Adding post market adaptive studies to existing noninferiority trials can provide clinicians with necessary data without slowing market introduction.
In the face of challenges posed by multidrug-resistant (MDR) infections, the world desperately needs new antibiotics—and fast.
And yet, the existing processes for the research and development of novel therapeutics may be flawed to such an extent that quickly and efficiently identifying agents that are safe and effective against MDR organisms may be next to impossible—at least according to an analysis published in The Lancet Infectious Diseases. Among the authors’ recommendations: augmenting the noninferiority trials currently used in the approval process for most new antibiotics with so-called “adaptive” post market studies that allow for modification of design parameters (including endpoints and inclusion/exclusion criteria) while research is ongoing.
Such an approach has been used successfully in the development of novel treatments for Ebola, the authors noted.
“Bacteria are extraordinary organisms that had been evolving for millennia before animals appeared on the earth,” co-author Giuseppe Ippolito, MD, MSc, of the National Institute for Infectious Diseases (INMI) in Rome, Italy, told Contagion®. “They have a remarkable evolutionary potential with an innate capability to become tolerant to harmful chemicals such as antimicrobials. The most topical issue is how to speed up the current process for developing new drugs at the pace of the bacterial evolution without compromising the integrity of scientific research.”
With deaths linked to infections caused by resistant bacteria expected to approach 10 million annually, according to recent projections, the need for truly effective novel therapeutics has arguably never been more paramount. However, as the authors of The Lancet paper note, new antibiotics for MDR gram-negative bacteria (eg, ceftazidime-avibactam) have been approved following noninferiority randomized controlled trials—designed to exclude only for an unacceptable loss in efficacy over existing options—that do not provide direct evidence of efficacy against active resistant strains.
Noninferiority trials are used because of their convenience compared with so-called superiority trials, which generally entail longer study times and higher costs and could yield negative results. Although these trials may enable a company to bring a new drug to market faster, they don’t necessarily mean there will be an improvement in treatment outcomes after using the products they study.
To highlight their point, the investigators use the example of ceftazidime-avibactam. Current treatment guidelines recommend the drug be used for severe infection due to carbapenem-resistant gram-negative bacteria. However, the drug was approved for this indication following 8 noninferiority trials in which it was shown to be noninferior to carbapenems but not necessarily effective against bacteria resistant to the older-line agents.
“New antibiotics hold the promise of improving or even saving lives,” Ippolito said. “I feel that pharma companies will respond positively to our approach. We propose a research framework for speeding up the approval of new drugs while preserving the quality of scientific evidence process, which can be of great interest for them. Our final goal is to expand and accelerate the access to new best of care and not the contrary.”
Indeed, Ippolito emphasized that the goal of the approach advocated by his team of colleagues was not to create additional hindrances to the introduction of new antibiotics, given that many have recently shown a spotlight on the challenges that already exist in the marketplace.
“HIV and hepatitis C would have been still untreatable conditions without the commitment of the pharma companies,” he noted. “Infectious disease specialists can play a dual role in the process for research and development of new drugs: by acting as the originator of topical real-life studies and by advocating post-marketing studies.”