How the immune system responds to therapeutic protein products has an impact on all the four key areas of drug development: pharmacodynamics, pharmacokinetics, efficacy, and safety. Such immune responses display great variations, spanning the entire range from no measurable effect to critically hazardous impact.
That makes the identification and analysis of anti-drug antibody (ADA) formation a critical technique in any therapeutic protein development process. This is why immunogenicity testing in the form of anti-drug antibody (ADA) assays play a crucial role.
Immunogenicity Assays: The Latest Guidelines
The U.S. Food and Drug Administration (FDA) issued new industry guidelines in January 2019 for immunogenicity testing of therapeutic proteins. These non-binding recommendations outline the FDA’s latest thinking on the development and validation of anti-drug antibody (ADA) assays.
This article analyzes these latest guidelines to understand what is new in the FDA’s thought domain with reference to ADA assay. The main tenet of the recommendations is to promote a risk-based approach in assessing the immune responses of therapeutic proteins during immunogenicity assays.
Immunogenicity: The FDA Definition
The FDA definition of immunogenicity encompasses two aspects:
• The capacity of a therapeutic protein product to cause immune responses to itself and to related proteins. OR
• The ability of a protein product to effect unfavorable clinical events related to the immune system.
Revisiting the definition is important. The feedback from the European Bioanalysis Forum’s (EBF) 2016 focus workshop on immunogenicity mentions variations in the understanding of the concept, especially with reference to peptides. The EBF conference strongly recommends the formulation of a standardized definition by the International Conference on Harmonisation (ICH).
The Scope of the Guidelines
The latest FDA guidelines specifically cover four types of immunogenicity assays as listed below:
• Confirmatory assays
• Neutralization assays
• Screening assays
• Titration assays
The latest recommendations by the FDA focus specifically on protein products developed for a “stand-alone” biologics license application (BLA). Also for protein products developed as biosimilars and substitutable biological products.
Section 351(a) of the Public Health Service (PHS) Act cover BLAs. Section 351(k) applies to licenses for biosimilars and exchangeable biological products.
The latest FDA guidelines do not cover the development and validation of immunogenicity assays for animal studies. The latest update on this aspect is available on page 35 of the FDA guidelines issued in 2014. This document mentions that immunogenetic assessment of therapeutic proteins in animal studies has limited utility.
That is because of significant differences between animal and human immune systems. However, the increasing use of laboratory mice with human genes addresses this problem to some extent. But in vitro and in silico studies remain the mainstay for the immunogenetic risk assessment of therapeutic proteins.
Three Critical Update Areas
Among the various updates the latest FDA guidelines provide, three areas are of particular importance to the pharmaceutical and allied industries:
• Determining the cut-point: The FDA recommends a “statistically determined” approach to determining the cut-point wherever possible.
• Development and validation of tests for neutralizing antibodies (NAbs): Pharmaceutical companies must develop assays to determine the presence of NAbs during early immunogenicity testing. The testing results must display ADA responses above the cut-point to be statistically significant.
• Alterations in the documentation requirements: There must be an immunogenicity summary report containing five clear sections.