Dose–response relationship, dose determination, and adjustment 271
9.5.4 Dose adjustment for causal effect determination: RCC
trials
Although dose adjustment may introduce bias, it can a lso be used to reduce
or eliminate the bias in exposure–re sponse r elationships, by controlling indi-
vidual patient’s exposure levels. It is often not possible to control individua l
concentrations, however, a partial control can be achieved by randomized con-
centration controlle d (RCC) trials (Sanathanan et al., 1991; FDA, 2003) in
which patients are randomized into two or three exposure ranges and the PK
exposure is measured repeatedly and the dose adjusted, if necessary, until
the individual expo sure level is within the range the patient is randomized
to. Design ...