Methodological Consideration for Clinical Development of Bevacizumab Biosimilar Candidate

Unlike chemical generics, biosimilars are not exact copies of the originator product, so are similar, but not identical, in efficacy and safety to the reference product (1, 2). This approach toward clinical development of large biologics is unified across WHO, EMA and USFDA. The purpose of the clinical similarity study is to directlycomparethe biosimilar candidate with the reference product, evaluating efficacy, safety, and immunogenicity. A biosimilar study is not intended to reestablish clinical efficacy or safety; instead the goal is to confirm there are no clinically meaningful differences. For these reasons, an applicant should consider the population, endpoints, sample size, and study duration in that these factors should be adequately sensitive to detect differences between products, should they exist. Assessment of clinical equivalence between a bevacizumab biosimilar candidate and the reference product (Avastin) should be performed in a sensitive population using a sensitive endpoint, and using an equivalence design. Across the seven tumor types that Avastin has proved efficacy and safety, non-small cell lung cancer shows the large magnitude of response that is needed in order to be able to detect a difference, with acceptable predicted maximal loss in long-term efficacy (3, 4). A key determinant in the design of a clinical biosimilar study is the selection of equivalence, or non-inferiority, margin for the primary endpoint. Such a margin must be chosen (1) to maintain a substantial part of the historically establishedefficacyof bevacizumab, and(2) to mitigate the risk of potential differences in long-term efficacy (3, 4).