Disproportionality Analysis of FAERS Data Divergence and a Systematic Review of Comparative Safety Studies: Lessons Learned from the Example of Ranitidine and Cancer Risk.

BACKGROUND

Ranitidine, a histamine-2 receptor antagonist, was withdrawn globally in 2020 following the detection of N-nitrosodimethylamine (NMDA), a probable human carcinogen.

OBJECTIVE

We aimed to assess advanced pharmacovigilance bias-mitigation approaches by evaluating ranitidine-associated cancer signals in the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases alongside a systematic review of comparative safety studies.

METHODS

A retrospective disproportionality analysis was conducted using the FAERS and the JADER databases. Signal detection was performed using four complementary algorithms (proportional reporting ratio (PRR), reporting odds ratio, information component, and empirical Bayes geometric mean), with an active comparator (famotidine) and time-restricted (pre- and post-recall) analyses, and a systematic review of comparative safety studies was also conducted.

RESULTS

A pronounced surge in cancer reporting was observed for ranitidine, with 140,985 reports recorded in FAERS during 2020-21, accounting for more than two thirds of all reported cancer cases. Most reports were consumer submitted and geographically clustered in regions affected by regulatory actions and litigation. Unrestricted analyses of the full FAERS database identified high-magnitude signals for multiple cancers, particularly gastrointestinal and genitourinary cancers. However, these signals were markedly attenuated or absent in active-comparator and time-restricted analyses, with convergence observed in the reporting profiles of ranitidine and famotidine. In the JADER analysis, a significant ranitidine-cancer signal among suspected drug reports (PRR = 3.54) disappeared completely when all involvement types were analyzed (PRR = 0.92), indicating that the observed association likely reflects protopathic bias, rather than a true carcinogenic effect. The systematic review revealed heterogeneous findings, with most large cohort studies demonstrating no increased risk of overall or site-specific cancers.

CONCLUSIONS

The observed cancer signals for ranitidine in spontaneous reporting systems were predominantly attributable to the NMDA related regulatory alerts rather than intrinsic carcinogenicity. Active-comparator and time-restricted analyses, together with systematic reviews of comparative safety studies, are essential to avoid misleading inferences in pharmacovigilance assessments.