Triangulation of pharmacoepidemiology and laboratory science to tackle otic quinolone safety

Abstract

Background: The scientific method requires studies with high internal and external validity. Though both are necessary, they do not go hand-in-hand: The more controlled a study is to enhance internal validity, the less applicable to real-world clinical care, and vice versa. In the many instances where evidence from clinical trials is not available, scientific inference must rely on more extreme approaches on this spectrum, such as mechanistic (limited generalizability/strong bias control) and real-world evidence (RWE) studies (higher generalizability/lesser bias control).

Objectives: Illustrate how triangulating mechanistic and RWE studies can enhance scientific inference by delivering the supporting evidence for both.

Methods: We describe our research on an unexpected and highly unlikely drug safety issue: the risk of tympanic membrane (TM) perforations resulting from otic quinolone therapy. Tightly controlled laboratory studies using cell culture and rodent models were complemented with pharmacoepidemiological studies of real-world data to translate mechanistic findings and corroborate RWE.

Results: We present a cascade of mechanistic and RWE studies investigating fibroblast cytotoxicity, delayed healing of perforated TMs, and spontaneous TM perforations after otic quinolone exposure, all suggesting local tissue toxicity.

Conclusion: Triangulation of mechanistic and RWE studies allowed incremental progress toward robust evidence on otic quinolone toxicity.

Keywords: drug safety; pharmacoepidemiology; quinolones; real-world evidence; translation; triangulation.