The EMA’s (European Medicines Agency) issued its latest guidelines in 2017. It revises the guidelines published in 2006. Both documents refer to the immunogenicity testing of therapeutic protein products (TPPs).

The document offers specific guidance on immunogenicity assays and on integrated analysis of the clinical significance of these assays.

General Pointers

• There are significant differences between the immune systems of animals and humans. The immunogenicity of human proteins in animals can also be different. Animal studies on the immunogenicity of TPPs have a low predictive value, therefore.
• Robust immunogenicity assays for TPPs are necessary. This is a regulatory need for screening and confirmation of immune responses.
• ADA assays must have applicable clinical trials correlations with ADAs (anti-drug antibodies). Applicants need to demonstrate that.
• All screening and confirmatory assays for immunogenicity testing of TPPs should integrate the following data:
  • Clinical and safety data
  • Pharmacokinetic (PK) data
  • Pharmacodynamic (PD) data
  • Immunological data
• Risk Management Plans (RMPs) should also address immunogenicity issues.
• The general guidelines would need case-to-case adaptations. Applicants should seek scientific advice from the EMA for individual TPP development programs. They can also seek advice from a competent national authority. The EMA recommends this.
• All applications for marketing authorization should include an integrated summary of immunogenicity. The summary should include a risk assessment supporting the adopted analytical testing.

Summary of the EMA’s Recommended Immunogenicity Testing Program for TPPs

The EMA outlines what the integrated summary document for a marketing authorization application should include. In reality, that presents an overview of how the EMA perceives a robust immunogenicity program.

Risk Factor Analysis

• Previous experience of the TPP or the TPP class, with special focus on:
  • The existence of an endogenous counterpart
  • Any known antigenic sites of the molecule
  • Useful findings from animal studies
  • Immunogenicity reduction attempts before and during clinical trials
• Physiochemical and structural aspects focused on:
  • New structures with immunogenic potentials
  • Non-human glycosylation patterns/glycans and similar other expression construct and posttranslational profile
  • Impurities and stability
  • Packaging and impurities
  • Impurities and packaging
• Concerns related to the route of administration
• Factors related to disease and patient:
  • State of immunological tolerance
  • Preexisting immunity

A Risk-Based Immunogenicity Program

Justification of Assay Strategy

• The rationale for choosing the immunogenicity assays for screening, confirmation, titration, and neutralization
• The justification of the choice of assays for determining the immunoglobulin class and subclass
• The specificity and sensitivity of selected assays should focus on positive controls relevant to the particular TPP
• ADA assays to determine the threshold of ADA positivity
• Measure the drug and target tolerance of the selected assay
• Matrix interference in different population segments

Immunogenicity Alertness in Clinical Trials

• Justification of the immunogenicity testing sample
• The rationale for the length of follow-up at on-treatment, off-treatment, and post-exposure levels
• PK data on the possibility of ADA-interference on assays used for product concentration
• Correlation between drug trough levels and the ADA-assay generated drug toleration level
• PD data for efficacy and safety trials should focus on:
  • Autoimmunity
  • Hypersensitivity
  • Loss of efficacy
  • The persistence and clinical significance of ADAs
• The influence of the risk assessment on the immunogenicity program

Results of Immunogenicity

Clinical trials should focus on capturing:

• The relative immunogenicity with reference to manufacturing changes and biosimilars.

Immunogenicity Risk/Benefit Analysis

This should also contain a post-marketing risk management plan.