Discordant MIC Analysis: A New Path to Licensure of Anti-Infective Drugs

• Activity Number: 56
• Type: Invited
• Date/Time: Sunday, August 9, 2015 : 4:00 PM to 5:50 PM
• Sponsor: CHANCE
• Author(s): Dean Follmann* and Erica Brittain
• Companies: National Institute of Allergy and Infectious Diseases and National Institute of Allergy and Infectious Diseases
• Keywords: Clinical Trials ; Logistic Regression

Abstract

Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is sometimes nonexistent. The MIC measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcome when treated with that drug. Thus a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g. low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of