Paediatric Drug Development
Formulation challenges, regulatory requirements and pharmacokinetic differences in children
Children are not small adults. Drug development for paediatric populations presents unique scientific, ethical, and regulatory challenges. Physiological differences across age groups profoundly affect how drugs are absorbed, distributed, metabolised, and excreted. Historically, most medicines were never tested in children — leading to off-label prescribing, dosing errors, and preventable harm. Regulatory frameworks now require paediatric investigation plans to ensure children have access to safe, appropriately formulated, and evidence-based medicines.
Why Paediatric Drug Development is Different
Children differ from adults in ways that directly affect drug behaviour. Gastric pH is higher in neonates (less acidic), affecting absorption of orally administered drugs. Body composition changes with age — neonates have a higher proportion of total body water and lower body fat, altering the volume of distribution for water-soluble and lipid-soluble drugs. Plasma protein binding is reduced in neonates (lower albumin, presence of foetal albumin), leading to higher free drug concentrations. Hepatic enzyme maturation is incomplete at birth — CYP3A4 and other CYP enzymes reach adult activity at different rates, making metabolic predictions unreliable. Renal function is immature in neonates, reaching adult values by approximately 1 year of age. These factors mean that adult doses cannot simply be extrapolated to children by weight alone.
Paediatric Age Groups and Pharmacokinetic Changes
Regulatory guidance divides children into distinct age groups: preterm neonates (born before 37 weeks), term neonates (0–27 days), infants (28 days to 23 months), children (2–11 years), and adolescents (12–17 years). Each group has different pharmacokinetic profiles. Neonates and infants have the greatest deviation from adult pharmacokinetics. As children grow, enzyme activity, renal function, and body composition progressively approach adult values — but at different rates for different pathways. Ontogeny (the developmental maturation of drug-metabolising enzymes and transporters) must be understood to predict paediatric drug behaviour. Physiologically based pharmacokinetic (PBPK) modelling is increasingly used to simulate paediatric PK and guide dose selection before clinical trials.
Formulation Challenges in Paediatrics
Children cannot reliably swallow tablets or capsules until approximately 6–7 years of age. This creates significant formulation challenges. Liquid formulations (oral solutions, suspensions) are preferred for younger children but require careful excipient selection — many standard excipients are unsuitable for paediatric use. Benzyl alcohol causes 'gasping syndrome' in neonates and is prohibited. Propylene glycol accumulates in neonates with immature metabolism. Ethanol is not appropriate for neonates or young children. Aspartame and saccharin should be avoided in phenylketonuria patients. Sucrose-containing preparations increase dental caries risk. The EMA has published lists of excipients to avoid or restrict in paediatric formulations. Mini-tablets (2 mm diameter), orodispersible tablets, and flexible solid dosage forms represent modern approaches to improving paediatric acceptability without liquid formulations.
Regulatory Framework — PUMA and PIP
The EU Paediatric Regulation (EC 1901/2006) requires pharmaceutical companies to submit a Paediatric Investigation Plan (PIP) as part of new medicine applications, unless a waiver or deferral is granted. A PIP specifies how the medicine will be developed and tested in children across relevant age groups. The Paediatric Use Marketing Authorisation (PUMA) was created to incentivise development of medicines for children that are off-patent, offering 10 years of market protection for a new paediatric formulation. In the USA, the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA) provide similar obligations and incentives. These frameworks have significantly increased the volume of paediatric clinical data available, reducing off-label prescribing.
Off-Label Prescribing and Ethical Considerations
Despite regulatory advances, off-label prescribing in children remains common — estimated at 50–90% in neonatal intensive care units. Off-label use means prescribing outside the terms of the product licence in terms of age, dose, indication, or route. It is legal but carries increased risk if dosing evidence is limited. Prescribers must document the rationale and inform parents. The ethical challenge in paediatric drug development is balancing the risk of clinical trials in a vulnerable population against the greater risk of using untested medicines. Informed consent must be obtained from parents or guardians, with assent sought from children old enough to understand. This article has been prepared following careful evaluation of EMA paediatric guidelines, ICH E11(R1), and current UK regulatory and clinical practice.