Comparative immunogenicity assessment Review
binding target. Its interference in the assay should be thoroughly evaluated and an appropriate approach to eliminate and/or mitigate the possible impact on ADA measurement should be implemented.
Data analysis Appropriate analysis of the data generated from the selected assay approach is the key step to compara- tive immunogenicity assessment. Limitations of each approach must be taken into considerations when interpreting the ADA data for comparative immuno- genicity assessment. In addition, development of bio- similars represents a clinical scenario different from development of new biologics. Due to the available prescription of
reference product from the market,
it is not uncommon to have subjects enrolled in the study who had prior treatment experience with the reference product. Therefore,
it is not surprising to
observe pre-existing antibodies in the clinical studies. Even though antibody prescreening can help exclude the subjects with pre-existing antibodies from enroll- ment in the study, monitoring the ADA responses dur- ing the study and comparison with the baseline can be important to determine if drug administration triggers a new immune response, boosts an existing immune response, or has no effect. Adequate ADA sampling time points should be well considered in the clinical study design in order to have sufficient and valid data points for the conclusion of immune response status. Positive ADA response only observed at a single point except the last sample collection will be defined as tran- sient, while positive results from two or more sampling time points spanning at least 16 weeks (equivalent to five half-lives of most human immunoglobulin G sub- classes) should be considered as a persistent immune response [23]. Comparative immunogenicity assessment should
focus on comparison of the incidence and severity of human immune responses observed for a proposed biosimilar product versus the reference product. While severity of immune response is qualitative, the differ- ence in immunogenicity incidence is a quantitative measure. The immunogenicity incidence is calculated as percentage of antibody positive subjects in total eval- uable subjects from each treatment arm of the study. The immunogenicity incidences derived from a head- to-head comparative clinical study and calculated from well-developed and validated assays allow comparative estimation of immunogenicity potential of the pro- posed biosimilar product. For this measurement, we recommend analyzing all types of immune responses (pre-existing, drug-induced, drug-boosted, transient or persistent response) thoroughly and taking them into consideration so that the totality of the data can
future science group
be utilized to fully characterize the immunogenicity on each product.
Conclusion Immunogenicity assessment for biosimilar products centers on the comparison of immunogenicity inci- dence and severity, which is a regulatory require- ment for the development of a biosimilar product. To achieve clinically meaningful comparison in immu- nogenicity incidence, well-developed and properly validated ADA methods and scientifically sound data analysis strategy must be in place. Whether the one- assay approach or the product-specific assay approach is chosen,
the assay(s) for immunogenicity testing
should have adequate sensitivity and therapeutic toler- ance toward each product to maximize detection of ADA. Evaluation of the positive control antibodies should be a critical consideration for the validation of the one-assay approach, while achieving comparable assay cut points, sensitivity and other critical perfor- mance parameters are necessary for demonstrating assay equivalence and performance validity of the product-specific assay approach. A well designed com- parative clinical
immunogenicity study, appropriate
assay approach and scientifically sound analysis strat- egy should all be taken into consideration for biosimi- lar product development so that the immunogenicity on each product can be adequately characterized and a clinically meaningful comparative assessment of immunogenicity can be achieved.
Future perspective Biosimilar development aim to provide a more afford- able option for patients to access biotechnological products. However, due to the high complexity of these drugs as compared with small molecule drugs, demon- stration of similarity of biologics to the reference prod- ucts is a complex and multistep process. A step-wise strategy with the totality of evidence is the general recommendation for the biosimialr development. One of these evidences is the demonstration of compara- bility in immunogenicity. The incidence and severity of immunogenicity of a proposed biosimilar product should not be worse than that of the reference product. Some of the major challenges in the immunogenicity comparability exercise are highlighted below.
Study design Considering a low immunogenicity incidence of the reference product, the trial design for a comparative clinical immunogenicity study is critically important in order to provide a statistically meaningful comparison. Future developments in study design strategy are needed to circumvent such hurdles in biosimilar development.
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