Biosimilars are biological products similar to, but not the same as, the innovator products. Both the European Medicines Agency and the Food and Drug Administration have released detailed guidance on the development of biosimilars. This guidance requires the pivotal phase 3 clinical study to have an equivalence design, which means that the study objective is to demonstrate that one treatment is neither "worse than" nor "better than" the other by some "clinically unimportant" amount. The most critical and controversial step in designing such a study is the choice of equivalence margin, as this determines the conclusion of the study. In this paper, we outline the methodology for determining an equivalence margin and, through case studies on biosimilar trastuzumab (HERCEPTIN ) and biosimilar bevacizumab (AVASTIN), explain the challenges of applying this in practice and why the synthesis method should be given greater consideration by regulatory authorities and biosimilar developers.
Keywords: biosimilar; equivalence margin; reference product; sample size.