Concentration-controlled or effect-controlled trials: useful alternatives to conventional dose-controlled trials?

Historically, dose-finding trials have been confirmatory in nature despite the fact that these trials represent an important and essential 'learning' phase in the drug development process. About 10 years ago 2 alternatives to the randomised dose-controlled trial (RDCT) were proposed as being more informative trial types. Controlling systemic drug exposure in order to improve efficiency of a trial forms the basis for the suggestion of a randomised concentration-controlled trial (RCCT). For the common instance where pharmacodynamic variability is larger than pharmacokinetic variability, the randomised effect-controlled trial (RECT), where patients are randomised to the effect of interest was suggested as even more informative. A survey of the literature shows that the RCCT has been sparsely applied and RECT not at all. For RCCT, the practical complications of carrying out the study seldom makes it the study type of choice. For RECT, the limited number of suitable situations for its application and the fact that the same effect is used for randomisation and analysis may explain the lack of applications. As a somewhat more favourable trial type, we suggest the randomised biomarker-controlled trial (RBCT), where patients are randomised to a certain value or range of a biomarker whereas the analysis is performed on another, clinically more relevant, effect. Although the RBCT has some attractive features, for example contributing to validation of a biomarker as a surrogate for clinical outcome, it is unlikely to be extensively used. Instead, the main shift from confirming to learning in dose-finding trials is coming from the incorporation of well-known learning components into the RDCT (e.g. sparse concentration measurements combined with population pharmacokinetic-pharmacodynamic, biomarker measurements and analysis of effect measures throughout the entire trial period).