Adaptive seamless design for establishing pharmacokinetics and efficacy equivalence in developing biosimilars

Recently, numerous pharmaceutical sponsors have expressed a great deal of interest in the development of biosimilars, which requires clinical trials to demonstrate the equivalence of pharmacokinetics (PK) and clinical efficacy. Pharmacodynamics (PD) may be used in evaluating efficacy if there are relevant PD markers available. However, in their absence, it is necessary to design the associated clinical trials to include efficacy measures as the primary endpoint. In this study, we propose an adaptive seamless PK and efficacy design with the frameworks to remedy the risk of misspecification of both PK and efficacy parameters. Here, we consider the clinical development of biosimilars including their evaluation in patients rather than healthy volunteers under a situation where both PK and efficacy parameters are required to demonstrate the equivalence. To avoid the risk associated with the failure to confirm equivalence, incorporating the new PK trial for PK equivalence within the PK portion, which is the early stage for the efficacy part, and sample size re-calculation for the efficacy equivalence are considered in the proposed method. This proposal provides appealing advantages such as a shorter period, additional cost saving, and smaller number of patients required.