title: International differences in treatment effect: do they really exist and why?
abstract: With the increasing globalization of clinical trials, the opportunity exists to explore potential geographic differences in treatment effect within any major trial. Such geographic differences may arise because of international differences in patient selection, medical practice, or evaluation of outcomes, and such international variations need better documentation in trial reports. Appropriate pre-defined statistical analyses, including statistical tests of interaction regarding geographic heterogeneity in treatment effect, are important. Geographic variations are a particularly tricky form of subgroup analysis: they lack statistical power, are at best hypothesis-generating and can generate more confusion than insight. Referring to key examples, e.g. the PLATO and MERIT-HF, we emphasize the need for caution in interpreting evidence of potential geographic inconsistencies in treatment effect. Although it is appropriate to explore any biological or practical reasons for apparent geographic anomalies in treatment effect, the play of chance is often the most plausible and wise interpretation.
authors.affiliation: Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pocock
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Calvo
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasad
authors.forename: Luigi
authors.initials: L
authors.lastname: Tavazzi
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.forename: Angeles
authors.initials: A
authors.lastname: Alonso Garcia
mesh_terms: D003625:Data Collection; D062306:Geography, Medical; D006801:Humans; D038622:Internationality; D018579:Patient Selection; D011364:Professional Practice; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards*; D016896:Treatment Outcome
keywords: Geographic differences; Randomized clinical trials; Subgroup analysis