Bridging the gap:a review of dose investigations in paediatric investigation plans

Aims In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children. Methods We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses. Results Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre-specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone. Conclusions Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre-specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies

High prevalence of glucose intolerance even among young adults in south India

India is experiencing an epidemic of Type 2 diabetes mellitus (DM) in young adults. This study reports the prevalence of glucose intolerance, and insulin profiles, and their relationship to lifestyle factors in 2218 young adults (aged 26-32 years; 997 urban, 1221 rural) in south India. They were drawn from a cohort of 10,691 individuals born during 1969-1973 in Vellore and nearby villages. Family history, socio-economic status, physical activity and tobacco and alcohol use were recorded. Oral glucose tolerance tests were performed for diagnosis (WHO recommendations). Insulin resistance and secretion were derived from plasma insulin concentrations. Median BMI was 20.0kg/m(2). The prevalence of Type 2 DM and impaired glucose tolerance (IGT) was higher in urban than in rural subjects (3.7% versus 2.1%, p=0.02; 18.9% versus 14.3%, p=0.002, respectively), while prevalence of impaired fasting glycaemia (IFG) was similar in urban and rural populations (3.8% versus 3.4%, p=0.04). Type 2 DM, IGT, IFG or higher insulin resistance and increment were associated with higher socio-economic status (more household possessions) and higher percentage body fat, body mass index and waist/hip ratio. Insulin increment was lower in men with higher alcohol consumption. Our data suggest high levels of glucose intolerance in young rural and urban adults highlighting an urgent need for preventive action to avert a public health catastrophe in India