Paediatric Phase I/II Clinical Trial Assessments Under the New EU Clinical Trial Regulation: A Descriptive Analysis

Children remain underrepresented in clinical research, despite regulatory frameworks like the EU Paediatric Regulation and Paediatric Investigation Plans (PIPs). The 2024 Declaration of Helsinki revision now recognises excluding vulnerable populations from research as a potential ethical concern. The Clinical Trial Regulation (EU) No 536/2014 aims to harmonise clinical trial application assessment procedures through a coordinated process involving a Reporting Member State (RMS) and Member States Concerned (MSCs).

To determine if harmonisation is occurring, we conducted the first systematic analysis of Phase I/II paediatric trial application assessments across Member States (MS) in the European Union (EU) focusing on assessment variability, evidence requirements, PIP integration, and adolescent inclusion practices in adult trials.

In the context of a fellowship at the European Medicines Agency, non-public data of 160 paediatric Clinical Trial Applications (CTAs) submitted through the Clinical Trial Information System (January 2022-July 2024) were screened, with inclusion of 55 Phase I/II trials in the main analysis (selected for their focus on innovative treatments and complex risk-benefit assessments). For each CTA, requests for information (consisting of considerations stated by the RMS and MSCs), assessment reports, sponsor responses, and PIP documentation were reviewed. The number of considerations in the requests for information per MS was analysed with median values calculated. Also, considerations were systemically categorised and assessment patterns between RMS and MSC roles were compared. It was examined how PIPs were integrated into assessments and approaches to adolescent inclusion in adult trials was analysed through systematic review of MS considerations.

Of the 160 paediatric CTAs screened, 145 received authorisation, 10 were not authorised, and 5 were withdrawn. Among the 145 authorised CTAs, 61 were Phase I/II trials, 55 of which were included in the main analysis. Analysis of these applications revealed significant heterogeneity in both the number and type of considerations raised across MS, with the median number of considerations per CTA ranging from 5.5 to 26 across MSs (p = 0.025), with particularly marked variation when MSs acted as MSCs compared to RMSs-where additional considerations ranged from zero to 25 per CTA on top of those raised by the RMS. In 36% (20/55), MSs raised concerns about insufficient (pre-)clinical evidence pointing to divergent interpretations of evidence requirements. The degree to which PIPs were integrated into CTA assessments varied considerably-ranging from strict adherence to PIP elements to minimal consideration. In 92% (11/12), MSs showed reluctance to include adolescents in adult Phase I/II trials.

Despite the CTR's harmonisation goals, substantial variations persist in assessment practices across MSs, particularly regarding evidence requirements, PIP integration, and adolescent inclusion in adult trials. These variations directly impact equitable access to clinical trials for children across the EU. Urgent regulatory guidance is needed to align interpretation of evidence standards, clarify the role of PIPs in CTA evaluation, and support evidence-based approaches to adolescent inclusion in adult trials.