Table 1.

Potential factors related to ontogeny or organ maturity to be considered in paediatric development

		Preterm and term newborn (0‐27 d) infants18	Infants and toddlers (28 d‐23 mo)	Children (2‐11 y)	Adolescents (12‐18 y)19
Factors associated to changes in organ function20, 21	Factors associated to changes in growth bodyweight and size, organ weight, tissue composition (plasma proteins, water, and fat composition)
	GI system	Attention must be paid to some increased or decreased enzyme activity or secretion such as enzyme activity increased such as lactase or CYP1A1 that increases over time to adult levels, but also to gastrointestinal (GI) pH, GI volume, GI transit times
	Lung	Alveolar proliferation, microvascular maturation, alveolar (expansion), normal lung growth period: until at least 8 y of age			Interpolation from data generated in studies in adults may be possible if specific studies have been carried out in children less than 12 y of age.22
	Renal system	Glomerular filtration rate (GFR), tubular secretion, tubular reabsorption key stage of maturation			Renal capacity can approach adult levels.
	Liver	Phase I enzymes, phase II enzymes, and bile flow			Hepatic enzyme expression can approach adult levels.
	Brain	Neural tube differentiation, blood brain barrier, proliferation and organisation of synapses, neurotransmitter system maturation (NMDA receptors), subcortical grey matter, myelination, brain size, cortical grey matter, amygdala and hippocampus, white matter maturation, prefrontal cortex maturation, cholinergic and serotonergic systems: up to at least 18 y of age
Extrapolation parameters	Disease	Many diseases in the preterm and term newborn infant are unique or have unique manifestations	Physiological development and maturity of organs, pathophysiology and natural history of the disease or condition, available treatment options, and the pharmacology of the investigational product are factors to be considered in determining the subgroups in paediatric studies.6		Pharmacokinetics in adolescent patients are often similar to the pharmacokinetics in adults but weight and clearance should be considered.
	Pharmacology	Physiology changes dramatically with both gestational age (ie, from 22 to 42 wk) and post‐natal age affecting medicinal product disposition and organ/tissue responsiveness.			Adolescent doses may be able to be derived from adult data using bodyweight‐based allometric scaling.
	Clinical response	The prediction and measurement of a medicinal product's PK (exposure) and PD (response) is essential to the clinical pharmacology assessment.			Confirmatory pharmacokinetic data may then be obtained through sparse sampling during pivotal efficacy and safety trials.
Extrapolation challenges		Factors such as physiological development including physical growth, organs maturation, transporters and enzymes ontogeny create size and age‐dependent variability in PK parameter.23 Therefore the response to intervention may be undefined or dissimilar to that in adults or older children.			Neurodevelopmental and behavioural disorders, monitoring the onset of puberty
Extrapolation opportunities		Extrapolation unlikely possible particularly for preterm neonates, but general modelling and simulation principles may be applied for rational interpretation of the available evidence in the context of information from other sources to guide study design and proposed dosages	Modelling and simulation to support study design and proposed dosages	Modelling and simulation (and interpolation where possible) to support study design and proposed dosages	Number of adolescents could be considered to be studied with the adult studies in appropriate paediatric setting, modelling and simulation can be used to support study design and proposed dosages