Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019

Abstract

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety.

Fig 1. Generation of the final dataset.

Fig 1 shows the analysis criteria and the number of ADR reports identified in EudraVigilance with regard to the defined inclusion and exclusion criteria. ¹The historic date corresponds to the date of the query. This date was set at the beginning and was applied to all subsequent analyses in order to exclude subsequent changes to the dataset (e.g. due to follow-up reports).

Fig 2. Total number of ADR reports per year stratified by seriousness and primary reporting source.

Fig 3. Annual number of ADR reports per 100,000 inhabitants and assumed drug-exposed inhabitants (based on two consecutive published estimations of assumed drug exposure).

Fig 3 depicts the annual number of ADR reports per 100,000 inhabitants and assumed drug- exposed inhabitants based on two consecutive published estimations of assumed drug exposure KiGGS 1 [23] and KiGGS 2 [22].

Fig 4

A) Average number of ADR reports per 100,000 inhabitants; B) Average number of ADR reports per 100,000 assumed drug-exposed inhabitants (KiGGS 1 [27]); C) Average number of ADR reports per 100,000 assumed drug-exposed inhabitants (KiGGS 2 [26]). Fig 4A shows the mean (+/- SD) number of ADR reports per 100,000 inhabitants distributed by age and sex. Fig 4B and 4C show the mean (+/- SD) number of ADR reports per 100,000 assumed drug-exposed inhabitants distributed by age and sex. The proportion of drug-exposed children was taken from the KiGGS 1 study (Fig 4B) [27] and the KiGGS 2 study (Fig 4C) [26]. KiGGS 2 [26] does not present the number of applied drugs for the age group 0–2 years, hence, no calculation for this age group is shown in Fig 4C. For the calculation of the assumed drug-exposed inhabitants, the number of inhabitants per year (2000–2018) was multiplied with the proportion of drug-exposed children.