Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance

Dear All:
Along with our co-authors (Mark Goldberger, Barry Eisenstein, Roger Echols, John Tomayko, Mike Dudley, and Aaron Dane), George Talbot and I delighted to be able to share the attached manuscript which was released online yesterday at Clinical Infectious Diseases (link for online access & the abstract are below my signature). We are also sharing this brief slide set summarizing the key ideas.
In brief, we have all been frustrated by well-intended but ill-founded critiques of the use of non-inferiority (NI) designs. Although superiority studies give very clear results and can (sometimes) be done with very small numbers of subjects, calls to only use superiority designs fail to understand what this would really mean for public health. And while NI studies are at risk for invalid results due to experimental noise, work over the past decade has led to articulation of design parameters that ensure NI studies of new antibiotics are very robust.
To address this concern, George and I (note that we share co-author status as first author) conceived of writing this paper as a reference for discussions of this topic. Along with our strong co-authors, we’ve worked hard to write a clear and detailed analysis that covers the strengths and weaknesses of both superiority and NI approaches, reviews the features of our updated & robust designs requirements for NI studies, and then analyzes the impact our updated approaches have had on the global pipeline.
As a quick guide to three of the key concepts from the paper, see also this slide deck. Both the paper (it is Open Access) and the PowerPoint can be freely forwarded.
All best wishes,
John (& George)
John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Chief Strategy Officer, CARB-X | Expert-in-Residence, Wellcome Trust
Follow me on Twitter: @JohnRex_NewAbx
Abstract: From a public health perspective, new antibacterial agents should be evaluated and approved for use before widespread resistance to existing agents emerges. However, for multidrug-resistant pathogens, demonstration of superior efficacy of a new agent over a current standard-of-care agent is routinely feasible only when epidemic spread of these dangerous organisms has already occurred.
One solution to enable proactive drug development is to evaluate new antibiotics with improved in vitro activity against MDR pathogens using recently updated guidelines for active control, noninferiority trials of selected severe infections caused by more susceptible pathogens. Such trials are feasible because they enroll patients with infections due to pathogens with a “usual drug resistance” phenotype that will be responsive to widely registered standard-of-care comparator antibiotics.
Such anticipatory drug development has constructively reshaped the antibiotic pipeline and offers the best chance of making safe and efficacious antibiotics available to the public ahead of epidemic resistance.


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