Recommendations for the Development and Validation of Immunogenicity Assays in Support of Biosimilar Programs

Abstract

For biosimilar drug development programs, it is essential to demonstrate that there are no clinically significant differences between the proposed biosimilar therapeutic (biosimilar) and its reference product (originator). Based on a stepwise comprehensive comparability exercise, the biosimilar must demonstrate similarity to the originator in physicochemical characteristics, biological activity, pharmacokinetics, efficacy, and safety, including immunogenicity. The goal of the immunogenicity assessment is to evaluate potential differences between the proposed biosimilar product and the originator product in the incidence and severity of human immune responses. Establishing that there are no clinically meaningful differences in the immune response between the products is a key element in the demonstration of biosimilarity. An issue of practical, regulatory, and financial importance is to establish whether a two-assay (based on the biosimilar and originator respectively) or a one-assay approach (based on the biosimilar) is optimal for the comparative immunogenicity assessment. This paper recommends the use of a single, biosimilar-based assay for assessing immunogenic similarity in support of biosimilar drug development. The development and validation of an ADA assay used for a biosimilar program should include all the assessments recommended for an innovator program (10-16, 29). In addition, specific parameters also need to be evaluated, to gain confidence that the assay can detect antibodies against both the biosimilar and the originator. Specifically, the biosimilar and the originator should be compared in antigenic equivalence, to assess the ability of the biosimilar and the originator to bind in a similar manner to the positive control(s), as well as in the confirmatory assay and drug tolerance experiments. Practical guidance for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity of a biosimilar in comparison to the originator, using the one-assay approach, are described herein.

Immunogenicity of LY2963016 insulin glargine and Lantus® insulin glargine in Chinese patients with type 1 or type 2 diabetes mellitus

“…The pertinent comparison could be an intra-study one, comparing the incidence of anti-insulin antibody across the LY IGlar and IGlar treatment arms. 33,34 In this analysis, no significant association or differential treatment effect was observed between anti-insulin antibody levels or TEAR status and HbA1c, insulin dose or hypoglycaemia for Chinese patients with T1DM or T2DM receiving LY IGlar or IGlar. In particular, there was no significant interaction between TEAR status (yes or no) and change from baseline HbA1c, insulin dose or overall total hypoglycaemia.…”

“…The WuXi assay involved the same methodology as the Millipore assay. The pertinent comparison could be an intra‐study one, comparing the incidence of anti‐insulin antibody across the LY IGlar and IGlar treatment arms 33,34 …”

Candidate Bevacizumab Biosimilar CT-P16 versus European Union Reference Bevacizumab in Patients with Metastatic or Recurrent Non-Small Cell Lung Cancer: A Randomized Controlled Trial

“…Pharmacokinetic evaluation comprised assessment of trough serum concentrations of CT-P16 ( C trough ). Immunogenicity was assessed in terms of the incidence of both antidrug antibodies (ADAs), antibodies that bind to the biologic agent (in this study, bevacizumab) in human serum, and neutralizing antibodies (NAbs), ADAs that bind to the biologic agent and neutralize its biologic activity [ 30 ].…”

Efficacy, Safety and Immunogenicity of AVT02 Versus Originator Adalimumab in Subjects with Moderate to Severe Chronic Plaque Psoriasis: A Multicentre, Double-Blind, Randomised, Parallel Group, Active Control, Phase III Study

“…A multi-tiered strategy consisting of screening assay, confirmation assay, titration assay and neutralising assay was performed for the evaluation of immunogenicity as recommended by the FDA and EMA [ 15 , 16 ]. The ADA and nAb assays were each designed as a one-assay approach to detect anti-AVT02 and anti-Humira antibodies in one assay setup following current recommendations [ 17 ]. Serum samples were evaluated for ADA presence and ADA titre using a screening cut point (plate-specific floating cut point using a correction factor [CF] of 1.17; CF was calculated with a non-parametric approach using the 95% percentile), a confirmatory cut point (threshold at 33% inhibition) and a titration cut point (plate-specific floating cut point using a titration CF [TCF] of 1.250; TCF was calculated using the 99.9th percentile).…”