Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars

Abstract

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

Biologic Drug Quality Assurance to Optimize HER2 + Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3

“…Based on the totality of the evidence, which includes sophisticated analytic and clinical assessments, approved biosimilars of trastuzumab, such as SB3, have the potential to increase accessibility to trastuzumab-based therapy without compromising efficacy or safety [ 13 , 15 , 27 , 30 , 38 , 41 , 44 ]. Furthermore, although the phase III study of SB3 in patients with early HER2 + breast cancer was not designed to detect a relationship between ADCC and clinical outcomes, and survival results by exposure to ADCC drift were derived from a post hoc analysis, the SB3 development process has provided some evidence to support the hypothesis of a relationship between ADCC activity and long-term survival [ 27 ].…”

“…A proposed biosimilar cannot be superior to its reference product [ 23 , 40 , 46 ], but in the ABP 980 and SB3 phase III equivalence studies, it was observed that pCR rates were lower in patients treated with drifted batches of the trastuzumab reference product than those treated with the pre-drifted trastuzumab reference product or biosimilar trastuzumab [ 42 , 43 ]. As described in European Public Assessment Reports for SB3 and ABP 980 [ 42 , 43 ], it has been acknowledged that the downward drifts in ADCC activity in some of the trastuzumab reference product batches used in these studies could have at least partially confounded the results by contributing to the observed differences in pCR rates between treatment arms and their relatively high upper CI limits [ 13 , 15 ]. Taking totality of evidence into account, SB3 and ABP 980 were therefore considered comparable, rather than superior, to the reference product, and approved as biosimilars of trastuzumab [ 15 , 42 , 43 , 45 ].…”

“…As described in European Public Assessment Reports for SB3 and ABP 980 [ 42 , 43 ], it has been acknowledged that the downward drifts in ADCC activity in some of the trastuzumab reference product batches used in these studies could have at least partially confounded the results by contributing to the observed differences in pCR rates between treatment arms and their relatively high upper CI limits [ 13 , 15 ]. Taking totality of evidence into account, SB3 and ABP 980 were therefore considered comparable, rather than superior, to the reference product, and approved as biosimilars of trastuzumab [ 15 , 42 , 43 , 45 ].…”

“…Patents for the trastuzumab reference product recently expired in the European Union (EU) and USA (2014 and 2019, respectively) [ 12 ], and several trastuzumab biosimilars have been approved for use in the treatment of HER2 + breast cancer, including SB3 (Ontruzant; Samsung Bioepis), PF-05280014 (Trazimera; Pfizer), MYL-1401O (Ogivri; Mylan), CT-P6 (Herzuma; Celltrion), and ABP 980 (Kanjinti; Amgen) [ 13 – 15 ]. These lower cost trastuzumab biosimilars, which are now being integrated into the latest European and North American breast cancer clinical practice guidelines [ 3 , 6 ], have the potential to help contain rising healthcare expenditure and provide sustainable access to trastuzumab-based therapies in breast cancer care [ 10 , 13 , 16 – 19 ].…”

Comparison of Rituximab Originator With CT-P10 Biosimilar in Patients With Primary Sjögren's Syndrome: A Retrospective Analysis in a Real-Life Setting

“…During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. These comparative data are generated in a stepwise hierarchical process from extensive laboratory-based structural analyses and functional assays, to clinical safety and efficacy (24). Demonstration of similarity in these trials, along with extensive evidence of similarity from other tests, allows the extrapolation of data with the reference compound to the biosimilar in other non-tested indications (25).…”