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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

Lanini, S; Ioannidis, JPA; Vairo, F; Pletschette, M; Portella, G; Di Bari, V; Mammone, A; ... Ippolito, G; + view all (2019) 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. The Lancet Infectious Diseases , 19 (12) e444-e451. 10.1016/S1473-3099(19)30284-1. Green open access

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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.

Type: Article
Title: 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
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/S1473-3099(19)30284-1
Publisher version: http://dx.doi.org/10.1016/ S1473-3099(19)30284-1
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Science and Technology Studies
URI: https://discovery.ucl.ac.uk/id/eprint/10081538
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