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.

Takes from the authors:

Simone Lanini of INMI said:
RCTs are the most solid way for generating evidence on the efficacy of new drugs. However in the present context of urgency, standard superiority RCTs may not be the most convenient way to deal with the emergency of AMR. Non-inferiority RTCs has been proposed instead, but they rise significant ethical and methodological issues. Here we described how adaptive superiority RCTs can provide an answerer to speed up antibiotic pipelines without undermining the integrity of scientific research. The major challenge for operational research on AMR is not how to speed up commercialization of multiple equivalent therapeutic alternatives, but how to assess the actual efficacy of new drugs in the safest and fastest way.

Gina Portella of EMERGENCY–NGO said:
Low-medium income countries (LMIC) have increased risk factors for communicable diseases that lead to extensive antibiotic use often without medical control and subsequent resistance. The burden of AMR is however under-estimated. The experience of Emergency in our hospital with microbiology facility (Salam center for cardiac surgery, Khartoum, Sudan) confirmed this hypothesis: many patients, previously hospitalized in other facilities, are colonized by AMR at the admission. LMIC countries don’t have comprehensive national surveillance systems that quantify the problem in human health. Political will to address the AMR only began to emerge and governments and international health organizations must take actions implementing awareness and education of local medical community.

Boniface Nguhuni of Tanzania Division of Health said:
AMR represents a substantial risk in LMICs and appropriate diagnostic is often difficult. Despite limited laboratory capacity to monitor AMR, available data suggest that the African Region shares the worldwide trend of increasing drug resistance. The African countries must build strong health systems and promote international cooperation to detect and respond quickly and effectively to this alarming problem.

Sir Professor Alimuddin Zumla of University College London said:
Post-marketing RCTs should be more comprehensive and go beyond the primary scope of monitoring infrequent side-effects, effectiveness and cost. aRCTs should be urgently taken forward as the ‘next generation, phase 4 trials’, facilitating evaluation of new antibiotic efficacy, optimal duration of therapy, cost and side effects in specific groups of patients who are usually excluded from earlier phase trials, such as those infected with multi-antibiotic -resistant bacteria. Urgent consensus by all stakeholders on global standardisation of aRCTs for post-marketing antibiotic evaluation is required.

The senior author of the study Giuseppe Ippolito of INMI said:
Antimicrobial resistant (AMR) bugs are increasing globally, threatening to render existing treatments ineffective against many infectious diseases. AMR constitutes one of the most pressing public health issues. The AMR magnitude is hampered by incomplete and inadequate data on the true extent of the problem. Predicting drug resistance evolution is really difficult. Only an integrated strategy combining promotion of innovative research, availability of believable data, technical expertise, scientific evidence, strategic and political coordination will allow to face this complex problem.

INMI general director Marta Branca said:
I am very satisfied with the positive results obtained by the Institute and by the contribution we constantly provide to the scientific community. These results will allow to increase the INMI’s activities in Italy and abroad to forefront classic and emerging infections.

* * *

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, September 2019, vol. 19, issue 9
Simone Lanini1, John P A Ioannidis2, Francesco Vairo1, Michel Pletschette3, Gina Portella4, Virginia Di Bari1, Alessia Mammone1, Raffaella Pisapia1, Stefano Merler5, Boniface Nguhuni6, Martin Langer4, Antonino Di Caro1, Sarah J L Edwards7, Nicola Petrosillo1, Alimuddin Zumla8, Giuseppe Ippolito.1

1 National Institute for Infectious Diseases (INMI) Lazzaro Spallanzani IRCSS, Roma, Italy
2 Department of Medicine, Stanford Prevention Research Center and Departments of Health Research and Policy and of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, USA
3 Department of Tropical and Infectious Diseases, Medical Center of the University of Munich, Munich, Germany;
4 EMERGENCY-NGO, Milan, Italy
5 Center for Information Technology, Bruno Kessler Foundation, Trento, Italy
6 Division of Health, President’s Office Regional Administration and Local Government (PORALG), Dodoma, Tanzania
7 Ethics and Governance, University College London, London, UK
8 Division of Infection and Immunity, University College London; and NIHR Biomedical Research Centre, University College London Hospitals, London, UK

For further info, please contact:
Salvatore Curiale – Science Communicator – INMI “Lazzaro Spallanzani”
Tel. +39 338 4860207 – email:

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