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.

Anthropometry, glucose tolerance, and insulin concentrations in Indian children: relationships to maternal glucose and insulin concentrations during pregnancy.

OBJECTIVE: The purpose of this study was to test the hypothesis that the environment experienced by fetuses of mothers with gestational diabetes mellitus (GDM) and mothers with higher glucose concentrations that are in the normal range causes increased adiposity and altered glucose/insulin metabolism in childhood. RESEARCH DESIGN AND METHODS: Children (n = 630) whose mothers were tested for glucose tolerance during pregnancy had detailed anthropometry performed at birth and annually thereafter. At 5 years, plasma glucose and insulin concentrations were measured in the children (2-h oral glucose tolerance test) and their fathers (fasting samples only). RESULTS: Newborns of diabetic mothers (n = 41) were larger in all body measurements than control newborns (babies with nondiabetic parents). At 1 year, these differences had diminished and were not statistically significant. At 5 years, female offspring of diabetic mothers had larger subscapular and triceps skinfold thicknesses (P = 0.01) and higher 30- and 120-min insulin concentrations (P < 0.05) than control children. Offspring of diabetic fathers (n = 41) were lighter at birth than control children (P < 0.001); they showed no differences in anthropometry at 5 years. In control children, skinfold thickness and 30-min insulin concentrations were positively related to maternal insulin area under the curve, and skinfold thicknesses were related to paternal fasting insulin concentrations independently of the parents' skinfold thickness and socioeconomic status. CONCLUSIONS: Maternal GDM is associated with adiposity and higher glucose and insulin concentrations in female offspring at 5 years. The absence of similar associations in offspring of diabetic fathers suggests a programming effect in the diabetic intrauterine environment. More research is needed to determine whether higher maternal glucose concentrations in the nondiabetic range have similar effects.

Glucose tolerance, insulin resistance and insulin secretion in young south Indian adults: Relationships to parental size, neonatal size and childhood body mass index.

OBJECTIVE: To study the relationship of newborn size and post-natal growth to glucose intolerance in south Indian adults. RESEARCH DESIGN AND METHODS: 2218 men and women (mean age 28 years) were studied from a population-based birth cohort born in a large town and adjacent rural villages. The prevalence of adult diabetes mellitus [DM] and impaired glucose tolerance [IGT], and insulin resistance and insulin secretion (calculated) were examined in relation to BMI and height at birth, and in infancy, childhood and adolescence and changes in BMI and height between these stages. RESULTS: Sixty-two (2.8%) subjects had Type 2 diabetes (DM) and 362 (16.3%) had impaired glucose tolerance (IGT). IGT and DM combined (IGT/DM) and insulin resistance were associated with low childhood body mass index (BMI) (p<0.001 for both) and above-average BMI gain between childhood or adolescence and adult life (p<0.001 for both). There were no direct associations between birthweight or infant size and IGT/DM; however, after adjusting for adult BMI, lower birthweight was associated with an increased risk. CONCLUSIONS: The occurrence of IGT and Type 2 DM is associated with thinness at birth and in childhood followed by accelerated BMI gain through adolescence.

Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review.

OBJECTIVE: To investigate whether selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with an increased risk of suicide related outcomes in adults. DESIGN: Meta-analysis of randomised controlled trials of SSRIs compared with placebo in adults submitted by pharmaceutical companies to the safety review of the Medicines and Healthcare products Regulatory Agency (MHRA). PARTICIPANTS: Over 40,000 individuals participating in 477 randomised controlled trials. MAIN OUTCOME MEASURES: Suicide, non-fatal self harm, and suicidal thoughts. RESULTS: An estimated 16 suicides, 172 episodes of non-fatal self harm, and 177 episodes of suicidal thoughts were reported. We found no evidence that SSRIs increased the risk of suicide, but important protective or hazardous effects cannot be excluded (odds ratio 0.85, 95% credible interval 0.20 to 3.40). We found weak evidence of an increased risk of self harm (1.57, 0.99 to 2.55). Risk estimates for suicidal thoughts were compatible with a modest protective or adverse effect (0.77, 0.37 to 1.55). The relative frequency of reported self harm and suicidal thoughts in the trials compared with suicide indicates non-fatal end points were under-recorded. CONCLUSION: Increased risks of suicide and self harm caused by SSRIs cannot be ruled out, but larger trials with longer follow up are required to assess the balance of risks and benefits fully. Any such risks should be balanced against the effectiveness of SSRIs in treating depression. When prescribing SSRIs, clinicians should warn patients of the possible risk of suicidal behaviour and monitor patients closely in the early stages of treatment.