An increasing number of patents for originator biologic products are due to expire, and therefore opportunity within the industry to develop additional biosimilars is growing. In response, more pieces of relevant guidance are being developed, and the increased knowledge being gained by the industry as a whole will continue to inform best practices in evolving biosimilar development processes, including those for immunogenicity testing.

According to most recent FDA and EMA guidances, a biosimilar is a biological product that is highly similar to an already authorized original biological medicinal product (reference medicinal product) notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the test and the reference product. Similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy needs to be established.

Data are needed to be shown that the test product can be expected to produce the same clinical result as the reference product. Biosimilarity is mainly, but not exclusively, supported by the identification and analysis of critical quality attributes. In addition, other product characteristics need to be demonstrated, such as analysis of mechanism of action in each condition of use, and also the pharmacokinetics and biodistribution of the product in different patient populations, as well as the immunogenicity risk of the product in different patient populations.

Within this context, the immunogenicity assessment of a biosimilar is one of the key aspects of clinical programs. Establishing that there are no clinically meaningful differences in immune response between the test and the reference product is a key element. It is critical to collect, evaluate, and compare the safety and immunogenicity data. According to the EMA Immunogenicity guideline, non-clinical studies aimed at predicting immunogenicity in humans are normally not required. Only in the absence of sufficient knowledge, and if theoretical considerations are suggestive of a safety risk, animal immunization studies with the therapeutic protein or the animal homolog may be considered.

Based on extensive quality characterization, a biosimilar drug’s immunogenic potential should be equal or lower to that of the reference drug. Like with any large molecule drug, the consequences of an adverse immune reaction can range from partial reduction or total loss of efficacy of the drug to severe life-threatening conditions.

Differences in immune responses between the test and the reference product in the absence of observed clinical sequelae may be of concern and may warrant further evaluation. Hence, sufficiently validated immunogenicity assays should be used for the assessment of relative immunogenicity. These assays need to avoid biases for one or the other assays to allow a thorough comparison including antibody incidence, titer or neutralizing capacity. With these preconditions the use of a single assay approach is recommended. This avoids inter-assay variabilities and therefore potentially conflicting assay results. Risks of detecting ADA reactive only with the reference product is of minimal regulatory concern. Another central question may be the source of the positive control. Controls can be generated using the biosimilar test product, but other sources are acceptable as long as it is clearly demonstrated in dose response spiking inhibition experiments that the control antibody recognizes the test and the reference product similarly. Clearly, as with any immunogenicity assay, the assessment of critical parameters such as specificity and selectivity, precision, and robustness is required.

The aim of relative immunogenicity testing is the demonstration of similarity between the test and reference product. This key element of biosimilar drug development is the approval of the biosimilar, and finally to allow future drug substitution and interchangeability of the approved biosimilar and the original drug product.

Check back soon for the next part in our series on Influencers in the Assessment of Immunogenicity, in which I will discuss further challenges and innovations in immunogenicity testing. You can also read the first blog in the series here.