The value of time-to-onset in statistical signal detection of adverse drug reactions: a comparison with disproportionality analysis in spontaneous reports from the Netherlands.
In pharmacovigilance, the commonly used disproportionality analysis (DPA) in statistical signal detection is known to have its limitations. The aim of this study was to investigate the value of the time to onset (TTO) of ADRs in addition to DPA.



We performed a pilot study using individual case safety reports (ICSRs) for three drugs (Cervarix®, nitrofurantoin and simvastatin) from the Lareb spontaneous reporting database. TTO distributions for drug - ADR associations were compared to other ADRs for the same drug and to other drugs for the same ADR using two-sample Anderson-Darling testing. Statistically significant associations were considered true positive (TP) signals if the association was present in the official product information of the drug. Sensitivity and specificity for the TTO method were compared with the DPA method. As a measure of disproportionality, the reporting odds ratio (ROR) was used.



In general, sensitivity was lower, and specificity was higher for the TTO method compared to DPA. The TTO method showed similar sensitivity for all three drugs, whereas specificity was lower for Cervarix®. Eight additional TP signals were found using the TTO method compared to DPA.



Our study shows that statistical signal detection based on the TTO alone resulted in a limited number of additional signals compared to DPA. We therefore conclude that the TTO method is of limited value for full database statistical screening in our setting. Copyright © 2016 John Wiley & Sons, Ltd.
Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, the Netherlands.
Joep H G
JH
Scholl
Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, the Netherlands.|Department of PharmacoTherapy, -Epidemiology and -Economics, University of Groningen, Groningen, the Netherlands.
Eugène P
EP
van Puijenbroek
D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D016208:Databases, Factual / Q000706:statistics & numerical data; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D006801:Humans; D009426:Netherlands / Q000453:epidemiology; D009582:Nitrofurantoin / Q000009:adverse effects; D016017:Odds Ratio; D053918:Papillomavirus Vaccines / Q000009:adverse effects; D060735:Pharmacovigilance; D010865:Pilot Projects; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000009:adverse effects; D013997:Time Factors
D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18; D009582:Nitrofurantoin; D019821:Simvastatin
ADR; latency; pharmacoepidemiology; pharmacovigilance; signal detection; time to onset