Partnership of I-ACT for children (US) and European pediatric clinical trial networks to facilitate pediatric clinical trials.

Background/aims: Due to a lack of standard pediatric prescribing information, medicines are often used in a dosage form or for an indication that has not been investigated in children. Pediatric clinical trial research networks aim to facilitate the timely availability of innovative drugs for children by developing standardized trial facilitation and conduct processes. This paper aims to assess the (pre)feasibility duration and characteristics of a US-sponsored clinical trial, in collaboration with I-ACT for Children, for distribution across European sites via European clinical research facilitation networks.

Better Medicines for Children: Lessons Learnt and Share Learnings at the EFGCP Annual Paediatric Conferences.

For many years, the European Forum for Good Clinical Practice (EFGCP) Children Medicines Working Party has organised a Paediatric conference annually. In the past, this event was organised jointly with the European Medicines Agency who was used to host it, along with the Drug Information Association (DIA). This conference is the opportunity for all involved in paediatric drug development, i.

Advocating for drug development in newborn infants.

Neonatal care needs more robust guidance on pharmacotherapy, (formulation, dosage regimen, safety and efficacy information). This requires structured advocacy. We therefore discuss advocacy related to improving information about medicines including current practices, clinical trials, the current setting, and trial preparedness.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

Introduction: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

Objective: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes.

Design: Superiority, double-blind randomised controlled trial.

Harmonizing Quality Improvement Metrics Across Global Trial Networks to Advance Paediatric Clinical Trials Delivery.

Background: Despite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct.

Preterm prelabour rupture of membranes before 23 weeks' gestation: prospective observational study.

Objective: To describe perinatal and maternal outcomes of preterm prelabour rupture of membranes (PPROM) before 23 weeks' gestation in a national cohort.

Design: Prospective observational study.

Setting: National population based cohort study with the UK Obstetric Surveillance System (UKOSS), a research infrastructure of all 194 obstetric units in the UK, 1 September 2019 to 28 February 2021.

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.

To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting.

The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

Background: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care.

Objectives: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing.

Methods: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam.

European expert recommendations on clinical investigation and evaluation of high-risk medical devices for children.

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023.

Use of Developmental Midazolam and 1-Hydroxymidazolam Data with Pediatric Physiologically Based Modeling to Assess Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyl Transferase 2B4 Ontogeny In Vivo.

Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study, a midazolam and 1-hydroxymidazolam physiologically based pharmacokinetic model (PBPK) model was developed and used to define the ontogeny for hepatic cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyl transferase (UGT) 2B4. Data for model development and pharmacokinetic studies on intravenous midazolam in adults and pediatrics were collated from the literature.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials.

The publication quality of laboratory values in clinical studies in neonates.

Background: There are no generally accepted age-appropriate reference ranges for laboratory values in neonates. This also matters for drug development. The International Neonatal Consortium (INC) is engaged to define actionable reference ranges of commonly used laboratory values in neonates.

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.

Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

Background: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity.

Methods: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed.

Development and evaluation of an assessment of the age-appropriateness/inappropriateness of formulations used in children.

Background: Medicines designed for adults may be inappropriate for use in children in terms of strength, dosage form and/or excipient content. There is currently no standardised method of assessing the age-appropriateness of a medicine for paediatric use.

Aim: To develop and test a tool to assess whether a dosage form (formulation) is appropriate for children and estimate the proportion of formulations considered 'inappropriate' in a cohort of hospitalised paediatric patients with a chronic illness.

Health Equity in Pediatric Drug Development: Translating Aspiration into Operation.

The concept of health equity-the attainment of the highest possible level of health for all members of society-requires equitable access to all aspects of healthcare, including pediatric drug development. However, many communities are under-represented in pediatric drug development programs. Barriers to participation include geographic, economic, racial/ethnic bias, legal, cultural, linguistic, and other factors.

From paediatric formulations development to access: Advances made and remaining challenges.

Developing suitable paediatric formulations and ensuring access to them by the greatest number of the 2.2 billion children worldwide are equally important to provide optimal pharmacotherapy. This review focuses on the progress made over the last two decades with paediatric oral formulations with respect to evidence for acceptability and dosing flexibility of liquid and solid oral dosage forms.