Last week I was able to share answers to several great questions I received during my recent webinar entitled “What the New AAPS White Paper Recommends for Immunogenicity Assays Supporting Biosimilars”. There were so many thoughtful questions submitted that I wanted to make sure I addressed them all, so this blog contains the rest that were posed and my thoughts on each:
With the newer assay technologies now used in biosimilar ADA assays, how often do you see a higher originator ADA rate compared to historical data?
When employing state-of-the-art bioanalytical methods – typically with superior performance around sensitivity and drug tolerance – higher ADA incidence for the originator is often revealed when compared with results reported for historical trials.
In these situations, a comparison with the originally-reported ADA rates is not relevant and should be avoided. If incidence of ADA for the originator is lower than reported in the literature, a reason should be considered and provided.
For clinical trials of biosimilars with EU-licensed originators and US-licensed originators, do you recommend a validation with EU and US originators for competition tests, etc.?
While ample opportunity typically exists to improve ADA assays throughout a clinical development program for a novel biologic therapeutic, opportunity for such optimization and improvement does not exist during the development of a biosimilar program. In general, for biosimilars, fewer clinical trials are required, development timelines are compressed, and clinical studies are usually conducted in parallel.
For that reason, it is crucial that the initial assay development for a biosimilar program is thorough and complete – with the immunogenicity assay optimized for detection of ADA to the biosimilar and all relevant variants of the originator product(s). The strategy for development and validation of the ADA assay should incorporate all necessary evaluations to assess critical program characteristics [e.g. version of reference used, such as originator manufactured in the United States (US) or European Union (EU)].
When the development strategy will include submission to both US- and EU-based regulatory authorities, the specific parameters (i.e. antigenic equivalence, drug tolerance, and performance in the confirmatory assay) critical to supporting the implementation of a one-assay approach should be evaluated in a manner that allows comparison of performance between both the biosimilar and US-originator and the biosimilar and EU-originator to gain confidence that the single assay can similarly detect antibodies against the biosimilar and each originator product.
How do you get robust assay performance over a period of time when you are observing lot-to-lot or labeling differences of the biosimilar on different timelines?
The good news is that in contrast to development programs for originator products, biosimilar development programs often have compressed timelines and fewer clinical trials. These unique characteristics lead to shorter overall assay lifecycles during which critical reagents must be maintained and available.
In order to minimize variability and potential bias stemming from the use of multiple batches of labeled reagents, a preferred approach would be to label enough material to cover anticipated use throughout the entire lifecycle of the assay (i.e. development, validation, and sample analysis). After estimating reagent needs, labeling should be conducted to yield quantities in excess of several folds higher than the initial estimates to account for unforeseen circumstances. They will occur.
If you find your program in need of re-labeling multiple batches of biosimilar over time, it is imperative to establish, document, and follow well-defined procedures for labeling. Conditions and variables known to impact the labeling procedures should be documented and tightly controlled (e.g. defined catalog numbers for consumables and reagents, consistent volumes, specific temperatures, controlled incubation times, defined clean-up steps, etc.).
After labeling, labeled reagents should be fully characterized, at minimum, for concentration and label incorporation ratio. The results of characterization should be compared to previous batches, and performance in the assay should be compared in a head-to-head manner.
Are neutralizing assays needed for comparison?
Absolutely! Check out the AAPS companion white paper for recommendations on the development and validation of NAb assays in support of biosimilar programs [Gouty, D., Cai, C.C., Cai, X.Y. et al. AAPS J (2018) 20: 25. https://doi.org/10.1208/s12248-017-0181-6] for details.
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Thank you again to those that submitted your question and to everyone who joined us for the live session. I welcome you to reach out to me with any additional inquiries about your biosimilar program and how BioAgilytix can support your development needs.
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