Why Is This Subgroup Different from All Other Subgroups? Thoughts on Regional Differences in Randomized Clinical Trials

Abstract

Many Phase 3 randomized clinical trials are currently being conducted multinationally with too few participants from any individual country to allow reliable inference about the beneficial or harmful effects of the tested product using data from that country alone. Instead, the conclusions for a given country will come from the totality of the data. Insofar as “country” is just another subgroup defined by baseline variables, this strategy is defensible. On the other hand, in cases where “country” stands as a surrogate for country-specific variables that importantly influence the benefits and harms of an intervention, inferring from the study population at large to specific countries may be less appropriate. Such variables may include the nature of the disease being studied, the country-specific standard of care, the patterns of safety reporting, and the extent of adherence to study protocol. This paper presents four examples of studies where the observed treatment effect in the USA differed considerably from the effect observed elsewhere. It argues that the problem is in some sense intractable because a study large enough to provide precise estimates of effect sizes within specific countries would likely be infeasible. Instead, although the paper recommends generally applying the overall result to the participating countries, it provides suggestions for strategies in the design and analysis phase to mitigate potential inferential ambiguities.