Time to onset in statistical signal detection revisited: A follow-up study in long-term onset adverse drug reactions

PURPOSE: In a previous study, we developed a signal detection method using the time to onset (TTO) of adverse drug reactions (ADRs). The aim of the current study was to investigate this method in a subset of ADRs with a longer TTO and to compare its performance with disproportionality analysis. METHODS: Using The Netherlands's spontaneous reporting database, TTO distributions for drug-ADR associations with a median TTO of 7 days or more were compared with other drugs with the same ADR using the two-sample Anderson-Darling (AD) test. Presence in the Summary of Product Characteristics (SPC) was used as the gold standard for identification of a true ADR. Twelve combinations with different values for the number of reports and median TTO were tested. Performance in terms of sensitivity and positive predictive value (PPV) was compared with disproportionality analysis. A sensitivity analysis was performed to compare the results with those from the previous study. RESULTS: A total of 38 017 case reports, containing 32 478 unique drug-ADR associations. Sensitivity was lower for the TTO method (range 0.08-0.34) compared with disproportionality analysis (range 0.60-0.87), whereas PPV was similar for both methods (range 0.93-1.0). The results from the sensitivity analysis were similar to the original analysis. CONCLUSIONS: Because of its low sensitivity, the developed TTO method cannot replace disproportionality analysis as a signal detection tool. It may be useful in combination with other methods