The European industry perspective on risk-based immunogenicity testing

By William Chin, PhD, Project Manager, EUCRAF

A recent review entitled “A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective” was published in the February 2015 issue of Journal of Immunological Methods.

In this paper, stakeholders from the European Immunogenicity Platform (EIP) presented a recommendation on how to translate the current guidelines on biotherapeutics immunogenicity testing into a strategy that suits the specific requirements of individual drug candidates. The authors also challenged the value of the extensive testing requirements currently in place for market authorization.

It was reported that the common theme shared among most publications in immunogenicity research is the classification of unwanted immune mediated events into a hierarchy of “low”, “medium” and “high” risk classes. The idea for this recommendation stemmed from the lack of guidance on the translation of risk class into a pre-defined testing strategy for prospective studies.

Therefore the proposed strategy is based on the anticipated level of harm resulting from anti-drug antibody (ADA):

    1. Evaluation of ADA-mediated clinical consequences and classification into 2 testing categories: Category 1 is defined as biotherapeutics without the potential to elicit ADA-mediated severe clinical consequences and Category 2 is defined as biotherapeutics with the potential to elicit ADA-mediated severe clinical consequences.
    2. Immunogenicity assessment throughout drug development: The authors have designed a development phase-based testing strategy with an emphasis on safety and efficacy to the patient. The development phase-based selection of assays and sampling procedure is independent of the structural classes of protein therapeutics.
    3. Non-clinical studies: Routine testing for immunogenicity is not recommended during non-clinical development. The objectiove of non-clinical immunogenicity testing is to assist in the interpretation of pharmacokinetic and toxicokinetic data to verify drug exposure and clearance.
    4. Clinical studies - sampling and screening: A fundamental difference in immunogenicity testing between category 1 and 2 biotherapeutics in all clinical phases is the timing of analysis and the availability of a validated assay.
    5. Clinical studies - neutralization and further characterization: The authors recommended that drug neutralization due to ADA should be assessed as part of the bioanalytical package from phase II onwards for all biotherapeutics.


1. J Immunol Methods. 2015 Feb;417C:1-9. A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective.