvenile
arthritis) and medicines for treatment must be investigated in children. Conducting
paediatric trials is difficult, not only because the patient population is low, but because
of ethical issues relating to the use of placebos and legal issues relating to liability.
Third, pharmaceutical companies do not often perform paediatric studies on medicines
which they intended to market primarily to adults, mainly because — despite various
governmental incentives — these medicines would provide little additional revenue
from use in children. There seems to be little incentive for medicine sponsors to
conduct paediatric research on off-patent medicines — a category which includes
many of the medicines which are widely used in children but which lack paediatric
information in their labelling.
There is a very important interaction between the regulatory environment and
paediatric medicines research in the USA and Europe. The U.S. FDA has developed a
number of initiatives to obtain more information on paediatric use of medical products.
The Paediatric Labeling Rule in 1994 resulted in The Best Pharmaceuticals for Children
Act (BPCA) in 2002.4 This law provides an additional six months' market exclusivity for
companies that are willing to test their medication voluntarily in children.
There are also important European initiatives commissioned by the EMEA. A
European guideline on paediatric clinical trials has been in force since July 2002 and a
Directive on Good Clinical Practice was adopted that takes into account some specific
concerns on performing clinical trials in children. However, these European initiatives
do not have the force of law and merely encourage the pharmaceutical industry to
investigate the use of medicines in children. Thus, the US pharmaceutical industry has
more incentive to conduct paediatric medicine studies than does the industry in
Europe. To reduce this gap, the European Commission-Enterprise Directorate has
proposed a European Legislative Initiative called ‘Better Medicines for Children’ which
would provide regulations to: provide incentives for research; introduce a period of
data protection; create a specific fund that could be used to finance paediatric research;
create legal requirements for paediatric clinical trials; create a central database on offlabel uses; and, among other initiatives, create a pan-European network of clinical
excellence for the performance of paediatric studies.5
To improve medicines development for children, there is a need to invest more in basic
paediatric research, to improve the participation of children in clinical trials, and to
reverse the underfunding of research on children-specific medicine formulations.
There is also a need for more information on the safety and efficacy of medication use
in children, especially for mental disorders, which account for a high burden of disease
(for example, depression, anxiety disorders).
On 29 September 2004, the European Commission published a proposal for the
regulation of medicines for children. The key elements of this proposal include creation
of a new expert committee within the EMEA, a requirement for data on the use of
medicines in children at the time of marketing authorization, a six-month patent
extension for paediatric use, increased safety monitoring, an EU inventory of
therapeutic needs of children, and the provision of free scientific advice by the EMEA
to the industry.i
1
't Jong GW, Vulto AG, de Hoog M, Schimmel KJM, Tibboel D, van den Anker JN. A
survey of the use of off-label and unlicensed drugs in a Dutch children's hospital.
Pediatrics 2001;108(5):1089-1093.
2
Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of
unlicensed and off label drug use in paediatric wards in European countries. BMJ
2000;320(7227):79-82.
3
't Jong GW. Unlicensed and off-label drug use in children [dissertation]. Rotterdam:
Erasmus University; 2002.
4
U.S. Best Pharmaceuticals for Children Act, 2001. Website:
http://www.fda.gov/opacom/laws/pharmkids/contents.html (accessed 21 September
2004).
5
Ceci A, Felisi M, Catapano M, Baiardi P, Cipollina L, Ravera S, et al. Medicines for
children licensed by the European Agency for the Evaluation of Medicinal Products.
Eur J Clin Pharmacol 2002;58(8):495-500.
i
See http://pharmacos.eudra.org/F2/Paediatrics/docs/Paeds%20press%20release%2029%20Sept.pdf