Review Liu, Zou, Sadhu, Shen & Nock
the one-assay approach would be ideal for analyzing the study samples regardless of which product is adminis- trated to the subjects. In addition, since the samples are analyzed in the same assay, the data comparison can be easily achieved with no concerns of cross-method vari- ability, which is commonly associated with the prod- uct-specific assay approach due to the variations from each assay. On the other hand, the product-specific assay approach, with the respective product as a spe- cific assay reagent, requires analyzing the study samples in each product-specific assay. Therefore, performance equivalence of these assays, especially assay sensitivity, therapeutic (or drug) tolerance, accuracy and precision, must be demonstrated to meet the comparison pur- pose. This approach also requires unblinding analysts for blinded studies so that the samples can be tested in respective product-specific assay. The one-assay approach with the proposed bio-
similar product as an assay reagent aims to detect all possible antibodies against the proposed biosimilar product, but it may not be able to reveal a complete picture of the immunogenicity of the reference prod- uct if there is any difference in epitope between the two products. On the other hand, the product-specific assay approach could result in enhanced assay capabil- ity of detecting all potential antibodies specific to each product and mitigate the potential for underestimat- ing immunogenicity incidence toward the product that is not used as an assay reagent (i.e. in the one- assay approach). It should be noted that much more resources and a longer timeline for assay development/ validation as well as sample analysis are required for the product-specific assay approach. The performance parameters of each product-specific assay should be well characterized and validated, and the performance equivalence of the two assays must be demonstrated for the comparative immunogenicity assessment purpose using adequate numbers of samples from the target population. It may be necessary to perform cross-anal- ysis of samples from different treatment groups in each assay as a part of equivalence demonstration. This will result in increased workload during sample analysis and additional challenges during data analysis. Key issues must be addressed when implementing
an assay approach for comparative immunogenicity assessment. Applying one-assay approach with a sensi- tive method, different epitopes on the proposed bio- similar product (if any) from the reference product can be identified. Such epitopes not present in the reference product may contribute to new episodes of immune response against the proposed biosimlar. One-assay approach is capable of providing a specific clinical immunogenicity picture for the biosimilar product, but possibly not for the reference product. If the com-
376 Bioanalysis (2015) 7(3)
paractive immunogenicity assessment of the two prod- ucts should be based on their complete immunogenic- ity profiles and comparison of the immunogenicity incidences, the one-assay approach may not be the best choice. On the other hand, the product-specific assay approach can provide a specific immunogenicity pic- ture for each product, which is the fundamental data source for immunogenicity incidence analysis. How- ever, there are technical challenges for implement- ing the product-specific assay approach. Variability is a common issue among different assays, method equivalence and performance consistence must be well controlled in order to have a meaningful comparison of the data generated from different assays. Poorly developed product-specific assays would result in chal- lenges in immunogenicity comparison due to lack of comparable sensitivity or precision between assays. If product-specific assay approach is selected, the equiva- lence of assay performance must be demonstrated with absence of statistically significant differences in these parameters between the assays in order to meet the immunogenicity comparison purpose.
Considerations for method development & sample analysis Although it may be tempting to use the same assay platform that was originally used by the originator for the purpose of comparison with the available immuno- genicity data of the reference product, this approach is not always practical. For example, details of the assay employed in the reference product development may not be available, or the assay platform requires a spe- cific instrumentation or a laboratory set up (e.g., radio- metric assay) that is not available to the sponsor of the proposed biosimilar product or no longer available to industry at all (e.g., BioVeris ECL). Immunogenicity studies designed for biosimilarity assessment empha- size on head-to-head comparison between a proposed biosimilar product and the reference product, which calls for a reliable method or comparable methods between the products to be used for ADA data genera- tion from such studies. An assay platform that meets current regulatory guidelines and scientific qual- ity should be appropriate. Regardless of which assay approach to be adopted, strict assay development and validation criteria, provided in subsequent sections, should be followed.
Critical reagents For the ADA assays, the therapeutic product of inter- est is certainly the most critical reagent. Regardless of the assay format selection, the therapeutic product, either used as capture or/and detection reagent needs to be well characterized and qualified for its appropri-
future science group
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