Scope

A selection of risk factors for ADRs defined the set of covariates to be screened in the statistical signal detection. The risk factors were selected based on clinical relevance and technical feasibility and included patient age, sex, body mass index (BMI), pregnancy, underlying condition, reporting country, and geographical region. Within each covariate, one or several subgroups were defined, representing the potential risk groups to be explored. The covariates and their corresponding subgroups with justifications are presented in Table 1.

Covariates and the corresponding subgroups with justifications

HLGTs High Level Group Terms

For patient age, the subgroups were 0–27 days, 28 days–23 months, 2–11 years, 12–17 years, 18–44 years, 45–64 years, 65–74 years, and ≥ 75 years, and for patient sex, female and male formed the two subgroups. For BMI, only underweight adults and obese adults were chosen as subgroups; the underweight subgroup comprised adults with BMI < 18.5, and the obese subgroup comprised adults with BMI ≥ 30, as defined by the reference cut-off values described by WHO [10].

The pregnancy subgroup aimed to identify harms primarily for the pregnant woman, not the foetus; however, there is no single structured field in VigiBase indicating the pregnancy status of a patient. To capture reports of likely pregnant patients, a simple algorithm was constructed to infer the pregnancy status from available information in VigiBase, such as reported terms, indications, medical history, tests and procedures, and the case narrative. For details, see Table S1 in the Electronic Supplementary Material.

Subgroups within the underlying condition covariate were defined using the reported drug indications grouped by MedDRA High Level Group Terms. The reported indications were used to infer the comorbidities of the patients, and thus the indications for all drugs on the reports were considered, not only the indication for the drug of interest.

Subgrouping by country or geographical region was primarily intended to be a surrogate for pharmaco-ethnic vulnerability. For the country covariate, each individual country holding reports in VigiBase represented a subgroup. The countries were grouped into regions to form subgroups within the geographical region covariate.