Review Liu, Zou, Sadhu, Shen & Nock Key terms
Biologic products: Therapeutic products of biological origin, specifically of large molecular weight.
Biosimilar: In the context of biologic therapeutic products, a biosimilar is a therapeutic with structurally and functionally high similarity to a previously approved biological therapeutic, that is, the reference product. Furthermore, the term ‘biosimilar’ implies that there is no clinically meaningful difference between the biosimilar and the reference products.
Immunogenicity: Immunogenicity refers to the propensity of the drug to elicit immune response in subjects administered with the drug. Although ‘immunogenicity’ encompasses both the humoral and cellular responses, for biologic drug products primarily the humoral immune response is measured for the analysis of immunogenicity.
Anti-drug antibody: Anti-drug antibody (also known as anti-product antibody or anti-therapeutic antibody) refers to the antibodies produced by the subjects and specific to the therapeutic. Since small molecule drugs are unlikely to elicit anti-drug antibodies, the term refers to the antibodies against the large molecule therapeutics.
Product-specific assay: The anti-drug antibody response in each study arm receiving treatment of a specific product is assessed specifically in an assay employing the corresponding product as the assay reagent.
One-assay approach: It is an approach to measure anti- drug antibody responses in both study arms treated by a proposed biosimilar and reference product in the same assay employing a single product as the assay reagent.
Residual uncertainties: In the context of a biosimilar product, residual uncertainties refer to the uncertainties that remain at each of the stages of its development. Residual uncertainties can come from physicochemical and biological aspects, and as well as functionality.
the methods properly validated for the demonstration of comparative immunogenicity profiles between the proposed biosimilar product and the reference product. During the past several years a number of guidance
documents and white papers have been published that provide valuable information on anti-drug antibody (ADA) (aka anti-product antibody or anti-therapeutic antibody) method development, validation and imple- mentation for immunogenicity testing [11–13]. Chal- lenges and issues on comparative immunogenicity anal- ysis for biosimilar products have also been discussed recently [14,15]. However, controversies over method application, assessment strategy and study design still exist regarding comparative immunogenicity assess- ment for biosimilar product development. Based on a recent European Biosimilar Forum Survey [16] more than half of the survey responders indicated that they conducted immunogenicity assessment using prod- uct-specific assays for proposed biosimilar product and reference product individually (herein called a product-specific assay approach), while others employed
374 Bioanalysis (2015) 7(3)
the same assay for the reference product as for the pro- posed biosimilar product (herein called one-assay approach). The FDA draft guidance [10] states: “The proposed product and reference product should be assessed in the same assay with the same patient sera whenever pos- sible”, which implies that one assay approach be pre- ferred for the ADA sample analysis of both proposed biosimilar- and reference-product treatment arms from the study. The debate on the comparative immuno- genicity assessment of biosimilar is around whether the immunogenicity comparison should examine the immune response mainly from the proposed biosimi- lar product or the comparison be based on the totality of immune responses from each of the two products. In this article, we discuss pros and cons of different approaches (one-assay vs product-specific assays), and provide points for consideration in terms of assay selec- tion, method development and implementation, sample testing and analysis. In addition, we review the fac- tors of clinical studies that could impact comparative immunogenicity assessment and provide comments on clinical study design and execution.
Factors impacting comparative immunogenicity assessment The objective of conducting a comparative immuno- genicity assessment in a head-to-head clinical study is to evaluate potential differences in immune responses between a proposed biosimilar product and its reference product with focus on the immunogenicity incidence and its severity impacting product safety and efficacy. In order to achieve a clinically meaningful comparative assessment of immunogenicity, the following factors should be carefully considered:
Subject factors & sampling A number of factors pertaining to the study sub- jects influence the immune response against the therapeutic [17–19]. Among them there are:
• Patient’s immune status (i.e., immunocompro- mised and immune activated) and genetic factors related to immune response;
• Previous exposure to the similar biological therapeutics;
reference product or
• Prior sensitization by drug components such as carbohydrates on the drug;
• Co-administration of other drugs (i.e., concomitant medication);
• The underlying disease and the stage of the disease. future science group
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