Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance.

Abstract

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.