Reserve antibiotics: overcoming limitations of evidence generated from regulatory approval trials.

IF 5.9 2区 医学 Q1 PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH
Lorenzo Moja, Mohamed Abbas, Marlieke Ea de Kraker, Veronica Zanichelli, Loice Achieng Ombajo, Mike Sharland, Benedikt Huttner
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引用次数: 0

Abstract

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.

储备抗生素:克服监管审批试验产生的证据的局限性。
针对多药耐药细菌(MDR-B)的新型抗生素由监管机构基于关键试验颁发许可,这些试验的主要目的是获得上市许可。越来越令人担忧的是,它们没有就如何最好地使用新抗生素、在哪些人群中使用以及在多大程度上克服现有耐药性提供指导。我们回顾了2010年1月至2023年5月在欧盟和美国批准的新抗生素的有效性和安全性的批准前研究(2期和3期随机对照试验)和批准后研究(随机和非随机对照试验)的文献,这些新抗生素被世卫组织列为储备药物。在生成指导常规临床应用的证据方面存在重大失败:预批准研究缺乏代表性,选择结局和比较物以追求统计显著性,并且经常避免使用预先指定的分析方法。三项建议对于提高临床数据的质量和相关性至关重要,这些数据是使用世卫组织AWaRe储备清单上抗耐碳青霉烯耐多药耐药药物的最后手段分子的基础:(1)将关键性试验与批准后研究分开,这些研究应由公共规划资助,并与商业目的脱钩;(2)发展和维护全球基础设施,开展批准后以公共卫生为重点的研究;iii)开发使用高效、适应性设计的试验平台,为临床决策和国家级技术评估提供信息。这些解决方案将使临床医生能够确定最近批准的储备抗生素对于具有耐多药b感染特别风险的脆弱患者群体是否不仅“更新”而且“更好”。
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来源期刊
Globalization and Health
Globalization and Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH-
CiteScore
18.40
自引率
1.90%
发文量
93
期刊介绍: "Globalization and Health" is a pioneering transdisciplinary journal dedicated to situating public health and well-being within the dynamic forces of global development. The journal is committed to publishing high-quality, original research that explores the impact of globalization processes on global public health. This includes examining how globalization influences health systems and the social, economic, commercial, and political determinants of health. The journal welcomes contributions from various disciplines, including policy, health systems, political economy, international relations, and community perspectives. While single-country studies are accepted, they must emphasize global/globalization mechanisms and their relevance to global-level policy discourse and decision-making.
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