By Kayla J. Spivey
Published on January 16, 2019, Immunogenicity Testing of Therapeutic Protein Products—Developing and Validating Assays for Anti-Drug Antibody Detection represents the first signed version of immunogenicity-specific guidance by the Food and Drug Administration. A draft version was released in April 2016, which detailed recommendations on the development and validation of assays for testing immunogenicity against therapeutic protein products. This newly signed version offers little in revolutionary insight when compared to the previous guidance, but offers increased clarity and added definition to pivotal components of immunogenicity testing.
Risk-based testing is at the foundation of immunogenicity testing. This guidance aims to facilitate its relevance throughout the method development, validation, and reporting processes with additional detail regarding real-time testing, clinical relevance of anti-drug antibodies in relation to pharmacokinetic and pharmacodynamic profiles, pre-existing antibodies, and neutralizing antibodies. The guidance also recognizes the importance of science driving assay design parameters and gives space for the emergence of innovative approaches to assay design as science and the industry evolve.
The main updates include the following:
- an expanded definition of minimal required dilution in relation to the reporting of mean assay sensitivity,
- a statement supporting ligand-binding or enzymatic assays as an alternative to cell-based neutralizing antibody assay formats,
- clarification of balanced cut point design with independent measurements by two analysts over three days totaling six observations, and
- an expanded documentation section with information regarding what needs to be included in the Integrated Summary of Immunogenicity.
The following subcategories give detailed suggestions on how to present the immunogenicity portion of the biologics license application:
- immunogenicity risk assessment,
- tiered strategy and stage-appropriate bioanalytical assays,
- clinical study design and sampling strategy,
- clinical immunogenicity data analysis, and
- conclusions and risk evaluation and mitigation strategies. ,
Comparing the final guidance to the 2016 draft version, this new release appears in its totality to be a clarification of the former version, with little novel information. Being so new, no focus group-based comments have yet been released therefore it will be interesting to see how the industry reacts to the guidance.