For the evaluation of pharmacokinetics, pharmacodynamics, efficacy and safety of biological drugs and active substances, possible immunareactions of patients are of decisive importance. Especially in the case of therapeutic protein products, immune reactions, i.e. the formation of so-called anti-drug antibodies (ADAs), can have the potential to negatively influence the therapeutic benefit or completely override it.
Experience so far shows that the immune reactions of test persons can be very different. Sometimes hardly measurable and sometimes extremely dangerous and harmful. Consequently, the recording of such immune responses and the detection and analysis of ADAs and their effects on pharmacokinetics, pharmacodynamics, safety or efficacy is an important building block in the development and testing of therapeutic protein products. The risk for subjects to develop an ADA-producing immune response to a therapeutic protein product also varies from product to product. The FDA recommends a risk-based approach to evaluating and managing immune responses to – or immunologically related adverse clinical events associated with therapeutic protein products. Such immunogenicity tests must be able to detect ADAs that can trigger undesirable biological or physiological consequences. Such immune responses should also be listed as a side effect in the product descriptions.
Content and Validity of the Guideline
It follows from the above facts that appropriate assays for the investigation and detection of ADAs and the triggered reactions represent a key aspect in the development of products for therapeutic proteins. For this reason, the FDA has now published the guide “Immunogenicity Testing of Therapeutic Protein Products – Developing and Validating Assays for Anti-Drug Antibody Detection“. It provides recommendations to facilitate the development and validation of assays by industry to assess the immunogenicity of therapeutic protein products during clinical trials. For the purposes of these guidelines, immunogenicity is defined as the willingness of a therapeutic protein product to generate immune responses to itself and related proteins or to induce immunologically related adverse clinical events.
To this end, the guide includes information for the development and validation of screening assays, confirmatory tests, titration tests and neutralisation tests. They apply to assays for the detection of one or more anti-drug antibodies. In some cases, the recommendations may also apply to certain peptides, oligonucleotides and combination products. However, this guidance does not apply to in vitro diagnostic medical devices.