Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials

Simone Lanini, John P.A. Ioannidis, Francesco Vairo, Michel Pletschette, Gina Portella, Virginia Di Bari, Alessia Mammone, Raffaella Pisapia, Stefano Merler, Boniface Nguhuni, Martin Langer, Antonino Di Caro, Sarah J.L. Edwards, Nicola Petrosillo, Alimuddin Zumla, Giuseppe Ippolito

Research output: Contribution to journalReview articlepeer-review

Abstract

Antimicrobial resistance is one of the most important threats to global health security. A range of Gram-negative bacteria associated with high morbidity and mortality are now resistant to almost all available antibiotics. In this context of urgency to develop novel drugs, new antibiotics for multidrug-resistant Gram-negative bacteria (namely, ceftazidime-avibactam, plazomicin, and meropenem-vaborbactam) have been approved by regulatory authorities based on non-inferiority trials that provided no direct evidence of their efficacy against multidrug-resistant bacteria such as Enterobacteriaceae spp, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, and Acinetobacter baumannii. The use of non-inferiority and superiority trials, and selection of appropriate and optimal study designs, remains a major challenge in the development, registration, and post-marketing implementation of new antibiotics. Using an example of the development process of ceftazidime-avibactam, we propose a strategy for a new research framework based on adaptive randomised clinical trials. The operational research strategy has the aim of assessing the efficacy of new antibiotics in special groups of patients, such as those infected with multidrug-resistant bacteria, who were not included in earlier phase studies, and for whom it is important to establish an appropriate standard of care.

Original languageEnglish
Pages (from-to)e444-e451
Number of pages8
JournalThe Lancet Infectious Diseases
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2019

ASJC Scopus subject areas

  • Infectious Diseases

Fingerprint Dive into the research topics of 'Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials'. Together they form a unique fingerprint.

Cite this