Comparative immunogenicity assessment Review Among the genetic factors that modulate immune
response, major histocompatibility (MHC) polymor- phism has been shown to play important roles in the generation of antibodies against biological products, such as interferon beta in multiple sclerosis [20]. It is not uncommon that some of the patients to be
enrolled in the comparative immunogenicity study have already received treatment with the reference product. In such cases, ADA to the reference product can be potentially present in the patients’ samples prior to enrolling in the study. Therefore, screening for pre- existing ADAs should be considered as a part of the enrollment activities and a decision should be made on how to deal with the ADA positive subjects in order to have a meaningful comparative study design. Particular attention must be paid in designing clini-
cal trials for immunogenicity comparison that takes into account the existing knowledge of the reference product’s immunogenicity and patient treatment background. A stratified randomization should be considered for the balance in the study design. In addition, the blood level of the reference prod-
uct and the proposed biosimilar product may critically affect the ADA measurement and the clearance profile of the proposed biosimilar product may not have been well established. Therefore, we recommend multiple sampling time points for ADA measurement after the administration of the products. For example, sampling after 2 weeks for potential IgM response, then 1 month and 3 months at minimum are used to cover IgG response. Sampling at the end of study or collecting samples during wash-out period should always be con- sidered. The number of sample collection time points should be selected to provide statistically meaningful data for the comparative immunogenicity assessment on the two products. If the immunogenicity incidence for the refer-
ence product is known to be low, the decision on the number of subjects to be enrolled for each study arm could be challenging to make as a statistically mean- ingful comparison would require a large number of subjects that may not be practical. The FDA recom- mends a head-to-head study to assess potential differ- ence of immunogenicity in appropriate indications, and considers it is important to demonstrate that the immunogenicity incidence of a proposed biosimilar product is not increased and its severity is not worse than that of its reference product [10]. It also recom- mends using the most sensitive study population and treatment regimen for which development of immune responses is more likely to occur than other popula- tions and regimens for detecting immune response if immunogenicity results will be extrapolated from one indication to another.
future science group
Product factors Resolving residual uncertainties of a proposed biosimilar product is the key to demonstrate its simi- larity to the reference product. Due to the biological nature of the manufacturing process and the inherent complexity of the biologics, even though no differences in their biological and physicochemical properties are observed from in vitro analysis, one should not assume that the two products are comparable in terms of their immunogenicity profiles. Any difference in the prod- ucts derived either directly from the manufacturing process or possible product molecule modifications could be a potential trigger for new ADA responses, and such difference may not be detectable with cur- rently available analytical methods. Data generated from physicochemical and functional assays in vitro are not adequate to predict immunogenicity of the product in vivo. The goal of the clinical immunogenicity assess-
ment is to evaluate the clinical consequences of those residual uncertainties in terms of immune responses to the products. Immune response is product spe- cific, and antibodies generated can specifically bind to its epitopes on the product. Therefore, in order to detect all possible antibodies specific to the epitopes on a product, such a specific product, either the refer- ence product or proposed biosimilar product should be used in the corresponding assay (product-specific assay approach).
Considerations for selection of assay approaches Both the one-assay approach and product-specific assay approach are currently implemented by the biosimilar developers for the comparative immunogenicity assess- ment between a proposed biosimilar product and the reference product. For the one-assay approach, the assay is commonly developed based on the proposed biosimilar product with positive controls for the refer- ence product and/or the proposed biosimilar product, and is implemented for the ADA sample bioanalysis of both proposed biosimilar product and reference prod- uct treatment arms from the study. On the other hand, the product-specific assay approach unitlizes two indi- vidual assays for specific analysis of samples from the study arms of proposed biosimilar product and refer- ence product, and each assay is built on assay reagents from the respective product itself. Each approach has its advantages and disadvantages.
The one-assay approach facilitates immunogenicity comparison because ADA samples from subjects treated with both products can be analyzed in the same assay, even possibly in the same assay runs. For blinded stud- ies where the treatment information is not provided,
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