Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance
Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance
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DOI：
10.1093/cid/ciz829
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发表时间：
2019-12-01
影响因子：
11.8
通讯作者：
Den Nagata, Tsutae
中科院分区：
文献类型：
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作者：
Echols, Roger;Ariyasu, Mari;Den Nagata, Tsutae
从历史上看，美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）对开发新抗生素的监管要求并没有针对药物批准的以病原体为重点的适应症。必要的随机对照试验的设计传统上包括纳入由易感和耐药病原体引起的部位特异性感染的患者。Cefiderocol经历了一个精简的临床开发项目，以解决严重的碳青霉烯耐药感染。监管方法和关键的临床试验在FDA和EMA之间有所不同。在美国，进行了APEKS-cUTI（不动杆菌、假单胞菌、大肠杆菌、克雷伯氏菌、窄养单胞菌合并尿路感染）研究，为FDA批准特定部位的cUTI适应症提供依据。然而，EMA更倾向于credit - cr（一项多中心，随机，开放标签临床研究，S-649266或治疗碳青霉烯耐药革兰氏阴性病原体引起的严重感染的最佳可用疗法）研究，在该研究中，如果患者患有碳青霉烯耐药病原体，则纳入院内肺炎，血液感染或cUTIs。由此产生的欧洲标签将以病原体为重点，而不是特定于感染部位（即，在治疗选择有限的患者中治疗革兰氏阴性感染）。讨论了这些不同监管过程的含义和局限性。
Historically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas-complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.