Biosimilar drugs: how safe are they?

Abstract

In this issue of Leukemia and Lymphoma, Candelaria et al. [1] report the results of a double-blind randomized multicenter international study comparing rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with the biosimilar RTXM83 in combination with CHOP chemotherapy in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). Biosimilar drugs are not the ‘low-cost’ version of expensive drugs. The development, production, and assessment of biosimilar drugs is a significantly complex procedure that involves a rigorous and thorough process [2,3]. The development of a biosimilar drug starts with an exhaustive characterization of the reference product to establish the manufacturing process of the biosimilar. The newly developed biosimilar has to undergo a comparability assessment that follows a comprehensive stepwise approach. This includes comparative quality studies, followed by comparative non-clinical studies and, finally, comparative clinical studies. The latter involves again a stepwise process starting with pharmacokinetic (PK) studies and, if feasible, pharmacodynamic (PD) studies, followed by clinical efficacy and safety studies. The last step thus required for the approval of a new biosimilar drug is the performance of comparative clinical trials aiming at demonstrating equivalence in efficacy with no differences in safety between the reference product and the biosimilar. The extent of comparative clinical studies required for the approval of a specific biosimilar is determined by the regulatory agencies based on a case-by-case approach. Hence, the approval of biosimilar products follows a process that is as comprehensive and rigorous as that required for novel agents. In addition, after being introduced to the market, biosimilar drugs in Europe are subject to ‘additional monitoring’, whereas this is a requirement only for biological drugs that have been approved after 2011. Of note, the European Medicines Agency (EMA) has now acquired a long experience in the assessment and approval of biosimilars, having approved more than 25 biosimilar drugs, the first one being approved in 2006. Importantly, none of them have been withdrawn or suspended for safety or efficacy reasons highlight the safety of these products [3]. Other studies have compared other rituximab biosimilars in patients with follicular lymphoma (FL), either as a single agent in patients with low-burden [4] or in combination with chemotherapy in patients with advanced disease [5,6], but thus far, no clinical trials using rituximab biosimilar had been performed in patients with DLBCL. Candelaria et al. have previously published the detailed PK and PD results of the RTXM83-AC-01-11 trial [7] and in the current paper [1], the authors demonstrate that six cycles of CHOP in combination with the biosimilar RTXM83 results in a non-inferior efficacy with similar safety as R-CHOP in patients with DLBCL. This study represents further evidence of the safety and efficacy of biosimilars and of the strength of the procedures developed to produce, assess, and approve such drugs. The relevance of the current study is that, although different regulatory bodies require different conditions, the results of previous studies in a given indication can be extrapolated to approve the biosimilar for another condition without requiring additional clinical trials. Once again, ‘extrapolation’ is not a simple and automatic decision but it follows a rigorous scientific analysis of the data available. The implication, thus, of this study not only for the management of patients with DLBCL but also for those with other types of lymphoma (and, beyond the oncology field, maybe for patients with other conditions such as rheumatological disorders) is huge in terms of potential cost-saving and the possibility of expanding the population of patients that can access standard therapies that would be otherwise prohibitive, either for patients or for healthcare systems [8].