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Time‐to‐onset in spontaneous reports: the possibility to detect the unexpected

We read with great interest the paper entitled Using time-to-onset for detecting safety signals in spontaneous reports of adverse events following immunization: a proof of concept study by Van Holle et al. published in the June 2012 issue of this journal.1 The authors propose that safety signals in collections of spontaneous reports (in their case, adverse events following immunization) can be identified based on patterns of reported time-toonset that deviate from the overall patterns of reported time-to-onset of that drug with other adverse drug reactions (ADRs) and of that ADR with other drugs. This is a novel approach that explicitly contradicts the alternative strategy of screening for reported time-to-onset patterns consistent with an overall pattern for the ADR (in particular, for drugs known to cause it). The assumption that underpins this approach is that most reported drug–ADR pairs are not causally related so that the overall time-to-onset patterns are dominated by reporting biases and noise. Wewould like to share the results of an analysis, which indicates that a method such as that proposed by van Holle et al. could have identified the deviating pattern of long-latency angioedema due to angiotensin-converting enzyme (ACE) inhibitors before the possibility of a delayed onset of angioedema for ACE inhibitors was first put forth.2–4 This was accomplished by a retrospective analysis of the WHO Global Individual Case Safety Reports database, VigiBase, restricted to reports up until 1990. Figure 1 shows the empirical distributions of reported time-to-onset for ACE inhibitors with any suspected ADR, for angioedema with any drug, and for angioedema with ACE inhibitors. The distribution of reported time-to-onset for angioedema with ACE inhibitors is shorter than that for ACE inhibitors in general and longer than that for angioedema in general, indicating that it could be detected by the proposed method. On a higher level, it is encouraging to note the capability of the spontaneous reporting system to overcome the confirmation bias; that is, health professionals reported the cases of angioedema as suspected adverse reactions despite the observed time-to-event much exceeding the expected latency known at that time. A strength of the method by van Holle and co-workers is that it automatically adjusts for variation in the duration of treatment between drugs. We have previously reported results that indicate that the expected duration of treatment may have considerable impact on the reported time-to-onset in collections of spontaneous reports: reported time-to-onset was shorter for hepatitis with six drugs that tend to be used short-term than for angioedema with six drugs that tend to be used long term.5 The method proposed by Van Holle et al.