3.1 ClinicalTrials.gov Data: Pediatric Clinical Trials Conducted in Europe (2007–24)

From 26 January, 2007, to 29 October, 2024, a total of 1,754 pediatric clinical trials initiated in European countries were registered in ClinicalTrials.gov. The distribution of the trials by research phase was as follows: early phase I (n = 14; 0.8%) phase I (n = 99; 5.6%), phase I/II (n = 121; 6.9%), phase II (n = 523; 29.8%), phase II/III (n = 128; 7.3%), and phase III (n = 869; 49.6%).

The majority of trials included both sexes (93.8%, n = 1,645), while 5.1% (n = 90) of the trials were restricted to male participants and 1.1% (n = 19) to female participants. Of the 1,754 trials, 20 were targeting gender-based conditions such as Duchenne muscular dystrophy, or Mucopolysaccharidosis II (Hunter syndrome). Of the 1,754 trials, 303 (17.3%) targeted both children and adult participants, while 1,451 trials (82.7%) addressed only pediatric participants.

As of the data collection completion date (29 October, 2024), 1,021 clinical trials (58.2%) were completed, and 290 trials (16.5%) were actively recruiting patients. Table 3 summarizes the overall status of all trials included in this research, noting that 94 of the trials (5.4%) were classified under the category of unknown status.

Table 3 Overall status of the clinical trials3.2 Use of Language (Mother Tongue) as Eligibility Criteria

In 95.2% (n = 1,669) of the clinical trials, there was no explicit reference to any of the official European languages or the patient’s mother tongue in the inclusion or exclusion criteria. Eighty-five (4.8%) of the 1,754 clinical trial protocols reported eligibility criteria (inclusion or exclusion criteria) regarding the language of the patient/family. Sixty-three of the 85 trials had an academic sponsor (74.1%) and 22 (25.9%) had a commercial sponsor.

The minimum and maximum number of countries involved in academic-sponsored clinical trials were 1 and 12, while for commercial-sponsored clinical trials these values were 1 and 10. The interquartile range for academic studies trials was 1 and for commercial trials was 3 (Table 4). These data demonstrate that usually academic-sponsored clinical trials are not conducted as multi-country trials.

Table 4 Statistics of European countries involved in the clinical trials

Regarding the distribution of clinical trials across pediatric subspecialties. The three pediatric subspecialties with the highest number of trials were: psychiatry (n = 25; 29.4%), neurology (n = 17; 20%), and endocrinology (n = 10; 11.8%) (Fig. 2).

Fig. 2

Number of clinical trials according to the pediatric subspecialties

References to European official languages or the term “language” with no specification of which language were found in 48 out of the 85 clinical trials (56.5%) as inclusion criteria, in 29 trials (34.1%) as exclusion criteria, in four trials (4.7%) in both inclusion and exclusion criteria. In these trials, the keyword language referred to “local language,” “primary language spoken at home,” “language that parents/caregivers clearly understand,” “understandable language,” and “language barrier”. In four clinical trials (4.7%), the reference of a European official language was in the study title (Table 5).

Table 5 Use of European languages or the word “language” as eligibility criteria in the clinical trial protocol

Of the 85 clinical trials that specified a language requirement as an eligibility criterion or in its title, English was the most frequent (n = 18, 21.2%) followed by French (n = 14, 16.5%). In total, 13 out of the 24 European official languages were included (Table 6).

Table 6 Search results of the keywords related to European official languages or related to language in the eligibility criteria and title

The Electronic Supplementary Material (ESM) includes a table summarizing the detailed references to one or more European official languages (keywords) across the 85 clinical trials, along with other parameters: therapeutic area, countries participating in the clinical trial, type of sponsor, and the section of the study protocol where the keywords were mentioned. In four of these trials, one of the keywords referred to a European official language in the title (Danish in one and Norwegian in three); in these cases, however, the terms referred to participants’ nationality and the country of the study rather than the requirement for these languages during the conduct of the trial.

3.3 Inclusion Criteria: Analysis of Text Referring to Language(s)

Of the 85 clinical trials analyzed, 48 (56.5%) included at least one keyword related to official European languages in the inclusion criteria. Each of these trials was assessed for potential language- and country-based requirements, as well as whether there was a scientific justification for requiring specific language proficiency (Table 7).

Table 7 Search results of the keywords related to European official languages or related to language in the inclusion criteria for 48 clinical trials

In 41 of the 48 clinical trials (85.4%), the requirement of proficiency in at least one European official language was found with no justification. This determination was based on the protocol design, specifically when the patient-reported outcomes, tools, or quality-of-life scales were accessible in a language(s) other than the one required in the inclusion criteria. The authors also considered that the language requirement was not necessary to ensure the achievement of the study’s scientific outcomes based on the analysis of the specifics of the clinical trial protocol review (condition, patient-reported outcomes).

In 35 of the 48 clinical trials (72.9%), the language requirement was also considered a case of country-based discrimination, as it required proficiency in a European official language other than English. In five cases, the inclusion criteria required affiliation with the French Social Security System, explicitly country-based discrimination, as it limited eligibility to residents of France.

Thirteen (27.1%) of the 48 trials included an acceptable scientific justification for the language requirement, related either to the therapeutic area that involved language or cognitive assessments or to patient- or parent-reported outcome measures that were only validated in certain languages. See the ESM for detailed information on the data findings.

3.4 Exclusion Criteria: Analysis of Text Referring to Language(s)

Of the 85 clinical trials analyzed, 29 (34.1%) included at least one keyword related to official European languages in the exclusion criteria. Language and country-based discrimination and whether there was a scientific justification for the language requirement were evaluated (Table 8). The analysis followed the inclusion criteria analysis.

Table 8 Search results of the keywords related to European official languages or related to language in the exclusion criteria from 29 pediatric clinical trials

In 26 of the 29 clinical trials (89.7%), the requirement of competence in at least one European official language was considered language-based discrimination, given that the protocol required a patient-reported outcomes tool or quality-of-life scale to be available and validated in a language other than the one required in the inclusion criterion. In 21 of the 29 clinical trials (72.4%), the language requirement was considered a case of language-based discrimination, as it required proficiency in an official language of only one European country and different from English.

In 10 of the 29 clinical trials (34.5%), the language requirement was scientifically justified, either because of the therapeutic area involving language or cognitive assessments, or because the patient/parent-reported outcome tools were only validated in certain languages. The authors considered reasonable the language requirement to ensure the achievement of the study’s scientific outcomes. See the ESM for detailed information about the data findings (keyword identified, type of study, type of discrimination, scientific justification, for or against, the use of language as an eligibility criterion, and the literal mention of the relevant keywords in the clinical trial protocol.

3.5 Inclusion and Exclusion Criteria: Analysis of Text Referring to Language(s)

Four (4.7%) of the 85 clinical trials included a reference to a European official language in both inclusion and exclusion criteria (Table 9). In two trials that required English as an eligibility criterion, caregivers of patients could participate if they had the appropriate language skills; further, the criteria did not specifically require residence in the UK, where the trials were conducted. One study conducted in France required proficiency in French and affiliation with the French healthcare system; given that, there was no option for inclusion of international patients, this study represents a case of country-based discrimination. The fourth study, conducted in Italy, required fluency in Italian. This requirement poses a significant barrier, as Italian is official only in one European country and not widely spoken as a second language across European countries.

Table 9 Language requirements in the inclusion and exclusion criteria3.6 Other Cases of Patient Discrimination Based on Eligibility Criteria

In addition to language-related criteria, other eligibility keywords were examined across the 1,754 European pediatric clinical trials. In 79 of 1,754 clinical trials (4.5%), the different keywords were included as an inclusion criterion (77.2%; n = 61), exclusion criteria (21.5%; n = 17), or both (1.3%; n = 1) (Table 10).

Table 10 Keywords distribution in study protocols in eligibility criteria for pediatric clinical trials in Europe

Specifically regarding the keyword “travel,” which appeared in 16 out of the 79 study protocols (20.3%), it was referenced in various contexts, including: “travel time and distance,” “willingness to travel to the site,” “plans to travel outside the country,” “ground-travel distance,” “ability/inability to travel,” and “safety to travel to the study site.” Of these clinical trials, 72.1% were commercially sponsored, while 27.8% were academically sponsored. With regard to pediatric subspecialties, the majority (50.6%) were in the field of infectious diseases followed by neurology (21.5%) (Table 11).

Table 11 Distribution of clinical trials according to pediatric subspecialties