Clinical, methodology, and patient/carer expert advice in pediatric drug development by conect4children.

Many medicines are used "off-label" in children outside the terms of the license. Feasible pediatric clinical trials are a challenge to design. Conect4children (c4c) is an Innovative Medicines Initiative project to set up a pan-European pediatric clinical trial network aiming to facilitate the development of new medicines for children. To optimize pediatric trial development by promoting innovative trial design, c4c set up a European multidisciplinary advice service, including the voice of young patients and families, tailored to industry and academia. A network of experts was established to provide multidisciplinary advice to trial sponsors. Experts were selected to join clinical and innovative methodology expert groups. A patient and public involvement (PPI) database, to include the expert opinion of patients and parents/carers was formed. A stepwise process was developed: (1) sponsors contact c4c, (2) scoping interview takes place, (3) ad hoc advice group formed, (5) advice meeting held, and (6) advice report provided. Feedback on the process was collected. Twenty-four clinical and innovative methodology expert groups (>400 experts) and a PPI database of 135 registrants were established. As of September 30, 2022, 36 advice requests were received, with 25 requests completed. Clinical and methodology experts and PPI representatives participated in several advice requests. Sponsors appreciated the advice quality and the multidisciplinary experts from different countries, including experts not known before. Experts and PPI participants were generally satisfied with the process. The c4c project has shown successful proof of concept for a service that presents a new framework to plan innovative and feasible pediatric trials.

Extrapolation as a Default Strategy in Pediatric Drug Development.

Pediatric drug development lags adult development by about 8 years (Mulugeta et al. in Pediatr Clin 64(6):1185-1196, 2017). In such context, many incentives, regulations, and innovative techniques have been proposed to address the disparity for pediatric patients. One such strategy is extrapolation of efficacy from a reference population. Extrapolation is currently justified by providing evidence in support of the effective use of drugs in children when the course of the disease and the expected treatment response would be sufficiently similar in the pediatric and reference population. This paper's position is that, despite uncertainties, pediatric drug development programs should initially assume some degree of extrapolation. The degree to which extrapolation can be used lies along a continuum representing the uncertainties to be addressed through generation of new pediatric evidence. In addressing these uncertainties, the extrapolation strategy should reflect the level of tolerable uncertainty concerning the decision to expose a child to the risks of a new drug. This judgment about the level of tolerable uncertainty should vary with the context (e.g., disease severity, existing therapeutic options) and can be embedded into pediatric drug development archetypes to ascertain the extent of studies needed and whether simultaneous development for adults and adolescents be considered.

Recommendations for the design of therapeutic trials for neonatal seizures.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

Blood pressure differences by ethnic group among United States children and adolescents.

Large differences in blood pressure (BP) by ethnic group are apparent among adults. There is uncertainty as to whether similar differences by ethnic group exist among children and, if so, the age of onset. BP measurements were obtained from 58 698 children at 78 556 visits using Pediatric Task Force data, a collection of 11 studies with BP data from children and adolescents age 1 to 17 years. Generalized estimating equation methods were used to identify sex-specific differences in body mass index (BMI)-adjusted rates of BP elevation and prehypertension by ethnic group. Significant BMI-adjusted differences in rates of BP elevation were found between Hispanic boys versus white boys (odds ratio: 1.21; 95% CI: 1.07 to 1.37; P=0.002). No overall significant differences were found between black boys versus white boys (odds ratio: 1.03; 95% CI: 0.95 to 1.12; P=0.49); however, there was significant effect modification (P=0.01) with significant differences found for normal-weight boys (BMI: <85th percentile; OR black versus white: 1.14; 95% CI: 1.03 to 1.27; P=0.01) but not for overweight boys (BMI: > or =85th percentile; OR black versus white: 0.90; 95% CI: 0.78 to 1.05; P=0.20). No overall ethnic group differences in BMI-adjusted rates of hypertension were found for girls. Ethnic differences in prevalence rates of pediatric BP elevation that are not explained by obesity are present, primarily in boys. Whether these differences are attributable to genetic or environmental factors is unknown.