<p>New antibiotics active against multidrug resistant bacteria (MDR-B) are licensed by regulatory agencies based on pivotal trials that serve the primary purpose of obtaining marketing-authorization. There is increasing concern that they do not offer guidance on how to best use new antibiotics, in which population, and to what extent they overcome existing resistance. We reviewed the literature for pre-approval studies (phase 2 and 3 randomized controlled trials) and post-approval studies (randomized and non-randomized controlled trials) evaluating efficacy and safety of new antibiotics, classified by WHO as Reserve, approved in the European Union and the US from January 2010 to May 2023. Substantial failures occur in generating evidence to guide routine clinical use: preapproval studies lack representativeness, select outcomes and comparators to chase statistical significance, and often avoid using prespecified analytical methods. Three recommendations are key to enhance the quality and relevance of clinical data underpinning use of last resort molecules on the WHO AWaRe Reserve list active against carbapenem-resistant MDR-B i). separation of pivotal trials from post-approval studies, which should be funded by public programs and de-linked from commercial purposes, ii). development and maintenance of a global infrastructure to conduct post-approval public health focused studies, and iii). development of trial platforms that use efficient, adaptive designs to inform clinical decision making and country level technology appraisal. These solutions will allow clinicians to determine whether recently approved Reserve antibiotics are not only “newer” but also “better” for vulnerable patient populations at particular risk for infections by MDR-B.</p>