Bioequivalence and Bioavailability Forum

From Book, Lawrence X. Yu • Bing V. Li Editors FDA Bioequivalence Standards

"The US FDA has generally recommended single-dose pharmacokinetic studies for BE demonstration of both immediate- and modified-release products (FDA 2003a). However, steady-state studies may be needed for BE demonstration in some cases (FDA 2003a). As an example, safety considerations for healthy volunteers may suggest the use of patients who are already receiving the medication and it is possible to establish BE without disrupting the ongoing treatment of a patient using a steady-state study. This scenario can be illustrated by clozapine, a drug used to treat the symptoms of schizophrenia (FDA 2005). To demonstrate BE of clozapine tablets, applicants are requested to conduct a single-dose (100 mg), two-treatment, two-period crossover study at steady state. In this case, subjects recruited are patients receiving a stable daily dose of clozapine administered in equally divided doses at 12 h intervals. In addition, patients who are receiving multiples of 100 mg every 12 h can participate in the study of the 100 mg strength by continuing their established maintenance dose. The US FDA recommends that these studies not be conducted using healthy subjects because of safety concerns. According to the crossover randomization schedule, an equal number of patients would receive either the generic or reference formulation in the same dose as administered prior to the study every 12 h for 10 days. Patients would then be switched to the other product for a second period of 10 days. No washout period is necessary between the two treatment periods since it is a steady-state study. After the study is completed, patients could be continued on their current dose of clozapine using an approved clozapine product as prescribed by their clinicians. In all cases where a steady-state study is indicated, applicants are required to carry out appropriate dosage administration and sampling to document the attainment of steady state."

"In all cases where a steady-state study is indicated, applicants are required to carry out appropriate dosage administration and sampling to document the attainment of steady state"

https://www.fda.gov/media/88254/download