Using Multiple Pharmacovigilance Models Improves the Timeliness of Signal Detection in Simulated Prospective Surveillance

Drug Saf. 2017 Nov;40(11):1119-1129. doi: 10.1007/s40264-017-0555-9.


Introduction: Prospective pharmacovigilance aims to rapidly detect safety concerns related to medical products. The exposure model selected for pharmacovigilance impacts the timeliness of signal detection. However, in most real-life pharmacovigilance studies, little is known about which model correctly represents the association and there is no evidence to guide the selection of an exposure model. Different exposure models reflect different aspects of exposure history, and their relevance varies across studies. Therefore, one potential solution is to apply several alternative exposure models simultaneously, with each model assuming a different exposure-risk association, and then combine the model results.

Methods: We simulated alternative clinically plausible associations between time-varying drug exposure and the hazard of an adverse event. Prospective surveillance was conducted on the simulated data by estimating parametric and semi-parametric exposure-risk models at multiple times during follow-up. For each model separately, and using combined evidence from different subsets of models, we compared the time to signal detection.

Results: Timely detection across the simulated associations was obtained by fitting a set of pharmacovigilance models. This set included alternative parametric models that assumed different exposure-risk associations and flexible models that made no assumptions regarding the form/shape of the association. Times to detection generated using a simple combination of evidence from multiple models were comparable to those observed under the ideal, but unrealistic, scenario where pharmacovigilance relied on the single 'true' model used for data generation.

Conclusions: Simulation results indicate that, if the true model is not known, an association can be detected in a more timely manner by first fitting a carefully selected set of exposure-risk models and then generating a signal as soon as any of the models considered yields a test statistic value below a predetermined testing threshold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adverse Drug Reaction Reporting Systems / statistics & numerical data*
  • Computer Simulation
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Humans
  • Models, Theoretical*
  • Pharmacovigilance*
  • Prospective Studies
  • Risk
  • Time Factors

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