title: Computing limits on medicine risks based on collections of individual case reports.
abstract: BACKGROUND
  Quantifying a medicine's risks for adverse effects is crucial in assessing its value as a therapeutic agent. Rare adverse effects are often not detected until after the medicine is marketed and used in large and heterogeneous patient populations, and risk quantification is even more difficult. While individual case reports of suspected harm from medicines are instrumental in the detection of previously unknown adverse effects, they are currently not used for risk quantification. The aim of this article is to demonstrate how and when limits on medicine risks can be computed from collections of individual case reports.
  
  
  METHODS
  We propose a model where drug exposures in the real world may be followed by adverse episodes, each containing one or several adverse effects. Any adverse episode can be reported at most once, and each report corresponds to a single adverse episode. Based on this model, we derive upper and lower limits for the per-exposure risk of an adverse effect for a given drug.
  
  
  RESULTS
  An upper limit for the per-exposure risk of the adverse effect Y for a given drug X is provided by the reporting ratio of X together with Y relative to all reports on X, under two assumptions: (i) the average number of adverse episodes following exposure to X is one or less; and (ii) adverse episodes that follow X and contain Y are more frequently reported than adverse episodes in general that follow X. Further, a lower risk limit is provided by dividing the number of reports on X together with Y by the total number of exposures to X, under the assumption that exposures to X that are followed by Y generate on average at most one report on X together with Y. Using real data, limits for the narcolepsy risk following Pandemrix vaccination and the risk of coeliac disease following antihypertensive treatment were computed and found to conform to reference risk values from epidemiological studies.
  
  
  CONCLUSIONS
  Our framework enables quantification of medicine risks in situations where this is otherwise difficult or impossible. It has wide applicability, but should be particularly useful in structured benefit-risk assessments that include rare adverse effects.
authors.affiliation: Uppsala Monitoring Centre, Box 1051, SE-751 40, Uppsala, Sweden. ola.caster@who-umc.org.
authors.forename: Ola
authors.initials: O
authors.lastname: Caster
authors.forename: G Niklas
authors.initials: GN
authors.lastname: Norén
authors.forename: I Ralph
authors.initials: IR
authors.lastname: Edwards
mesh_terms: D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D018570:Risk Assessment