ABSTRACT
Clinical drug development aims at developing medical treatments that are both safe and effective, or more generally, have a favorable risk-benefit relation, in a specified indication (ICH E9 1998). This, however, depends on the employed formulation, route of administration, regimen, and perhaps most importantly, dose. Every compound is toxic at excessive doses, and conversely, ineffective at sufficiently low doses. It is well recognized that in the past many drugs have initially been marketed at too high doses, leading to unnecessary safety risks and subsequent dose reductions (FDC Report 1991). Worse even, it is likely that potentially effective compounds could not be made available to patients because wrong doses were investigated in the pivotal trials. The importance of accurate dose-response information, and the frequent lack thereof, has led to the publication of a dedicated guidance on Dose-Response Information to Support Drug Registration by the International Conference of Harmonization (ICH E4 1994). According to this guidance, “assessment of dose-response should be an integral component of drug development.”
