After the Second World War, the so-called pharmacological explosion took place, leading
to
major advances in the treatment of diseases that were once inevitably fatal or
disabling.
This pharmacological expansion contributed to the occurrence of catastrophic incidents,
such as the phocomelia epidemic attributed to thalidomide. Since then, concerns about
drug
safety have contributed to the development and application of clinical and epidemiological
methods to assess the benefits and potential risks of any type of therapeutic intervention,
whether pharmacological or not.1
Indisputably, the administration of a medication aims to obtain a beneficial effect
for
those who take it. Nonetheless, it is important that the assumptions arising from
the
analysis of scientific evidence are not forgotten: firstly, some drugs do not have
the
desired efficacy, and secondly, regardless of their beneficial effects, every medication
may produce undesired effects.
When a drug is launched on the market, all the knowledge about it is based on pre-marketing
studies: during the development of the molecule, experimental studies on its effects
and
toxicity are conducted in animals (pre-clinical studies). If no unacceptable toxic
effects
are observed, the first clinical trials in humans are conducted. These are termed
phase I,
II, and III studies, which investigate aspects of the pharmacokinetics, toxicity,
and
efficacy in humans.
In clinical trials, several factors may interfere with the results, such as inclusion
and
exclusion criteria, sample sizes, and even “apparently ethical” criteria, which, while
fully justified in the early stages of the assessment of a new drug, preclude scientific
study in certain populations. For a long time, with some exceptions, children have
been
excluded from clinical trials. Only in phase IV (post-marketing) are the drugs used
in
children, which may lead them to become the subjects of uncontrolled clinical
practice.1
,
2
This practice of pediatric prescription without clinical evidence, in situations that
are
different from those studied and advocated (indications, dosages, extemporaneous
formulations, age group in which tested), is known as off-label use, which has been
demonstrated to be associated with an increase in adverse effects3
–
5 and should be discouraged.
In this issue of the Revista Paulista de Pediatria, Gonçalves and Heineck conducted
a
cross-sectional study, with a simple methodology.6 In
their study, the authors demonstrated that, of the total, 232 (31.7%) prescriptions
were
off-label, and the following types and frequency were observed: off-label dose – 90
(38.8%); age – 73 (31.5%); and administration frequency – 68 (29.3%). The greatest
concern
was the finding of overdose of medications whose use in this situation may be fatal,
such
as salbutamol.
In Brazil, off-label prescription in pediatrics is a frequent practice. Is this practice
necessary? What can be done to ensure the safety of children?
In order to protect the health of children and to ensure that medications are used
in a
more ethical way, in 2007 the European Union issued legislation for the development
and
authorization of pediatric drugs.7 Since then,
pharmaceutical companies have been required to develop their medicines both for the
adult
and pediatric populations, aiming to adapt the drug to the needs, dosage, dosage form,
and
administration route, among others, in order to ensure effectiveness and that safety
is not
affected by the risk of overdose. A Pediatric Committee was also created to evaluate
the
pediatric investigation plans (PIPs) presented by pharmaceutical companies. The committee
consists of 12 representatives of the member states; among its functions, the elaboration
of an inventory of specific pediatric needs is noteworthy.7
Also in 2007, the World Health Organization (WHO) published the first list of Essential
Medicines for Children, which is reviewed every 2 years, and launched the “make medicines
child size” campaign, in order to raise awareness and promote a global action on the
problem of lack of pediatric formulations.8
In 2012, under the Investigational New Drug (IND) program, the Food and Drug Administration
(FDA), the regulation agency of the United States, created the Safety and Innovation
Act
(FDASIA-2012), which established the Pediatric Study Plan. This plan is required for
new
molecules, new indications, new dosage forms, new dosages, and new administration
routes.9
,
10
In Brazil, there are isolated initiatives by healthcare institutions that, by standardizing
drugs and creating pharmacology committees, among other measures, are able to evaluate
the
off-label use of drugs. In the state of São Paulo, the Health Surveillance Center
(Centro
de Vigilância Sanitária [CVS]) acts in the pharmacovigilance area based on the reports
of
adverse events, publishing Therapeutic Alerts on Pharmacovigilance in the Official
Journal.
The CVS has recently published two alerts, “Methylphenidate: indications and adverse
reactions” (July 2013) and “Risk of pancreatic cancer associated with incretin-based
therapy” (February 2014). Both are focused on alerting, following adverse reactions
from
the off-label use of drugs. The first is widely used in children.11
,
12 At the federal level, the Collegiate Board
Resolution (Resolução da Diretoria Colegiada [RDC]) No. 9, of 20 February 2015, which
aims
to establish the procedures and requirements for the conduction of clinical drug trials,
indicated that post-marketing clinical trials are subject only to the Notification
of
Clinical Trial.13
Above all, to foster ethical off-label drug use, it is necessary that this exceptional
use
is clinically justified, even if it is accompanied by clarification and consent of
the
parents or guardians.14 This measure can be taken by
healthcare facilities. The Brazilian National Health Surveillance Agency (Agência
Nacional
de Vigilância Sanitária [Anvisa]), following the example of the regulatory body of
the
European Union, should establish criteria and standards that stimulate comparative
studies
and demonstrate the efficacy and safety of medication use in children. When promising,
therapies should be tested in controlled clinical trials and their package inserts
should
be reformulated.