In multi-national studies the general level of care (concomitant therapies, access to technologies, patent support programmes) received by trial participants in some healthcare systems or study sites may differ from usual practice in the healthcare system of interest. This may have implications for the generalisability of the effectiveness results to that system. Recruitment of study participants may require a specific diagnostic activity that is currently not part of usual practice. Clinicians’ or participants’ willingness to participate or complete the trial may not be independent of factors such as adherence or underlying risk, which may be associated with effectiveness. This may be important when considering the applicability of results from studies in highly-resourced healthcare systems such as US, with increased access to sophisticated diagnostic and monitoring services as well as high-intensity care, to local populations where such services may not be available. If the effect of the medicine itself cannot be isolated from trial setting, then the combination of setting and intervention may need to be considered more broadly as an intervention strategy in its own right.