Reanalysis of Plasma Samples Collected from a CRO Reveals Possible Patterns of Bioanalytical Misconduct

Data integrity is necessary to help ensure the accuracy, consistency, validity and completeness of data. Data can be untraceably manipulated when it lacks adequate integrity. The FDA identified data integrity concerns with the pharmacokinetic data of a bioequivalence (BE) study for rivaroxaban 20 mg tablets, which was conducted by a contract research organization (CRO) in support of an abbreviated new drug application (ANDA) submission. The hypothesis was that samples from the late cohort of the study might have been substituted or manipulated to allow an otherwise failing study to meet the BE endpoint. To test this hypothesis FDA investigators collected 2,392 plasma samples from the BE study at the CRO's clinical site. FDA laboratory then developed and validated a bioanalytical method and re-analyzed the BE study plasma samples. Comparison of the data generated by the CRO and FDA suggested that the study was manipulated by altering the volume of plasma samples used for bioanalysis. This manipulation was likely done to achieve a lower than actual maximum plasma concentration test/reference (C_max T/R) ratio.