Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

Abstract

The US Food and Drug Administration solicited evidence-based recommendations to improve guidance for studies of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM). ACM at day 28 differed for ventilated HABP (27.8%), VABP (18.0%), and nonventilated HABP (14.5%). A "mortality-plus" (ACM+) composite endpoint was constructed by combining ACM with patient-relevant, infection-related adverse events from the Medical Dictionary for Regulatory Activities toxic/septic shock standardized query. The ACM+ rate was 3-10 percentage points above that of ACM across the studies and treatment groups. Predictors of higher ACM/ACM+ rates included older age and elevated acute physiology and chronic health evaluation (APACHE) II score. Only patients in the nonventilated HABP group were able to report pneumonia symptom changes. If disease groups and patient characteristics in future studies produce an ACM rate so low (<10%-15%) that a fixed noninferiority margin of 10% cannot be justified (requiring an odds ratio analysis), an ACM+ endpoint could lower sample size. Enrichment of studies with patients with a higher severity of illness would increase ACM. Data on symptom resolution in nonventilated HABP support development of a patient-reported outcome instrument.