Medicines in children
A child's response to a medicine follows development rather than body weight, so the dose, the formulation, the way pharmacokinetics is estimated and the conduct of a trial all change across the paediatric age categories, and much of what children are given has never been licensed for them. Illness itself differs in childhood, from the diseases that present to what care at the end of life asks of communication.
Paediatric age categories
ICH E11 is the guideline on clinical investigation of medicinal products in the paediatric population. It divides the paediatric population into age categories, which two 2012 accounts give differently. One gives preterm newborns as below 36 weeks gestational age, newborns as 0 to 27 days, infants and toddlers as 1 to 23 months, children as 2 to 11 years and adolescents as 12 to 17 years. The other gives preterm newborn infants, term newborn infants at 0 to 27 days, infants and toddlers at 28 days to 23 months, children at 2 to 11 years, and adolescents at 12 to 16 or 18 years depending on region. On organ maturation, body weight and body composition, children can be classified into at least four categories: neonates from birth to 28 days, infants from 28 days to 23 months, children from 2 to 11 years and adolescents from 12 to 16 or 18 years.
Development and drug response
Infants, children and adolescents are not "small adults". For many years, though, the therapeutic dose in children was set by adjusting the adult dose in proportion to the child's weight relative to the adult's. The view that children are just small adults has been debunked by a greater understanding of physiological and biochemical ontogeny and of the pharmacological differences that can occur in children compared with adults. One editor held in 2012 that drug research had been tardy in recognising the importance of differentiating children from adults.
Developmental changes have been noted in the four main pharmacokinetic processes: absorption, distribution, metabolism and elimination. Changes with age in the absorptive surfaces, such as the gastrointestinal tract, the skin and the lungs, can influence a drug's bioavailability. Clearance mechanisms in infancy and early childhood are generally inefficient. The drug-metabolising enzyme cytochrome P450 1A2 is absent in neonates, so they cannot metabolise caffeine to paraxanthine, and adult levels are reached only after one year of age. The activity of CYP2C9, which accounts for approximately 20% of oxidative drug metabolism, increases from birth to ten years of age, when it exceeds an adult's, and then declines to adult levels. Renal function, measured as glomerular filtration rate, develops with age and generally reaches adult values by one year of age. Genetic variants of the genes behind these processes, different disease phenotypes, disease progression and concomitant treatment all add to the variation.
The paediatric population is far from homogeneous, and its variability is potentially larger than that of the adult population. The drug developer's challenge is to understand this heterogeneity, how it affects the pharmacokinetic and pharmacodynamic relationship and ultimately the therapeutic dose, and whether that dose differs enough from adults' to warrant a dose adjustment.
Unlicensed and off-label use
Up to 2012, most medications had not been licensed for use in children. In 2012, around 70% of the medicines given to the paediatric population, and 93% of those given to critically ill neonates, remained unlicensed or were used off-label. In 2012, paediatricians were often confronted with off-label use, doctors felt unsure, medication errors were frequent, and suitable forms of administration were often missing. Pharmacokinetics in children differ greatly from those in adults and depend on age, and knowing this is crucial when prescribing off-label for children. By 2012, the regulatory authorities had taken steps to address this imbalance. One editor held in 2012 that regulators were only then forcing researchers to consider children in their own right.
Neonatal diabetes mellitus is an extremely rare form of diabetes diagnosed in the first six months of life. It is life-threatening and debilitating because of the symptoms of high blood sugar and the risk of ketoacidosis, a serious problem that can occur in people with diabetes if their body starts to run out of insulin and ketones build up. Different gene mutations have been identified that cause it. As of February 2018 it was treated with insulin or with commercially available glibenclamide tablets licensed for adults only, used off-label and given by nursing staff under medical prescription or by parents at home. To make the tablets suitable for newborns and children, they were crushed into small pieces, mixed with a small amount of water and given with an oral syringe, a practice that can cause errors in administration and potentially a risk of under- or over-dosing.
On 23 February 2018 the European Medicines Agency's Committee for Medicinal Products for Human Use recommended granting an EU marketing authorisation for Amglidia, a new oral formulation of glibenclamide developed specifically for newborns, toddlers and children with neonatal diabetes. Glibenclamide was already authorised for treating type 2 diabetes. Amglidia's formulation is meant to allow more accurate dosing, and patients treated with it may not need insulin or may need a smaller dose. Glibenclamide acts on the insulin-producing cells of the pancreas by attaching to the ATP-sensitive potassium channel, which controls the release of insulin. In many newborns with neonatal diabetes these cells produce insulin but cannot release it into the blood, because their gene mutations lead to dysfunctional channels, and the lack of insulin in the blood causes the symptoms of diabetes. Glibenclamide's effect on the channel restores the cells' ability to release insulin into the blood, which is expected to reduce the symptoms. Amglidia's benefits are supported by data published in the literature, a bioavailability study and the NEOGLI study. Because the disease is so rare, the NEOGLI study included only 10 patients, and it showed that glycaemic control remained stable after switching from crushed tablets to the oral suspension.
Paediatric drug development
Besides medicines for their own diseases, children need adapted dosing and suitable forms of administration. Paediatric drug development does not mirror the development of drugs for adults. Its key elements are assessing epidemiology and existing therapies in children, and all the elements of adult drug development adapted to children's different anatomy, metabolism and developmental stage. It might include, for example, developing liquid formulations for children rather than tablets, studies in juvenile animals and paediatric clinical studies.
Understanding drug behaviour in children has great societal value: for new medicines it will lead to the early licensing of innovative products for paediatric use, and for existing drugs, child-appropriate formulations together with a greater understanding of the pharmacokinetic and pharmacodynamic relationships in children will widen the range of safe and effective medicines available to treat childhood disease.
Estimating pharmacokinetics in children
Estimating pharmacokinetics in children can be challenging, and an often-repeated mantra is the need to do more with less. Blood sampling for drug measurement is less extensive than in adults, because of the volume involved, and subjects tend to be fewer. That situation lends itself to population pharmacokinetic methods, in which data from all patients are analysed together to estimate a mean set of population parameters, generally clearance and apparent volume of distribution, and the variability around them can then be investigated across the age groups within the paediatric population. The caveat is that fully understanding dose adjustment in each of these cohorts needs a sufficient number of patients in each sub-group of interest.
Paediatric extrapolation
The ICH E11(R1) guideline defines paediatric extrapolation as an approach to providing evidence in support of the effective and safe use of drugs in the paediatric population when the course of the disease and the expected response to a medicinal product can be assumed sufficiently similar in the paediatric target population and the reference population, which may be adults or other paediatric age subsets. Extrapolation can extend what is known about the reference population, such as pharmacokinetics and dosing, efficacy and safety, to the target population, based on an assessment of the relevant similarities of disease, drug pharmacology and response to treatment between the two.
The ICH E11A guideline on paediatric extrapolation, dated 27 August 2024, recommends harmonised approaches to paediatric extrapolation to support the development and authorisation of paediatric medicines. It provides a framework for using extrapolation as a tool to support paediatric drug development that encompasses an iterative process for understanding the existing information, the gaps in information needed to inform development, and the ways to generate additional information when needed. E11A is to be read with the ICH E11 guideline and its R1 addendum, and applicants wishing to follow an extrapolation approach are also advised to look at the European Medicines Agency's structured guidance on the use of extrapolation.
Paediatric clinical trials
In the last century the prevailing opinion was that exposing children to clinical trials would be unethical. By 2012 mainstream thinking was that it is unethical and more dangerous to treat children with drugs never properly investigated in children, although a sceptical attitude remained. The parents' position also depends on the seriousness of the disease, and in 2012 almost all children with cancer took part in clinical trials. Thanks to decades of research, a diagnosis of acute lymphatic leukaemia in a child was by 2012 no longer a death sentence, although still a horror: 80 to 90% of children survive, thanks to cytostatic and other medicines developed for adult cancer treatment decades earlier.
Clinical trials in children are always more demanding than those in adults. Phase 1 studies in healthy children are not allowed, but children receiving treatment can be given experimental drugs as add-ons, which allows pharmacokinetic and pharmacodynamic measurements. Further challenges include laboratory issues, how much blood can be taken and how often, and the need for adequately trained study personnel.
Children are always part of a family, and the clinical investigator must be aware of this. Parents often come to visits with their other children, and if the study centre is shabby, the study personnel unfriendly or the scheduled visits too rigid, the parent will not return.
By 2012 there were many paediatric research networks in Europe, partially coordinated by the European Medicines Agency under the European Network for Paediatric Research (Enpr-EMA).
Illness in childhood
The spectrum of illnesses in children differs from that in adults. Infections such as chickenpox, measles and scarlet fever can also trouble adults but usually peak in childhood. Some very rare illnesses occur only in children or start in early infancy, especially genetic diseases such as Gaucher disease and Legg–Calvé–Perthes disease. Other illnesses, such as osteoporosis, dementia and heart attack, are largely unknown in children. By 2012, some diseases that once presented only in adults were on the rise in children and adolescents: the Western lifestyle boosts obesity, so type 2 diabetes and arthrosis, for example, were already affecting the young.
End-of-life care
One writer counts chronic and severe illness that leads to death at a young age as the most unsettling thing paediatrics confronts. Palliative and psychological end-of-life care has to be tailored to young patients and the way they see the world. End-of-life care for children and adolescents raises aspects that usually play no role in adult palliative care. Morally it seems clear that a young patient's preferences about treatment, and especially about ending it, should be taken seriously, but legally these patients lack the authority to decide. Communication also plays a very important role: medical information has to be given in a way a child or adolescent can understand and cope with psychologically, which depends heavily on age and developmental stage.