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A lesson learned from COVID-19: The importance of non-inferiority (NI) trials for developing new antimicrobial agents before widespread need
– by John Rex


A lesson learned from COVID-19: The importance of non-inferiority (NI) trials for developing new antimicrobial agents before widespread need
– by John Rex

PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This commentary was originally published on 19 September 2020 on the AMR.Solutions website (amr.solutions) and adapted on 6 October 2020 as a Viewpoint for the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

In this Antimicrobial Viewpoint article, I explore the two types of clinical trials: Superiority and non-inferiority (NI) as well as the lethal danger of Infections and how antibiotics are best developed before we need them. I also explain how non-inferiority trials are for the public good and allow us to avoid COVID-19-like situations and explain why superiority efficacy is (hopefully) unattainable, but superior utility is possible.

There are two kinds of clinical trials in which all pharmaceutical products must show which individuals can benefit from the product. They should also demonstrate a way to identify those individuals and document the benefit received from the product. Clear answers to these questions are required for product approval and acceptance. To achieve this, one of two types of trial designs can be used:
• A superiority trial – the goal of this is to show that the new agent is measurably superior to existing treatments or to a placebo.
• A non-inferiority (NI) trial – Sometimes formerly referred to as an “equivalence trial”, the goal of this is to show that the agent has efficacy similar (within the bounds of a pre-specified non-inferiority margin) to that of existing treatments.

By using non-inferiority (NI) trials to develop new antibiotics in advance of the (next) pandemic, we can save lives and avoid panic.

Infections can be lethal

From a public health perspective, new antimicrobial agents with an improved microbiologic spectrum of activity should be developed before widespread bacterial resistance emerges. This desire leads immediately, however, to a paradox: although it is easy to demonstrate that a novel test agent has an improved spectrum both in vitro and in preclinical animal infection models, rigorous demonstrations of the new agent’s superior clinical efficacy over existing drugs both are and should be difficult to implement on a routine basis in trials of human infections:
Infections move quickly and can be fatal! As inadequately treated acute infections can be rapidly fatal and enrolment into a trial must often be undertaken empirically before culture results are known, it is obviously desirable that the control arm be predicted to be efficacious in all studies, including studies of potentially superior new agents.
We always seek to give effective therapy to all patients! Indeed, if resistance is known or suspected to the control arm, then the control arm should always be adapted to offer some form of best available therapy that is predicted to be efficacious. In short, it is important from an ethical viewpoint that the trial make every attempt to use an efficacious control and not anticipate showing superiority relative to ineffective or substandard control.

The time to develop new antimicrobial agents is before we need them

When we lack any effective therapies, placebo-controlled trials are possible, at least in theory:
• COVID-19 highlights the only exception to the prior rule! The only exception to the above-noted ethical imperative would be if there were either no efficacious options whatsoever for the infecting strain (or if all forms of best available therapy were meaningfully suboptimal). It is of course obvious that such a situation would imply a situation with grim public health implications.
For (fatal!) infections, study enrolment is made challenging by both the impact of infection control efforts and the desire to avoid placebo1: Again COVID-19 has shown us that trials may not run as quickly as you’d expect. If local control measures can reduce the spread of the target infection (good for the community!), infected patients can become hard to find (bad for the study!). And the desire to be treated with something (anything!) can overwhelm the ability to enroll even in properly designed and ethical trials.
And once you definitively have an effective therapy, the rules change! The window of opportunity to reliably design trials to show superiority because of a complete lack of therapeutic options would close with the emergence of a new efficacious therapy. Would you be willing to be randomized to placebo if you were in the ICU with COVID-19?

From a public health perspective, new antimicrobial agents with an improved microbiologic spectrum of activity should be developed before widespread bacterial resistance emerges.

NI trials are a public good

By using NI trials to develop new antibiotics in advance of the (next) pandemic, we can save lives and avoid panic. Think about how different the world would be right now if we (as a global community) had substantially completed the development a few years ago of one or more therapies and vaccines for the coronaviridae (SARS, COVID-19, etc.) based on measures of immune response and perhaps even controlled human infection models (CHIMs)2.

Superior utility is possible

Although superior efficacy is thus hopefully something we rarely see, superior utility is entirely possible. Oral rather than IV? A shorter course of therapy? Fewer associated side-effects? Better taste in a pediatric formulation? All of these are entirely possible and could be pursued — the only thing that is off the table is superior efficacy. Indeed, the ARLG (Antibiotic Resistance Leadership Group) is pursuing studies of this type based on the Desirability Of Outcome Ranking (DOOR) suggested by Scott Evans and colleagues3.

References

  1. Joseph A. STAT News: Efforts to beat back the coronavirus are critical. They’re also making clinical trials harder. 2020 
  2. Deming ME, Michael NL, Robb M, Cohen M and Neuzil K. Accelerating development of SARS-CoV-2 Vaccines – The role for controlled human infection models. The New England Journal of Medicine. 2020; 383:e63 
  3. Antibacterial Resistance Leadership Group. Desirability of outcome ranking (DOOR) 2020. 
  4. Rex JH, Talbot GH, Goldberger MJ, Eisenstein BI, Echols RM, Tomayko JF, Dudley MN, and Dane A. Progress in the fight against multidrug-resistant bacteria 2005-2016: Modern non-inferiority trial designs enable antibiotic development in advance of epidemic bacterial resistance. Clinical Infectious Diseases. 2017; 65:141-6.
  5. Fernandez Lynch H, Cohen IG, Darrow JJ, Outterson K. Designing development programs for non-traditional antibacterial agents. Nature Communications. 2019;10(1):3416.

This Antimicrobial Viewpoint has been adapted from a 19 September 2020 newsletter posted to the AMR.solutions website by the author. The original text can be accessed here.

John Rex is Chief Medical Officer and Director of F2G, LTD, a UK-based antifungal drug discovery and development company.

He is a physician and drug developer with more than 30 years of development and policy experience focused on antimicrobial agents. Throughout his career, he has moved antifungal and antibacterial agents from preclinical development through all development phases. He has held academic positions in the USA at the National Institute of Allergy and Infectious Diseases (NIAID) and the University of Texas Health Science Center at Houston (UTHealth). He also holds a board-level role at Adenium Biotech ApS and is an Expert-in-Residence at Wellcome Trust.

The first 15 years of his career focused on medical mycology and spanned susceptibility testing methods, in vitro-in vivo translational studies, and clinical trials. More recently, he broadened his focus to include advancing novel regulatory and reimbursement paradigms for antimicrobial agents, the founding of the New Drugs for Bad Bugs (ND4BB) programme of Europe’s Innovative Medicines Initiative (IMI), and leadership of an antifungal-focused biotech company.

2020-11-10T17:32:53+00:00

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