At present, there are situations in antibiotic drug development where the low number of enrollable patients with key problem pathogens makes it impossible to conduct fully powered non-inferiority trials in the traditional way. Recent regulatory changes have begun to address this situation. In parallel, statistical issues regarding the application of alternative techniques, balancing the unmet need with the level of certainty in the approval process, and the use of additional sources of data are critical areas to increase development feasibility. Although such approaches increase uncertainty compared with a traditional development program, this will be necessary to allow new agents to be made available. Identification of these risks and explicit discussion around requirements in these areas should help clarify the situation, and hence, the feasibility of developing drugs to treat the most concerning pathogens before the unmet need becomes even more acute than at present. Copyright © 2014 John Wiley & Sons, Ltd.