How is anti-drug antibody testing for a biologic structured?

Why

The tiers trade sensitivity for specificity in steps. The FDA's 2019 guidance asks that the screening assay be set to a false positive rate of about 5 percent, so true positives are rarely missed. The confirmatory assay, usually adding excess drug to see whether the signal drops, removes false positives.

Titer matters because effects on pharmacokinetics, safety and efficacy may track titer and persistence more than incidence. Neutralizing antibodies interfere with the drug's binding to its target, and their effect may matter more than simple incidence. The guidance recommends that screening and confirmatory IgG and IgM assays reach a sensitivity of at least 100 ng per milliliter, with some flexibility based on risk.

Drug in the sample can hide antibodies, so drug tolerance must be tested. The guidance also warns that comparing immunogenicity rates across products is misleading, because results depend on assay sensitivity, drug tolerance, sampling times and the patients. For example, an assay with poor drug tolerance may report low incidence simply because patients still had drug in their blood when sampled.

Sampling before dosing, at trough, and after washout helps.