Concentration-controlled or effect-controlled trials - Useful alternativesto 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 in formative trial types. Controlling systemic drug exposure in order to impro ve efficiency of a trial forms the basis for the suggestion of a randomised concentration-controlled trial (RCCT). For the common instance where pharm acodynamic variability is larger than pharmacokinetic variability, the rand omised 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 an d RECT not at all. For RCCT, the practical complications of carrying out th e study seldom makes it the study type of choice. For RECT, the limited num ber of suitable situations for its application and the fact that the same e ffect is used for randomisation and analysis may explain the lack of applic ations. As a somewhat more favourable trial type, we suggest the randomised biomark er-controlled trial (RBCT), where patients are randomised to a certain valu e or range of a biomarker whereas the analysis is performed on another, cli nically more relevant, effect. Although the RBCT has some attractive featur es, for example contributing to validation of a biomarker as a surrogate fo r clinical outcome, it is unlikely to be extensively used. Instead, the mai n shift from confirming to learning in dose-finding trials is coming from t he incorporation of well-known learning components into the RDCT (e.g. spar se concentration measurements combined with population pharmacokinetic-phar macodynamic, biomarker measurements and analysis of effect measures through out the entire trial period).