Safety Related Drug-Labelling Changes

Abstract

Introduction: With increasing volumes of postmarketing safety surveillance data, data mining algorithms (DMAs) have been developed to search large spontaneous reporting system (SRS) databases for disproportional statistical dependencies between drugs and events. A crucial question is the proper deployment of such techniques within the universe of methods historically used for signal detection. One question of interest is comparative performance of algorithms based on simple forms of disproportionality analysis versus those incorporating Bayesian modelling. A potential benefit of Bayesian methods is a reduced volume of signals, including false-positive signals.

Objective: To compare performance of two well described DMAs (proportional reporting ratios [PRRs] and an empirical Bayesian algorithm known as multi-item gamma Poisson shrinker [MGPS]) using commonly recommended thresholds on a diverse data set of adverse events that triggered drug labelling changes.

Methods: PRRs and MGPS were retrospectively applied to a diverse sample of drug-event combinations (DECs) identified on a government Internet site for a 7-month period. Metrics for this comparative analysis included the number and proportion of these DECs that generated signals of disproportionate reporting with PRRs, MGPS, both or neither method, differential timing of signal generation between the two methods, and clinical nature of events that generated signals with only one, both or neither method.

Results: There were 136 relevant DECs that triggered safety-related labelling changes for 39 drugs during a 7-month period. PRRs generated a signal of disproportionate reporting with almost twice as many DECs as MGPS (77 vs 40). No DECs were flagged by MGPS only. PRRs highlighted DECs in advance of MGPS (1–15 years) and a label change (1–30 years). For 59 DECs, there was no signal with either DMA. DECs generating signals of disproportionate reporting with only PRRs were both medically serious and non-serious.

Discussion/conclusion: In most instances in which a DEC generated a signal of disproportionate reporting with both DMAs (almost twice as many with PRRs), the signal was generated using PRRs in advance of MGPS. No medically important events were signalled only by MGPS. It is likely that the incremental utility of DMAs are highly situation-dependent. It is clear, however, that the volume of signals generated by itself is an inadequate criterion for comparison and that clinical nature of signalled events and differential timing of signals needs to be considered. Accepting commonly recommended threshold criteria for DMAs examined in this study as universal benchmarks for signal detection is not justified.