The Era of Growing Global Antibiotic Resistance – International Researchers Propose an Innovative Strategy for a New Research Framework Based on More Efficient Trial Design for Post Marketing Evaluation of New antibiotics

Rome, August 30th, 2019 – Anti-Microbial Resistance (AMR) has become a serious public health threat worldwide. According to The Review on Antimicrobial Resistance, known as the Jim O’Neill Commission setup by the UK Government, deaths attributable every year to AMR could rise from today’s 700.000 to ten million by 2050. On May 14, 2015, the Review published their third report, titled “Securing new drugs for future generations: The pipeline of antibiotics“. This report examines the need to boost the development of new antibiotic drugs, and proposes reforms to the current economic models surrounding antibiotic development and sales.

A paper just published on The Lancet Infectious Diseases analyses critical issues on the development and commercialization of novel antibiotics against emerging multi-resistant bacteria. The study, authored by a multidisciplinary group of international experts from Italy (INMI “Lazzaro Spallanzani”, EMERGENCY-NGO, Bruno Kessler Foundation), United Kingdom (University College of London), USA (Stanford University), Germany (the University of Munich), and Tanzania (the Division of Health, President’s Office), highlights that current strategies for evaluating new antibiotics may be flawed, and presents an alternative, more efficient way for generating scientific evidence.

A major challenge in the development, registration, and marketing of new antibiotics is the selection of appropriate and efficient clinical trial study designs. In the actual context of urgency, new antibiotics for multidrug-resistant Gram-negative bacteria (namely, ceftazidime-avibactam, plazomicin, and meropenem-vaborbactam) have been approved by non-inferiority randomized controlled trials (RCT). However, these studies did not provide direct evidence of efficacy against multidrug-resistant bacteria, including those resistant to current standard of care, antibiotics like carbapenems.

By contrast to superiority RCTs, which assess whether the new drugs perform better than the old ones, non-inferiority RCTs are designed just for excluding an unacceptable loss in efficacy. The choice of developing new drugs with non-inferiority, instead of superiority RCTs, is primarily a matter of convenience: in terms of logistics, a superiority RCT requires longer study time and higher costs for testing, and could lead to a negative result, meaning absence of adequate data to support the approval of the drug.

Ceftazidime-avibactam (AvycazTM, ZaviceftaTM) is an example of such new antibiotics approved following a set of non-inferiority RCTs. Current guidelines recommend to use ceftazidime avibactam for severe infection due to carbapenem resistant Gram-negative bacteria. However, this drug was approved on the results of eight non inferiority RCTs suggesting that ceftazidime-avibactam is a non inferior alternative to carbapenems, but provided no evidence of efficacy of ceftazidime-avibactam against Gram-negative bacteria resistant to carbapenems.

In addition to the above issue on efficacy, severe ethical concerns emerge if non-inferiority RCTs were used for accelerating marketing of alternative compounds with no expected greater efficacy, no self-evident advantage, and no evident biosimilarity compared to a consolidated standard of care.
Based on experience in operational research for other severe infections, such as Ebola virus disease, authors suggest that adaptive RCTs (aRCTs) could provide a viable solution. Adaptation is a carefully considered investigational procedure for modifying study parameters while the aRCT is ongoing, on the basis of a review of the interim data analyses. Thus, it might be possible to build on available evidence from existing non-inferiority RCTs for producing new, solid, evidence and for providing all patients with the best treatment as soon as possible.

In their insightful article, the authors suggest novel alternative ways to promote aRCTs, integrating them as part of infection control programmes within health-care settings with a high prevalence of multidrug resistance. In this context, aRCTs could be viewed as next generation, post-marketing trials that could also include elements directly associated with drug efficacy 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 urgent to establish the appropriate therapy.