Clinical Trials Increase Off-Study Drug Use: A Segmented Time-Series Analysis

Abstract

Abstract Background The effect of participation in a clinical trial on concomitant off-study investigational drug use has not been described. We sought to determine if participation in the Daptomycin as Adjunctive Therapy for Staphylococcus aureus bacteremia (DASH) trial increased overall daptomycin prescribing at study sites. Methods We retrospectively analyzed daptomycin use for 8 years preceding the trial, off-study daptomycin use during the trial itself (31 months), and daptomycin use for 6 fiscal months after trial completion. We used a segmented linear regression analysis of an interrupted time series to analyze changes in each drug’s defined daily doses (DDD) per 1000 patient-days. As a control, we analyzed use of linezolid over these periods and also accounted for rates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections. Results For 1.5 years before the DASH trial, daptomycin use was decreasing by –0.30 DDD per 1000 patient-days per fiscal period (95% CI, –0.52 to –0.07). Following the initiation of the study, there was a statistically significant increase in daptomycin use of 0.28 DDD per 1000 patient-days per fiscal period (95% CI, 0.03 to 0.52), despite low, stable rates of MRSA and VRE infections. Following trial completion, daptomycin use decreased back toward prestudy rates. Use of linezolid remained stable throughout. Conclusions Despite the DASH trial being a negative study, it impacted the prescribing habits of local clinicians during recruitment. Trialists should be aware of potential off-target study effects, and prescribers should be wary of early uptake of interventions before definitive study results.