Future Challenges
As we look to continue to strengthen both clinical and regulatory
protections for children, a number of significant challenges require the
attention of paediatricians, pharmacologists, pharmacists and policy
makers.
Off Label Use. The regulatory environment for new drug
approvals in the United States and the European Union has resulted in an
increase in paediatric labelling for new therapeutic entities and a
parallel decrease in off-label use (49). This is an important issue.
While off-label drug use does occur in adults, this is typically on the
basis of new evidence that demonstrates safety and efficacy of drugs for
new indications. In contrast, in children off-label drug use has often
been on the basis of extrapolation in the absence of firm evidence, and
on many occasions has been associated with adverse outcomes. Off label
drug use has been identified as a separate and distinct risk factor for
adverse drug reactions in children (49, 50).
However, the decrease in off-label use in Europe has been marginal
despite these changes (64% post legislative changes versus 58% prior
the changes) (50). This is likely due to the fact that the existing
regulatory mechanisms address only novel products, and the majority of
drug use in children is concentrated in older, often off-patent
medications.The best approach to enhancing paediatric labelling and
reducing off-label use, notably for older medications, remains unclear.
Child Friendly Formulations. The issue of child-friendly
formulations remains an important issue and one that, in pragmatic
terms, often“orphans” children from safe and effective therapies (1).
Many children under the age of eight and essentially all children under
the age of four have difficulty in swallowing conventional tablets.
(Interestingly, up to 10% of adults and a higher number of senior
citizens report difficulty in swallowing conventional tablets and
capsules). Some medications - notably antibiotics – are available in
liquid form but for many other medications pharmacists or parents must
crush and dissolve or mix medications with flavour masking agents (51).
Creating a dosage form in this manner – a practice known as compounding
– is a skill that is less and less frequently taught in pharmacy
faculties and is often quite variable in approach and technique.
Compounding introduces a new series of risks including dose and drug
errors. Importantly, compounding also circumvents the carefully designed
regulations for Good Manufacturing Practice established to provide safe
dosage forms for adults.
There have been a number of innovative approaches to enhance oral drug
delivery for children, and while many such as mini-tablets, gel
technology and 3D printing onto orodispensible films offer great
promise, their uptake has been less rapid and certainly less generalized
than desired (52). In the area of child-friendly formulations, European
research groups have been among the world leaders (53). However, the
dissemination of these formulations beyond Europe and the United States
is much at best spotty and certainly less than optimal (47). Work in a
number of centres and by a number of regulators is exploring the safety
and optimal nature of excipients in paediatric formulations.. Given that
children will likely always represent a small market for pharmaceuticals
compared to adults, it is likely that this work would benefit
substantially form incentives to counterbalance the impact of market
forces on the impetus for formulation development.
Design of Clinical Trials in Children. A further regulatory
challenge lies in the area of clinical trial design. While regulatory
approval has relied heavily on conventional randomized double-blind
controlled trials - the “gold standard” for drug approval – this has
been problematic for drugs for children, related to issues such as small
sample size, selection of appropriate and clinically meaningful
outcomes, appropriate instruments for evaluation and suitable safety
monitoring (26). To address these issues and to meet the challenges of
the new revolution in therapeutics, investigators have developed a
number of novel clinical trial designs tailored to the unique problems
in paediatric drug research (55-58). Examples of these include adaptive
design, in which trial design is changed over the course of a trial
based on interim analysis; this is a different approach than the
conventional randomized double blind trial and requires meticulous
pre-study planning (55). A challenge for drug regulatory agencies is how
to best accept the results of these studies for drug approval and to
inform product monographs.
Regulatory Harmonization. An additional challenge for drug
development in general but for paediatrics in particular is
harmonization of requirements and regulations across multiple
jurisdictions. The International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use (ICH) is a Swiss-based
group that for the past twenty-five years has been working to harmonize
the regulatory requirements of multiple jurisdictions. Over the past
decade, many jurisdictions have modified their requirements for new drug
submissions to better align across international boundaries, and
although there has been some success in this area much work remains to
be done (54). The frequent and increasing dialogue between the FDA and
EMA as to how to encourage drug studies in children is an encouraging
development, notably given that regulators for other jurisdictions are
involved in these discussions as observers.
Brexit. In addition to global issues there are interesting
challenges in how Brexit will impact on paediatric drug development in
the UK – which has a number of talented paediatric clinical
pharmacologists and some of the best academic child health care centres
in Europe – has yet to be determined (59). The UK academic and
industrial community and EMA have benefited greatly from close
interaction and it is hoped that whatever agreements are negotiated as
the UK leaves the European Union can preserve these benefits.
Talent Pool and Pipeline. A challenge and an opportunity is the
talent pool of researchers with interest and expertise in conducting
drug research in children. The number of investigators is limited and
primarily located in developing countries (60). In part this is due to
the perception that immediate clinical needs in developing nations may
be seen to be a higher priority than the development of drug researchers
and is in part due to the fact that promising young investigators who
train in the developing world are often attracted to the deeper
resources available for research in the developed world. However, there
is a cadre of young pharmacologists with interest in moving drug
research in children forward and in working together across countries
and across regions in creating the critical mass needed to surmount the
challenges detailed above.