title: The effect of exposure misclassification in spontaneous ADR reports on the time to detection of product-specific risks for biologicals: a simulation study.
abstract: OBJECTIVE
  The availability of accurate product-specific exposure information is essential in the pharmacovigilance of biologicals, because differences in the safety profile may emerge between products containing the same active substance. In spontaneous adverse drug reaction (ADR) reports, drug exposure may, however, be misclassified, that is, attributed to the incorrect product. The aim of this study was to explore the effect of exposure misclassification on the time to detection of product-specific risks in spontaneous reporting systems.
  
  
  METHODS
  We used data simulations to explore the effect of exposure misclassification. We simulated an active substance-specific subset of a spontaneous reporting system and used the proportional reporting ratio for signal detection. The effect of exposure misclassification was evaluated in three test cases representing product-specific ADRs that may occur for biologicals and studied in relative terms by varying the model parameters (market share and relative risk).
  
  
  RESULTS
  We found that exposure misclassification results in the largest delay in identification of risks that have a weak association (relative risk < 2 or 3) with the product of interest and in situations where the product associated with the unique risk has a large (>50%) market share. The absolute public health impact of exposure misclassification, in terms of cases/time to detection, varied considerably across the test cases.
  
  
  CONCLUSIONS
  Exposure misclassification in ADR reports may result in a delayed detection of product-specific risks, particularly in the detection of weak drug-event associations. Our findings can help inform the future implementation and refinement of product-specific and batch-specific signal detection procedures.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: Niels S
authors.initials: NS
authors.lastname: Vermeer
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Ebbers
authors.affiliation: Medicines Evaluation Board, Utrecht, The Netherlands.|Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sabine M J M
authors.initials: SM
authors.lastname: Straus
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.|Medicines Evaluation Board, Utrecht, The Netherlands.
authors.forename: Marie L
authors.initials: ML
authors.lastname: De Bruin
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D001688:Biological Products / Q000008:administration & dosage* / Q000009:adverse effects / Q000592:standards; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D006801:Humans; D060735:Pharmacovigilance; D018570:Risk Assessment
chemical_list: D001688:Biological Products
keywords: biological; biosimilars; disproportionality; exposure misclassification; pharmacoepidemiology; signal detection; spontaneous reports