Use of measures of disproportionality in pharmacovigilance: three Dutch examples.

Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance. In The Netherlands 'the Netherlands Pharmacovigilance Foundation Lareb' maintains such a system. A primary aim in pharmacovigilance is the timely detection of either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved, i.e. signal detection. Adequate signal detection solely based on the human intellect (case by case analysis or qualitative signal detection) is becoming time consuming given the increasingly large number of data, as well as less effective, especially in more complex associations such as drug-drug interactions, syndromes and when various covariates are involved. In quantitative signal detection measures that express the extent in which combinations of drug(s) and clinical event(s) are disproportionately present in the database of reported suspected ADRs are used to reveal associations of interest. Although the rationale and the methodology of the various quantitative approaches differ, they all share the characteristic that they express to what extent the number of observed cases differs from the number of expected cases. In this paper three Dutch examples are described in which a measure of disproportionality is used in quantitative signal detection in pharmacovigilance: (i) the association between antidepressant drugs and the occurrence of non-puerpural lactation as an example of an association between a single drug and a single event; (ii) the onset or worsening of congestive heart failure associated with the combined use of nonsteroidal anti-inflammatory drugs and diuretics as an example of an association between two drugs and a single event (drug-drug interaction); and the (iii) (co)-occurrence of fever, urticaria and arthralgia and the use of terbinafine as an example of an association between a single drug and multiple events (syndrome). We conclude that the use of quantitative measures in addition to qualitative analysis is a step forward in signal detection in pharmacovigilance. More research is necessary into the performance of these approaches, especially its predictive value, its robustness as well as into further extensions of the methodology.