Global Regulatory and Public Health Initiatives to Advance Pediatric Drug Development for Rare Diseases.

The literature thoroughly describes the challenges of pediatric drug development for rare diseases. This includes (1) generating interest from sponsors, (2) small numbers of children affected by a particular disease, (3) difficulties with study design, (4) lack of definitive outcome measures and assessment tools, (5) the need for additional safeguards for children as a vulnerable population, and (6) logistical hurdles to completing trials, especially with the need for longer term follow-up to establish safety and efficacy. There has also been an increasing awareness of the need to engage patients and their families in drug development processes and to address inequities in access to pediatric clinical trials. The year 2020 ushered in yet another challenge-the COVID-19 pandemic. The pediatric drug development ecosystem continues to evolve to meet these challenges. This article will focus on several key factors including recent regulatory approaches and public health policies to facilitate pediatric rare disease drug development, emerging trends in product development (biologics, molecularly targeted therapies), innovations in trial design/endpoints and data collection, and current efforts to increase patient engagement and promote equity. Finally, lessons learned from COVID-19 about building adaptable pediatric rare disease drug development processes will be discussed.

Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. RESEARCH DESIGN AND METHODS: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. RESULTS: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). CONCLUSIONS: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.

Population-based incidence of diabetes in Australian youth aged 10-18 yr: increase in type 1 diabetes but not type 2 diabetes.

BACKGROUND: Global incidence of childhood type 2 diabetes has increased, with a greater rise amongst certain ethnic groups. OBJECTIVES: To examine the change in the incidence of type 1 and type 2 diabetes in Australian youth, aged 10-18 yr, in New South Wales, Australia. METHODS: Prospective population-based incidence study (2001-2008). Primary case ascertainment was from the Australasian Paediatric Endocrine Group Diabetes Register, secondary independent ascertainment from the National Diabetes Register. RESULTS: There were 202 incident cases of type 2 diabetes (96 boys, 48%). The mean age at diagnosis (±SD) was 14.6 ± 2.5 yr; 93% were overweight (International Obesity Taskforce Grade ≥1). Mean HbA1c was 8.8 ± 2.8%. Ethnicity was Caucasian 31%, Indigenous Australian 20%, Southeast Asian 11%, North African/Middle Eastern 9%, and NewZealander/Melanesian/Polynesian 8%. The mean annual incidence of type 2 diabetes was 3.0 per 100 000 per year (95% confidence interval (CI): 2.6-3.4) and did not change over time. The mean annual incidence of type 1 diabetes was 22.0 per 100 000 per year (95% CI: 20.8-23.1), and increased by 3.8% per year [incidence rate ratio IRR: 1.04, 95% CI: 1.02-1.06, p = 0.001]. Incidence was higher in Indigenous vs. non-Indigenous youth, IRR: 6.9 (95% CI: 4.7-10.2, p < 0.001). CONCLUSION: In 10-18 yr old youth, in Australia, the incidence of type 2 diabetes has remained steady during the last decade; however, the incidence of type 1 diabetes continues to rise. Most common diabetes in Australian youth is type 1 diabetes.

The prevalence of vitamin D deficiency in children in the Northern Territory.

AIMS: The primary aim of this study was to determine the frequency of vitD deficiency/insufficiency in an opportunistic sample of Northern Territory (NT) children. The secondary aim was to evaluate whether: (i) 25(OH)vitD (25(OH)D) levels differ between Indigenous/non-Indigenous children; and (ii) VitD insufficiency is associated with increased acute/infective hospitalisations. METHODS: Twenty-five (OH)D levels were measured in 98 children <16 years between August 2011 and January 2012 (children hospitalised acutely/non-acutely and well children from other studies based in Darwin). VitD deficiency was defined as 25(OH)D < 50 nmol/L, and insufficiency was postulated to be <75 nmol/L. Demographic data were collected, and computer records were reviewed. RESULTS: Median age was 59 months (range 2-161); 3.1% were vitD deficient, 19.4% insufficient. There was no significant difference in mean 25(OH)D level between Indigenous (93.2, standard deviation (SD) 21.9, n = 42) and non-Indigenous (97.3, SD 27.9, n = 56) children (P = 0.32). Median number of hospitalisations/year were similar (P = 0.319) between vitD sufficient (0.34, range 0-12, n = 76) and insufficient (0.22, 0-6, n = 22) children. There was no significant difference between number of infective admissions per year between vitD sufficient/insufficient groups (P = 0.119). CONCLUSIONS: Compared with US data (19% deficient, 65% insufficient) fewer NT children are vitD deficient/insufficient. In our limited sample, being vitD insufficient was not associated with increased acute/infective hospitalisations, but a larger unbiased sample of NT children is needed. More information is needed about the optimum level of vitD for non-bone-related health in children.

Pregnancy And Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study.

BACKGROUND: Diabetes in pregnancy carries an increased risk of adverse pregnancy outcomes for both the mother and foetus, but it also provides an excellent early opportunity for intervention in the life course for both mother and baby. In the context of the escalating epidemic of chronic diseases among Indigenous Australians, it is vital that this risk is reduced as early as possible in the life course of the individual. The aims of the PANDORA Study are to: (i) accurately assess rates of diabetes in pregnancy in the Northern Territory (NT) of Australia, where 38% of babies are born to Indigenous mothers; (ii) assess demographic, clinical, biochemical, anthropometric, socioeconomic and early life development factors that may contribute to key maternal and neonatal birth outcomes associated with diabetes in pregnancy; and (iii) monitor relevant post-partum clinical outcomes for both the mothers and their babies. METHODS/DESIGN: Eligible participants are all NT women with diabetes in pregnancy aged 16 years and over. Information collected includes: standard antenatal clinical information, diagnosis and management of diabetes in pregnancy, socio-economic status, standard clinical birth information (delivery, gestational age, birth weight, adverse antenatal and birth outcomes). Cord blood is collected at the time of delivery and detailed neonatal anthropometric measurements performed within 72 hours of birth. Information will also be collected regarding maternal post-partum glucose tolerance and cardio-metabolic risk factor status, breastfeeding and growth of the baby up to 2 years post-partum in the first instance. DISCUSSION: This study will accurately document rates and outcomes of diabetes in pregnancy in the NT of Australia, including the high-risk Indigenous Australian population. The results of this study should contribute to policy and clinical guidelines with the goal of reducing the future risk of obesity and diabetes in both mothers and their offspring.

Diabetes in young people in the Top End of the Northern Territory.

AIM: There is an increasing prevalence and burden of diabetes in young people, particularly Indigenous Australians. There have been no previous reports of the prevalence or burden of diabetes in young people in the Top End of the Northern Territory, a region of many risk factors for diabetes. METHODS: This is a retrospective study of cases of diabetes in children and adults aged less than 25 years who were seen at Royal Darwin Hospital as inpatients or outpatients between 2007 and 2011. RESULTS: From a population base of approximately 75 000 young people living north of Tenant Creek, there were 70 young people with type 1 diabetes (12 Aboriginal and/or Torres Strait Islander Australians) and 37 young people with type 2 diabetes (31 Aboriginal or Torres Strait Islander Australians). The median body mass index of those with type 2 diabetes was 28 kg/m(2) , and only 29% had a body mass index >30 kg/m(2) . Overall, glycaemic control was poor. CONCLUSIONS: Rates of diabetes in young people in the Top End appear high. Case ascertainment and data collection were difficult for this study, highlighting the need for better database and systems for diabetes management.

Type 2 diabetes in young Indigenous Australians in rural and remote areas: diagnosis, screening, management and prevention.

The burden of type 2 diabetes mellitus (T2DM) among Indigenous children and adolescents is much greater than in non-Indigenous young people and appears to be rising, although data on epidemiology and complications are limited. Young Indigenous people living in remote areas appear to be at excess risk of T2DM. Most young Indigenous people with T2DM are asymptomatic at diagnosis and typically have a family history of T2DM, are overweight or obese and may have signs of hyperinsulinism such as acanthosis nigricans. Onset is usually during early adolescence. Barriers to addressing T2DM in young Indigenous people living in rural and remote settings relate to health service access, demographics, socioeconomic factors, cultural factors, and limited resources at individual and health service levels. We recommend screening for T2DM for any Aboriginal or Torres Strait Islander person aged > 10 years (or past the onset of puberty) who is overweight or obese, has a positive family history of diabetes, has signs of insulin resistance, has dyslipidaemia, has received psychotropic therapy, or has been exposed to diabetes in utero. Individualised management plans should include identification of risk factors, complications, behavioural factors and treatment targets, and should take into account psychosocial factors which may influence health care interaction, treatment success and clinical outcomes. Preventive strategies, including lifestyle modification, need to play a dominant role in tackling T2DM in young Indigenous people.

Metabolic bone disease of prematurity and secondary hyperparathyroidism.

AIM: To illustrate, via case histories, the importance of laboratory investigations for the early diagnosis and management of metabolic bone disease (MBD). METHODS: We report three cases of extreme premature infants with MBD. RESULTS: These three infants had several risk factors for MBD of prematurity: very low birthweight, delayed enteral feeds, cholestatic liver disease, intolerance of fortification, the use of glucocorticoids and diuretics. Serum alkaline phosphatase and parathyroid hormone (PTH) were elevated despite relatively normal calcium and phosphate levels. These parameters were corrected with additional supplementation of calcium, phosphate and vitamin D. CONCLUSIONS: Infants born extremely prematurely have significant calcium and phosphate depletion by the time they reach full term compared with the normal fetal accretion rate. This is exacerbated if there is poor tolerability to feeds where extra calcium and phosphate could not be added either by additives or via human milk fortifier. Serum calcium and phosphate levels may be normal despite inadequate intake or stores due to the counter-regulatory effect of PTH. In infants at risk of MBD, testing serum alkaline phosphatase, vitamin D and PTH with calcium and phosphate may assist in the monitoring and management of MBD.

Neonatal hypercalcemia due to polymorphisms of the calcium sensing receptor.

Familial hypocalciuric hypercalcemia (FHH) is known to be caused by heterozygous inactivating mutations of the calcium sensing receptor (CaSR) gene. We report an infant with transient neonatal hypercalcemia who was found to be homozygous for a polymorphism at A986S of the CaSR.

The addition of rosiglitazone to insulin in adolescents with type 1 diabetes and poor glycaemic control: a randomized-controlled trial.

OBJECTIVE: To evaluate the effect of rosiglitazone, an insulin sensitizer, on glycaemic control and insulin resistance in adolescents with type 1 diabetes mellitus (T1DM) RESEARCH DESIGN AND METHODS: Randomized, double-blind, placebo-controlled crossover trial of rosiglitazone (4 mg twice daily) vs. placebo (24 wk each, with a 4 wk washout period). Entry criteria were diabetes duration >1 yr, age 10-18 yr, puberty (>or=Tanner breast stage 2 or testicular volume >4 mL), insulin dose >or=1.1 units/kg/day, and haemoglobin A1c (HbA1c) >8%. Responses to rosiglitazone were compared with placebo using paired t-tests. RESULTS: Of 36 adolescents recruited (17 males), 28 completed the trial. At baseline, age was 13.6 +/- 1.8 yr, HbA1c 8.9 +/- 0.96%, body mass index standard deviation scores (BMI-SDS) 0.94 +/- 0.74 and insulin dose 1.5 +/- 0.3 units/kg/day. Compared with placebo, rosiglitazone resulted in decreased insulin dose (5.8% decrease vs. 9.4% increase, p = 0.02), increased serum adiponectin (84.8% increase vs. 26.0% decrease, p < 0.01), increased cholesterol (+0.5 mmol/L vs. no change, p = 0.02), but no significant change in HbA1c (-0.3 vs. -0.1, p = 0.57) or BMI-SDS (0.08 vs. 0.04, p = 0.31). Insulin sensitivity was highly variable in the seven subjects who consented to euglycaemic hyperinsulinaemic clamps. There were no major adverse effects attributable to rosiglitazone. CONCLUSION: The addition of rosiglitazone to insulin did not improve HbA1c in this group of normal weight adolescents with T1DM.

Bone changes in adolescent girls with anorexia nervosa.

PURPOSE: To clarify the effect of chronological age, height, lean tissue mass, and menstrual status on standard reported DXA (dual-energy x-ray absorptiometry) measures. METHODS: Growth and DXA data from a retrospective longitudinal cohort of 30 adolescent females with anorexia nervosa (AN) were examined. Areal bone mineral density (aBMD), total body bone mineral content (BMC) and total body bone area were measured and standardized for age, height, lean tissue mass, and total bone area. We then examined the changes in these parameters after 12 months of multidisciplinary treatment. RESULTS: The subjects had lower BMC and aBMD than the age- and height-matched reference population at baseline, there were further decreases in these parameters with treatment. BMC adjusted for lean tissue mass and bone area were normal at baseline and there was no significant change with treatment. Bone area adjusted for height was low at baseline and decreased despite treatment. CONCLUSION: Our data suggest that the low age- and height-adjusted bone mineral content and bone mineral density in females with AN is secondary to poor bone growth leading to low bone area. These subjects had relatively normal bone mineral content for their bone size and lean tissue mass. Changes in bone size were proportional to changes in lean tissue mass.

Natural history and risk factors for microalbuminuria in adolescents with type 1 diabetes: a longitudinal study.

OBJECTIVE: To describe the natural history and risk factors for persistent microalbuminuria in children and adolescents with type 1 diabetes followed for up to 15 years. RESEARCH DESIGN AND METHODS: This study contained a longitudinal cohort of 972 patients; analysis of baseline risk factors was performed using logistic regression and predictors over time using survival analysis. Albumin excretion rate was measured on three consecutive timed overnight urine collections on at least two occasions. Normoalbuminuria was defined as a median albumin excretion rate < 7.5 microg/min, borderline microalbuminuria as 7.5-20 microg/min, and microalbuminuria as 20-200 microg/min. Microalbuminuria was further classified as persistent if its duration was >12 months. Median age was 12.7 years (interquartile range 11.5-14.4) and diabetes duration 6.5 years (4.1-9.3) at first assessment, and median follow-up was 6.2 years (range 1-15.3). RESULTS: The incidence of persistent microalbuminuria was 4.6 (95% CI 3.3-6.1) per 1,000 patient-years. Predictors of persistent microalbuminuria from the first assessment using multiple logistic regression were high cholesterol (odds ratio 2.2 [95% CI 1.2-4.0]) and borderline microalbuminuria (2.5 [1.2-5.2]). Predictors using Cox regression were HbA(1c) (hazard ratio 1.4 [95% CI 1.1-1.7]), age at diagnosis (1.2 [1.1-1.3]), obesity (3.6 [0.8-15.5]), and insulin dose (2.7 [1.0-7.5]). CONCLUSIONS: Children and adolescents with type 1 diabetes who have borderline microalbuminuria are more than twice as likely to develop persistent microalbuminuria. In addition to poor glycemic control, clinical markers of insulin resistance were associated with an increased risk of microalbuminuria.

Age related clinical features of childhood coeliac disease in Australia.

BACKGROUND: To describe the presenting clinical features of coeliac disease in a single paediatric centre, and to determine if the presenting features vary with age. METHODS: A review was conducted of children who had been referred with clinical suspicion of coeliac disease to the paediatric gastroenterology department of a tertiary paediatric hospital in Sydney, Australia. Coeliac disease was defined using standard histological criteria. Medical records were reviewed retrospectively. RESULTS: Clinical data were available for 74 cases of proven coeliac disease. Only 9% of patients were less than 2 years of age at diagnosis. Pre-school children (age < 5 years) presented with different symptoms to school children (age > or = 5 years). The most common presenting features in younger children were diarrhoea, irritability and weight loss. However, in older children, abdominal pain was the most common presenting feature. CONCLUSION: We found a significant difference in the clinical features of coeliac disease in pre-school compared to school age children.