ABSTRACT
Multiregional clinical trials (MRCTs) provide not only opportunities but also challenges. In each of two recent MRCTs (MERIT-HF Study Group, 1999; Wallentin et al., 2009), although the overall treatment effect based on all patients was statistically superior to the control, the point estimate of treatment effect in patients from the United States (US) was numerically inferior. Such inconsistency made the interpretation of the results difficult. At the 2007 FDA/Industry Workshop, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) study was used in several presentations as a motivating example for MRCT issues such as lack of prespecification of the approach to regional analysis, lack of power for regional differences making interpretation challenging, and issues of ex-US regional drivers of results. In another study called Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), the estimate of treatment effect appeared greater in North America than in Western Europe, whereas no treatment effect was apparent in Latin America and Eastern Europe (Akkerhuis et al., 2000). The apparent difference in treatment effect can be explained largely by differences in baseline characteristics, adjunctive treatment strategies as well as the methodology of myocardial infarction definition and the adjudication process.
