Table 1.
The 6 Types of Severe Infection Recommended for General Antibacterial Development
| Infection | Enrollment Criteria | Endpoint | Untreated/Delayed Therapy Response Rate | Active Therapy Response Rate | Treatment Effect Size (M1)a | Recommended NI Margin (M2) |
|---|---|---|---|---|---|---|
| Acute bacterial skin and skin structure infection [16] | 75-cm2 area of erythema (approximately the size of a dinner plate) | 20% reduction in size of area of erythema at 48 h of therapy | 73%–77% | 98%–99% | 18% | 10% |
| Community-acquired bacterial pneumonia [17] | A specific set of pulmonary symptoms plus a high level of severity | Improvement at days 3–5 in baseline symptoms based on a specific scale | 5%–40% | >70% | >20% | 12.5% |
| Hospital-acquired and ventilator- associated bacterial pneumonia [18] | A specific set of pulmonary symptoms | 28-d all-cause mortality | 62% (here, higher is worse, unlike the other situations) |
20% | 20% | 10% |
| Complicated intra-abdominal infections [19] | Operative diagnosis | Resolution of baseline symptoms | 39% | 82% | 14% | 10% |
| Complicated urinary tract infection [20] | Risk factors plus symptoms plus evidence of pyuria | Resolution of symptoms and sterilization of urine | 33% | 69% | 36% | 10% |
Other important types of infection (eg, gonorrhea) can also be studied, but these 6 infections (note that hospital-acquired and ventilator-associated bacterial pneumonia are often studied together but count as two different types of pneumonia) provide pathways that will be relevant for most antibacterial agents.
Abbreviation: NI, noninferiority.
aThe estimate of treatment effect size (M1) is not just the mathematical difference between the response rates for untreated/delayed therapy and response rates for active therapy but is conservatively estimated as the distance between the upper bound of the 95% confidence interval (CI) around the known or estimated placebo response rate (which can be greater than zero) and the lower bound of the 95% CI around the active treatment response rate [10]. After estimating M1, a decision must be made about the maximum clinically acceptable potential difference between the investigational antibiotic and the comparator antibiotic [10, 21]. This maximum difference is the noninferiority margin, also known as M2, and must be smaller than M1. Selection of M2 should consider differences between the historical and current trials, the potential loss of efficacy deemed clinically important, the feasibility of generation of clinical data, and the magnitude of unmet medical need [21, 22], and it is these factors that lead to the range of selected values of M2. For more details, the interested reader is referred to the detailed methodology for computing M1 and M2 discussed in the 2016 publication on this topic from the US Food and Drug Administration [10].