Justification for non-inferiority margin in community-acquired pneumonia
Abstract number: O77
Echols R., Tillotson G., Tosiello R., Kowalsky S., Verderame A.
Objective: To determine the NI margin for clinical trials in mild-moderate community-acquired pneumonia (CAP) when placebo-controlled trials of adequate design are unavailable.
Methods: ICH guidelines identify 5 types of control groups: placebo, no treatment, different dose, different active treatment, external or historical. Efficacy is established when new drug demonstrates clinically meaningful superiority over a control regimen. An active control trial can demonstrate efficacy when a new treatment is similar (non-inferior) to a known effective treatment when the new treatment is not less effective than control by a predetermined margin (M2), identifying the lower boundary of a 95% CI. M2 can only be determined after the benefit of the active control over placebo (M1) has been demonstrated in studies showing superiority over placebo or a less effective active control. No placebo-controlled trials have been conducted in CAP. Historical evidence of antibiotic efficacy in CAP has been derived from estimates of mortality. Thus, an estimate of clinical response for M1 can only be derived indirectly. Some assumptions are made:1) efficacy can only be estimated for an antibiotic with in vitro activity; 2) efficacy in CAP is derived from patients with bacterial infection; 3) clinical response results in improvement within 72 hrs; 4) M2 should preserve 50% of M1. The natural history of spontaneously resolving (non-fatal) pneumococcal pneumonia in the pre-antibiotic era was estimated. Publications and Summary Basis of Approvals for antibiotics from 19962006 were reviewed for microbial aetiology and treatment response.
Results: For contemporary CAP, 30% are caused by typical bacteria, 20% atypical pathogens and 50% viral or other causes. Clinical success is 87% in mild-moderate CAP. Clinical improvement does not occur before 72 hrs in untreated non-fatal pneumococcal pneumonia. Thus, for an antibiotic with activity against only typical bacteria, M1 equals 0.30(% CAP typical pathogens) × 0.87 (clinical response). Using these data and assumptions a M2 margin of 13% would provide evidence of treatment efficacy in mild-moderate CAP when an appropriate control drug is used.
Conclusion: The M2 margin for CAP can be derived from knowledge of spontaneous recovery in the pre-antibiotic era combined with a careful analysis of contemporary aetiologies and treatment response of CAP.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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