A stepwise approach to provide the totality-of-the-evidence regarding the safety and efficacy of the proposed biosimilar products is recommended for the regulatory approval of biosimilar products by the United States Food and Drug Administration (FDA). The stepwise approach involves similarity assessment on (i) critical quality attributes (CQAs) that are relevant to clinical outcomes in analytical studies, (ii) extent and rate of drug absorption in pharmacokinetic and pharmacodynamics (PK/PD) studies, and (iii) safety, tolerability and efficacy primary endpoints in clinical and immunogenicity studies. Similarity assessment depends heavily on the selection of similarity margins. For analytical and PK/PD similarity assessment, similarity margins are well-established. For clinical similarity assessment, however, no explicit and universally accepted similarity margins exist in practice. In this article, we reviewed several methods provided in literature and regulatory guidance for the determination of similarity margins. Extensive simulation studies were conducted to evaluate the relative performances of these methods. A couple of case studies were presented to illustrate the proposed methods for selection of similarity margins.
Author(s): Jiancheng Cheng, Wenting Qiu, Ni Gao, Jun Zhu, and Shein-Chung Chow