Postmarketing Safety Signals of Microbiota-Based Live Biotherapeutic Products for Recurrent Clostridioides difficile Infection: A FDA Adverse Event Reporting System Pharmacovigilance Study.

INTRODUCTION

REBYOTA and VOWST are the first FDA-approved live biotherapeutic products for recurrent Clostridioides difficile infection (CDI). Previous FDA safety alerts (2019-2020) regarding invasive infections from investigational fecal microbiota transplantation underscore the need for postmarketing surveillance of these novel products. The aims of this study were to characterize the real-world safety profiles of REBYOTA and VOWST using the FDA Adverse Event Reporting System and compare them against established CDI therapeutics.

METHODS

We performed a disproportionality analysis of FDA Adverse Event Reporting System data (Q1; 2020-Q4; 2025). REBYOTA and VOWST were identified as primary suspect drugs using Biologics License Application numbers and drug name matching. Comparators included fidaxomicin, bezlotoxumab, and vancomycin (CDI-filtered). Four methods were applied: reporting odds ratio (ROR), proportional reporting ratio, information component, and empirical Bayes geometric mean. Signals required ≥2 methods agreement.

RESULTS

We identified 231 REBYOTA and 813 VOWST primary suspect reports, yielding 18 and 54 disproportionality signals, respectively. Both products' signals were consistent with known gastrointestinal adverse events. No signals were detected for bacteremia, septic shock, or anaphylaxis. Death was reported at lower-than-expected frequency for VOWST (ROR 0.29; 95% confidence interval 0.15-0.53). A VOWST-specific urinary tract infection (UTI) cluster (Klebsiella UTI ROR 405.73; Pseudomonal UTI ROR 168.54) was identified; head-to-head comparison showed no significant UTI difference vs REBYOTA (ROR 1.39, not significant), suggesting stimulated reporting bias rather than a biological signal. Route-dependent adverse event profiles differed between oral VOWST and rectal REBYOTA.

DISCUSSION: FDA-approved live biotherapeutic products demonstrate reassuring postmarketing safety profiles without transmitted infection signals. The extreme VOWST UTI signal is likely attributable to FDA-mandated expedited reporting obligations rather than a causal drug effect.