Therapeutic Product Immunogenicity Community

Dear community members, 

An ADA assay in use for a FIH study met with an LPC confirmatory cut point failure. Although, this failure is inconsistent between analysts with the preliminary data we have, and failure only with LPC (HPC works similar to validation), parallel sensitivity assessments indicate a shift in the assay sensitivity by greater than 2-fold (assay indicates less sensitivity than at validation). However, still within100ng/ml required as per regulatory guidelines. No change in reagents could be attributed to this difference. If ADA assay sensitivity shift is confirmed, and LPC needs to be increased what steps should be taken to ensure the interpretation of the existing data? Of note, the screening cut point has not changed. Does this scenario warrant reevaluating CCP?  What are the factors to be considered if CCP is different, as the assay is in use for an FIH study?

Thank you!

Was the cause for the sensitivity shift (e.g., differences in critical reagents, instruments, or analyst technique) investigated?. If the issue persists, a reevaluation of the confirmatory cut point may be necessary, since a change in the low positive control due to reduced sensitivity could impact confirmatory assay performance. For samples that have already been analyzed, higher-titer ADA responses are less likely to be affected, but low-level ADA samples may be impacted and should be carefully considered.