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.

Keywords: carbapenem resistance; cefiderocol; nonfermenters; pathogen-focused drug development; regulatory drug approval.

Figure 1.

Pathogen-focused clinical development program. This is a theoretical strategic concept and not an approved regulatory pathway in the United States. Abbreviation: CR, carbapenem resistant.

Figure 2.

CREDIBLE-CR (Clinical Trials.gov identifier NCT02714595): Diagnostic pathways for enrollment of patients with carbapenem-resistant infections within a restricted time window of ≤24 hours for patients with complicated urinary tract infection and ≤36 hours for other diagnoses. A, Rapid diagnostics. Cepheid GeneXpert CARBA-R polymerase chain reaction instrument was provided to study sites to identify the presence of various carbapenemase genes (eg, Klebsiella pneumoniae carbapenemase [KPC], New Delhi metallo-β-lactamase [NDM], Verona integron-encoded metallo-β-lactamase [VIM], imipenemase metallo-β-lactamase [IMP], oxacillinase [OXA]-48) from samples. Testing of either direct clinical specimens (endotracheal aspirates, bronchoalveolar lavage, or urine) or cultures was allowed. B, Patients could have failed treatment on empirical therapy, and the primary culture and susceptibility confirmed the presence of a pathogen resistant or nonsusceptible to carbapenems. C, Confirmed carbapenem resistance from a surveillance culture from same anatomical site within 72 hours of enrollment. *To cover gram-negative bacteria. **To cover gram-positive bacteria. Abbreviations: CR-GNB, carbapenem-resistant gram-negative bacteria; Rx, therapy.