Overview of Recent Studies of Community‐Acquired Pneumonia

Abstract

All recent studies of antibacterial drugs for the indication of community-acquired pneumonia submitted to the US Food and Drug Administration have been designed as noninferiority studies. We provide a summary of results of 7 recent clinical studies of oral antibacterial drugs for treatment of community-acquired pneumonia. In these 7 studies, the majority of patients enrolled had Pneumonia Patient Outcomes Research Team scores of I or II. The percentage of randomized subjects with pathogens identified at baseline ranged from 47% to 76%, and the percentage of subjects with Streptoccocus pneumoniae isolated at baseline ranged from approximately 6% to 20%. The primary end point in these studies was clinical cure, assessed 7-21 days after completion of therapy. Clinical cure rates were >80% in the intent-to-treat populations and >90% in the per-protocol populations. We also briefly summarize the results from several recently submitted clinical studies of intravenously administered antibacterial drugs for treatment of community-acquired pneumonia, in which we found similar results.

Historical and Regulatory Perspectives on the Treatment Effect of Antibacterial Drugs for Community‐Acquired Pneumonia

“…Although the studies enrolled patients aged 165 years, the mean age tended to be between 40 and 50 years. S. pneumoniae was identified as the etiological agent in only a fraction of cases, and mortality rates in these studies were very low [31].…”

“…The overall health of the population, including comorbidities; earlier diagnosis; more readily available access to care; and current practice guideline recommendations for early treatment all substantially contribute to the likelihood that patients enrolled in any of the studies described above would not be comparable to patients enrolled in a contemporary CAP trial, even if controlled for age. Higgins et al [31] have summarized data from recent CAP registrational trials. Most of these studies were conducted in outpatients and evaluated oral antibacterial therapy.…”

A Simulation Study Evaluating Bio-Creep Risk in Serial Noninferiority Clinical Trials for Preservation of Effect

“…Then, a minimum of 150 per arm and a maximum of 400 per arm were imposed to avoid simulating unrealistic samples sizes relative to those typically seen in the motivating setting. This choice of range is approximately based upon a study by Higgins et al (2008), in which authors reviewed all comparative studies that were submitted to the Office of Antimicrobial Products to support indications for CAP in the 8 years prior to 2008. They found that among the 7 studies submitted, sample sizes ranged in from about 300 to 500 subjects for oral antibiotics and from about 300 to 700 for intravenous antibacterial drugs.…”

Cethromycin versus Clarithromycin for Community-Acquired Pneumonia: Comparative Efficacy and Safety Outcomes from Two Double-Blinded, Randomized, Parallel-Group, Multicenter, Multinational Noninferiority Studies

“…Demonstrating clinical utility of a ketolide agent in precisely the patient population most likely to benefit from this intervention remains a development challenge. The applicability and utility of noninferiority trials in determining the efficacy of new treatment regimens for mild to moderate CAP has come under scrutiny by regulatory agencies (16) and academic investigators since the initiation of this program (12). Specifically, the determination of an acceptable noninferiority margin in the absence of a supported treatment effect of the comparator agent has proven problematic.…”

“…This method has also been recently debated, as researchers contest the objectivity of investigator-based assessments as well as their potential to introduce intra-and interobserver variability (16). Current discussion regarding appropriate outcome measurements often centers on the use of patient-reported outcome assessments to circumvent these potential biases.…”