The inherent time-varying nature of dynamics in chemical processes often limits the lifetime performance of model-based control systems, as the plant and disturbance dynamics change over time. A critical step in the maintenance of model-based controllers is distinguishing control-relevant plant changes from variations in disturbance characteristics. In this paper, prediction error identification is used to evaluate a hypothesis test that detects if the performance drop arises from control-relevant plant changes. The decision rule is assessed by verifying whether an identified model of the true plant lies outside the set of all plant models that lead to adequate closed-loop performance. A unified experiment design framework is presented in the least costly context (i.e., least intrusion of nominal plant operation) to address the problem of input signal design for performance diagnosis and plant re-identification when the performance drop is due to plant changes. The application of the presented performance diagnosis approach to a (nonlinear) chemical reactor demonstrates the effectiveness of the approach in detecting the cause of an observed closed-loop performance drop based on the designed least costly diagnosis experiment.