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

Area of Science:

• Clinical microbiology
• Infectious diseases
• Clinical trial design

Background:

• US Food and Drug Administration sought recommendations to enhance guidance for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) studies.
• Current study guidance may benefit from updated endpoints and methodologies.

Purpose of the Study:

• To explore novel noninferiority study endpoints and designs for HABP and VABP.
• To identify alternatives to all-cause mortality (ACM) as a primary endpoint.

Main Methods:

• Analysis of 7 HABP/VABP datasets.
• Exploration of novel noninferiority endpoints and study designs.
• Construction of a composite "mortality-plus" (ACM+) endpoint.

Main Results:

• All-cause mortality (ACM) at day 28 varied across patient groups (ventilated HABP: 27.8%, VABP: 18.0%, nonventilated HABP: 14.5%).
• The ACM+ endpoint was 3-10 percentage points higher than ACM across studies.
• Older age and higher APACHE II scores predicted increased ACM/ACM+ rates.

Conclusions:

• An ACM+ endpoint could potentially reduce sample size requirements in future studies.
• Enriching studies with more severe cases would increase ACM.
• Patient-reported outcomes for symptom resolution in nonventilated HABP warrant further development.