Keywords: mutliregional clinical trials; safety; adverse events
Country to country differences may play into the observations from randomized trials in many ways. While an obvious difference in response to drugs may arise from genetic heterogeneity, cultural and social factors often influence the apparent response to therapy. Cultural habits may lead to different thresholds for seeking care in different countries. Some important influences on treatment effect relate to the different medical interventions commonly used in different countries; some to the variety of ways that physicians may diagnose disease. Other influences relate to different motivations patients have for entering trials and clinicians may have for serving as investigators. Many differences between countries are prognostic factors; that is, they influence the event rate but not the effect size. Of particular importance are differences that lead to differential treatment effect. This talk briefly mentions these features of efficacy but deals more specifically with differential reporting of adverse events by geographic region observed in many trials. Many FDA-approved drug labels include information treatment effects in the US and outside the US. Very few (if any) show country-specific rates of serious adverse events even though the relative event rates may be three or even fourfold higher in one country than in another. The data presented will show systematic (and non-systematic) differences in reporting rates across several disease areas and classes of drugs - differences that cannot be dismissed as random variation. The talk will conclude with some suggestions for data collection and reporting that aim at allowing reasonably accurate estimates of rates of adverse events.