A cross-sectional study of participant recruitment rates in published phase III influenza therapeutic randomized controlled trials conducted in the clinical setting

Objective: A recent academic-government partnership demonstrated the feasibility of utilizing Emergency Departments (ED) as a primary site for subject enrollment in clinical trials and achieved high rates of recruitment in two U.S. EDs. Given the ongoing need to test new therapeutics for influenza and other emerging infections, we sought to describe the historical rates of participant recruitment into influenza Phase III therapeutic RCTs in various clinical venues, including EDs. Study design: A cross-sectional study was performed of influenza therapeutic Phase III RCTs published in PubMed, Embase, Scopus, and Clinicaltrials.gov from January 2000 to June 2019. Main outcome: To estimate the weighted-average number of influenza-positive participants enrolled per site per season in influenza therapeutic RCT conducted in clinical settings, and to describe basic trial site characteristics. Results: 47 (0.7%) of 7008 articles were included for review of which 43 of 47 (91%) included information regarding enrollment sites; of these, 2 (5%) recruited exclusively from EDs with the remainder recruiting from mixed clinical settings (inpatient, outpatient, and ED). The median enrollment per study was 326 (IQR: 110, 502.5) with a median of 11 sites per study (IQR: 2, 59.5). Included studies reported a median of 201 (IQR: 74, 344.5) confirmed influenza-positive participants per study. The pooled number of participants enrolled per site per season was 11 (95% CI: 10, 12). The pooled enrollment numbers per clinical site after excluding the two ‘ED only recruitment’ studies were less [10.7 (95% CI: 9.9, 11.6)] than the pooled enrollment numbers per clinical site for the two ‘ED only recruitment’ studies [89.5 (95% CI 89.2–89.27)]. Conclusion and relevance: Published RCTs evaluating influenza therapeutics in clinical settings recruit participants from multiple sites but enroll relatively few participants, per site, per season. The few ED-based studies reported recruited more subjects per site per season. Untapped opportunities likely exist for EDs to participate and/or lead therapeutic RCTs for influenza or other emerging respiratory pathogens.