We summarise a recent article, published in BMJ, that explored why certain age bands used for children in paediatric studies of medicine exist and why it maybe time to change this.
Rational prescribing of medicines requires evidence from clinical trials on efficacy, safety and dose. Regulatory authorities assess the data and information, which are then included in the approved summary of product characteristics.
Children were initially rarely included in clinical trials of medicines due to previous paediatric tragedies. Many argued that it was unethical for infants and children to participate, with concerns about costs and consent. Real progress came with the FDA Modernisation Act of 1997 and the subsequent legislation in Europe that in 2007 introduced requirements to study some new medicines in paediatric patients. Nonetheless, not all medicines on the market for adults are currently authorised for children. As a result, off-label prescribing in children remains high.
In addition, paediatric dosing is still commonly related to body size. This relies on the assumption of a linear correlation between dose and size. As a result, this can lead to overdosing or underdosing, increasing the risk of toxicity or reduced efficacy.
Pharmaceutical companies tend to plan their studies using age groups that regulatory guidelines suggest. This is because it typically avoids problems when applying for marketing authorisation. Within clinical trials, age bands should be defined to include a physiologically and developmentally homogenous group of children to control variability. In some cases, a staggered approach has been used, which aims to protect children from unexpected adverse events, starting with the oldest adolescents. This approach can delay the completion of paediatric studies with a potential for off-label use in the youngest subsets.
Current age bands – neonates, infants and toddlers, children (age 2-11 years) and adolescents (age 12-18 years) – are more historical rather than based on physiology or normal development of children. The authors noted that the age bands for neonates and adolescents are particularly problematic.
Defining the neonatal age band as time from birth up to 1 month is problematic, as it does not take into consideration developmental age. With neonatal survival at earlier stages of gestation, this definition has become increasingly inappropriate to thoroughly describe the neonatal population. Additionally, it is apparent that the breakpoint of 12 years between child and adolescent has remained for historical reasons. Meanwhile, the upper limit of this age band was set by the definition of paediatric age in healthcare, which varies according to region. Puberty also plays a big role. Adolescents progress through stages of pubertal development but this progression does not follow the same timelines for every adolescent.
The authors believe that the paediatric age bands defined by regulatory guidelines and discussed above are not well based on physiological growth and development. In the last decade, innovative strategies, such as modelling and simulation, are being increasingly used in paediatric drug development. They allow for the assessment of growth and/or development as continuous covariables. Moreover, they have strengthened the appropriate use of extrapolation, particularly in areas of infectious diseases and oncology.
Choosing distinct age groups based on what is known about the prevalence and incidence of the disease would be optimal. Also, taking into consideration the role of developmental growth, maturation processes and ontogeny will be important as they can affect pharmacokinetics, pharmacodynamics and the safety profile of a drug. The current arbitrary division of paediatric subgroups by chronological age appears to have no scientific basis. These subgroups could unnecessarily delay development of medicines for children. The authors believe that it is time for regulatory authorities to reconsider the use of the traditional age bands.
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