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FDA flagged a CRO site after reversed bioequivalence ratios; sponsor withdrew application and FDA reclassified approvals to BX
Summary
Case 2 showed dramatic, opposing geometric mean ratios across two dosing groups (Cmax GMRs 2.86 versus 0.32; AUC GMRs 2.77 versus 0.236), prompting inspection, an untitled letter, study repetition requirements, and BX reclassification for some approved ANDAs.
The Agency official presented Case 2 in which two dosing groups at the same clinical site produced markedly different geometric mean ratios: Cmax GMR ~2.86 for group 1 and ~0.32 for group 2, and AUC GMRs ~2.77 and ~0.236 respectively. The presenter said the pattern was "highly suspicious" for switching of test and reference samples between groups and that applicants did not satisfactorily explain the differences.
After OSIS inspection uncovered overlapping pharmacokinetic profiles and documentation suggesting identical concentration–time profiles, the agency issued an untitled letter, required affected ANDA studies be repeated at different CROs, and changed some approved products' therapeutic-equivalence rating to BX (no longer considered therapeutically equivalent to the reference product). The presenter said some applicants voluntarily proposed repeating studies and/or withdrew the applications.
