EVALUATION OF THE PROPOSED FDA PILOT DOSE-RESPONSE METHODOLOGY FOR TOPICAL CORTICOSTEROID BIOEQUIVALENCE TESTING

Purpose. The American FDA has recently released a Guidance document fo r topical corticosteroid bioequivalence testing. The purpose of this s tudy was to evaluate the recommendations of this document for appropri ateness. The new specifications require a dose-vasoconstriction respon se estimation by the use of a Minolta chromameter in a preliminary pil ot study to determine the parameters for use in a pivotal bioequivalen ce study. Methods. The visually-assessed human skin blanching assay me thodology routinely practiced in our laboratories was modified to comp ly with the requirements of the pilot study so that visual and chromam eter data could be compared. Two different cream formulations, each co ntaining 0.12% betamethasone 17-valerate, were used for this compariso n. Results. Visual data showed the expected rank order of AUC values f or most dose durations whereas the chromameter data did not show simil ar results. The expected rank order of AUC values for both chromameter and visual data was not observed at very short dose durations. In fit ting the data to pharmacodynamic models, equivalent goodness of fit cr iteria were obtained when several different parameter estimates were u sed in the model definition, however the visual data were best describ ed by the sigmoid E(max) model while the chromameter data were best de scribed by the simple E(max) model. Conclusions. The E(max) values pre dicted by the models were close to the observed values for both data s ets and, in addition, excellent correlation between the AUC values and the maximum blanching response (R(max)) (r > 0.95) was noted for both methods of assessment. The chromameter ED(50) values determined in th is study were approximately 2 hours for both preparations. At this dos e duration the instrument would not be sensitive enough to distinguish between weak blanching responses and normal skin for bioequivalence a ssessment purposes.