Mapping the rare disease paediatric clinical trial availabilities in Europe

Abstract

Introduction: The prevalence and complexity of rare diseases (RDs) require concerted efforts in research and clinical trial capabilities. This paper aims to map the clinical trial sites within the Collaborative Network for European Clinical Trials for Children (conect4children, c4c) consortium and the European Reference Networks for Rare Diseases (ERNs), assessing their potential overlap and opportunities for synergies to optimize the selection and preparedness of sites for paediatric RD clinical trials.

Method: A quantitative cross-mapping analysis was performed with publicly available data from ERN and c4c sites across 19 countries, complemented by information on paediatric site capabilities through interviews with network coordinators. Site analyses were done at country and setting levels. Heatmaps and an interactive matrix tool were developed using RStudio (v2023.12.0).

Results: The highest overlap between ERN and c4c networks is found in the Netherlands, Belgium, Sweden, Denmark, and the Czech Republic, indicating strong integration in these regions, while Nordic (Sweden and Denmark), Eastern, and Southern European countries show varying levels of overlap. The median proportion of regional sites to University sites is 0.05 (IQR 0.12) across ERNs and 0.25 (IQR 0.37) across c4c national networks. The matrix tool can identify overlap and its absence for both university and regional hospitals, enhancing the preparedness and reach of paediatric rare disease trials. ERN representatives confirm the heatmap and matrix tool's utility in improving site selection and fostering network cooperation.

Conclusion: Heatmap analyses reveal a significant but incomplete overlap of RD clinical trial sites between ERNs and c4c in parts of Europe, suggesting strong potential for cross-network collaboration to enhance paediatric RD trial recruitment and outcomes.

Keywords: drug development; network engagement; networks; paediatric; rare diseases c4c -ERN mapping clinical trial availabilities.

Figure 1

Mapping of available site information. The blue boxes include the publicly available information. The red box indicates where non-public available information had to be requested from the coordinators. The green boxes identifies cases where verification of non-public member sites for the three c4c national networks was required. The dark blue box with cross mapping analysis shows the source data basis for the site identification mapping between c4c and ERNs, including paediatric-oriented HCP, removal of non-paediatric or not applicable ERNs, for both adult and paediatric as well as paediatric only. Within the c4c networks, one network is representing two countries. *ERNs that do not see paediatric patients. **ERN not applicable for use within the c4c structure due to oncology focus. c4c, conect4children consortium; ERN, European Reference Network. Created with BioRender.com (2023).

Figure 2

Overview of overlapping countries between c4c and ERN. Countries included in both ERNs and c4c are shown in red. The countries that do not have a c4c national network are shown in yellow. The UK is a national network within c4c, however, does not showcase its involved sites and is shown in blue. One ERN involves the UK yet is not a standardly included country in the ERNs. c4c, conect4children consortium; ERN, European Reference Network. Created with Mapchart.net (2024).

Figure 3

Heatmap according to absolute numbers showing overlap between c4c-ERN paediatric health care provider (HCP) per country per ERN. Colour spectrum is ordered by grey (no inclusion), to yellow and orange, and the highest in light green. Each row and column are ordered by highest average and on an ascending order. c4c, conect4children consortium; ERN, European Reference Network. For ERN acronyms please see Table 1. For the country codes, please the ISO ALPHA-2 codes.

Figure 4

Heatmap according to absolute numbers showing the total amount of paediatric health care provider (HCP) sites within the ERNs. Colour spectrum is ordered by grey (no inclusion), to orange and red, and the highest in purple. Each row and column are ordered by highest average and on an ascending order.c4c, conect4children consortium; ERN, European Reference Network. For ERN acronyms please see Table 1. For the country codes, please the ISO ALPHA-2 codes.

Figure 5

Heatmap according to relative numbers showing overlap between c4c-ERN paediatric health care provider (HCP) per country per ERN on the total amount of HCP sites within the ERNs, according to formula (1). Colour spectrum is ordered by grey (no inclusion), red (having no overlapping sites), to orange and red, and the highest in green. The median overlap is 100% with IQR of 33%. Ordered by highest average for both column and row on an ascending order. c4c, conect4children consortium; ERN, European Reference Network. For ERN acronyms please see Table 1. For the country codes, please the ISO ALPHA-2 codes.

Figure 6

Heatmap according to relative numbers showing overlap between c4c-ERN paediatric health care provider (HCP) per country per ERN on the total amount of c4c university sites per country [according to formula (2)]. Colour spectrum is ordered by grey (no inclusion), to orange and red, and the highest in green. Ordered by highest average for both column and row on an descending order. Median overlap is 33% with IQR 20%. c4c, conect4children consortium; ERN, European Reference Network. For ERN acronyms please see Table 1. For the country codes, please the ISO ALPHA-2 codes.

Figure 7

Side Bar chart showing the proportion (0–1) of paediatric regional sites connected in the ERNs vs. c4c, including all ERNs per country and corrected for duplicated site names. The ratio of regional inclusion for ERNs has a median of 0.05 (IQR 0.12). The ratio of regional inclusion for c4c networks has a median of 0.25 (IQR 0.37) as calculated by formula 3. The countries Finland and Norway have no regional sites included within both c4c and ERNs. For Greece, all the sites connected over the ERNs are regional hospitals. In the Czech Republic, no regional hospitals are connected in the c4c network. c4c, conect4children consortium; ERN, European Reference Network. For the country codes, please the ISO ALPHA-2 codes.

Figure 8

Use-case of the ERN and c4c interactive matrix: an example of ERKNet in Denmark (DK). The matrix use-case showcases the integration of ERKNet paediatric sites within Denmark (DK), detailing connections by country, site names, c4c inclusion with respective country tags, site type distinction (University as “Yes”, Regional as “No”), and cross-ERN participation. The matrix tool can be used to analyse collaborative networks and paediatric clinical trial capacities through c4c connection. c4c, conect4children consortium; ERN, European Reference Network. For ERN acronyms please see Table 1. For the country codes, please the ISO ALPHA-2 codes.

Figure 9

Location of the coordination offices per ERN in the overlapping countries within both c4c and ERNs. c4c, conect4children consortium; ERN, European Reference Network. Created within RStudio (v2023.12.0). For ERN acronyms please see Table 1.