Table 6.

Examples of reasons for closing signals, grouped by category

Category	Reason for closing signal
Too broad subgroup	The adverse event was disproportionately over-reported with the drug in several age groups, resulting in too broad an age group to assess as a risk group (e.g. 12–64 years) The adverse event was disproportionately over-reported with the drug for both subgroups (underweight and obese adults), hence, difficult to argue for a risk group The underlying condition was too non-specific, and no common pattern was identified among the reported indications (e.g. general system disorders)
Alternative explanations for subgroup disproportionality	The drug was used for different indications in males vs females; the overrepresentation of the adverse event in one of the subgroups was more likely due to the underlying disease (e.g. prostate cancer vs endometriosis for leuprorelin) The subgroup was, to a greater extent, concomitantly using another drug known to cause the adverse event The underlying condition was closely related to the adverse event, and it was difficult to argue for a potential risk group (e.g. acetylsalicylic acid and pruritus in allergic conditions) Most cases in the subgroup described non-compliance with prescription instructions, including disregard of drug–drug interactions and dosage recommendations More likely that the increased reporting among females was related to a large number of reports describing overdoses, suicidal attempts, and brand switching/reported ineffectiveness
Lack of biological plausibility	Unlikely biologic plausibility that the reaction would be influenced by weight No logical genetic or cultural explanation, and no pharmacological mechanism or metabolism found to differ for the geographical region of interest
Lack of subgroup disproportionality for related adverse events/drugs	Other related adverse events commonly reported with the drug, but none of them reproduced the disproportionate reporting in the geographical region of interest The adverse event appeared to be a symptom reported with hypersensitivity; however, a similar pattern for other terms related to hypersensitivity was not seen for females
Drug/adverse event exclusive to subgroup	The drug was exclusively used in pregnancy; hence, not relevant to talk about a risk group
Targeted monitoring in subgroup	The disproportionate reporting within the specific country was likely due to close monitoring of the drug
Misclassification of subgroup	The patients were not pregnant at the time of exposure
Very common adverse drug reaction	The adverse event was labelled as very common in general, hard to justify further highlighting of this event specifically for patients 75 years and older