Review
Comparative immunogenicity assessment: a critical consideration for biosimilar development
An appropriate assessment strategy with validated anti-drug antibody (ADA) assays is critical for comparative evaluation of immunogenicity between a proposed biosimilar and its reference product. The strategy should aim to identify potential differences in immune responses between these products. While an ADA assay employing the proposed biosimilar product as the detecting reagent has been generally recommended for such evaluation, a product-specific assay using the product of interest may be of use as it offers a capability of detecting antibodies against specific epitopes from the respective product. Regardless of assay strategy, the performance of the assay must be fully assessed and method needs to be validated to meet the comparative purpose of immunogenicity assessment.
Compared to the small molecule drugs, biologic products are immensely complex, and it is nearly impossible to manufacture the same entities of such products and variability within the product specification is commonly acceptable. Primarily due to this reason a need for an abbreviated approval pathway, which is separate from that of the small molecule generic drugs, was realized for the biosimilars (i.e., follow-on biologic products). Accordingly, in 2005 the European Medicines Agency (EMA) issued a general guidance document outlining the approval pathway for ‘Similar Biological Medicinal Products’ [1]. Subsequently, detail guidance on quality [2], nonclinical, clinical [3] and also several product-specific guidance documents have been issued by EMA [4–8]. In 2010, as part of the ‘Patient Protection and Affordable Care Act,’ the United States (US) federal government outlined an approval path- way for biosimilar products. Among the other requirements, the Act specifically requires clinical study/studies ‘including assessment of immunogenicity’ for the biological product developed as a biosimilar product. This has been followed by release of the draft guidance documents for biosimilar development and approval considerations by the US FDA [9,10]. A biosimilar product should demonstrate no
10.4155/BIO.14.311 © 2015 Future Science Ltd
clinically meaningful difference comparing to its reference product in terms of its safety, effi- cacy, purity and potency. Comparative immu- nogenicity with the reference product is a critical consideration for a biosimilar product approval. As for studies required for demonstrating
comparability of immunogenicity profiles of a biosimilar product in different test sys- tems, the EMA guidance generally does not require repeat-dose toxicity and immuno- genicity studies in animals. The FDA guid- ance, although not explicitly requiring animal immunogenicity data, does suggest that the immunogenicity data in animal may provide useful information relevant to patient safety, and help clinical immunogenicity assessment design. On the other hand, both EMA and FDA require comparative immunogenicity data from a clinical study. The FDA guid- ance document states that “at least one clinical study that includes a comparison of the immu- nogenicity of the proposed product to that of the reference product will generally be expected” [10]. Therefore, it is imperative for the spon- sor of the biosimilar development to collect and furnish such data through execution of a study with appropriate design, adequate dura- tion of sample collection and bioanalysis using
Bioanalysis (2015) 7(3), 373–381 ISSN 1757-6180
Patrick M Liu*,1 Zou1
Nock4 1
, Chanchal Sadhu2 Wenyan D Shen3
, Linglong ,
& Steffen
Global Bioassays & Technology, Teva Pharmaceuticals, 145 Brandywine
Parkway, West Chester, PA 19380, USA 2
MD 20878, USA 3
Analytical Biotechnology, MedImmune, 1 MedImmune Way, Gaithersburgh,
Biologics Department, NGM
Biopharmaceuticals, 630 Gateway Boulevard, South San Francisco,
CA 94080, USA 4
Global Biologics, Teva Pharmaceuticals,
610 Galveston Drive, Redwood City, CA 94063, USA *Author for correspondence: patrick.
liu@tevapharm.com
part of
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