REQUEST FOR PROPOSAL for Public health value and cost-effectiveness modelling for reserve antibiotics
Closing date: 09.12.2024
ABOUT GARDP FOUNDATION
The Global Antibiotic Research & Development Partnership (GARDP Foundation) is a not-for-profit global health organization registered in Geneva, Switzerland. GARDP’s mission is to accelerate the development and access of treatments for drug-resistant bacterial infections. It does so by forging public-private partnerships all over the world to develop and expand access to treatments for serious bacterial infections and sepsis in adults, children and newborns, as well as sexually transmitted infections (STIs).
GARDP Foundation responds to the crisis in antimicrobial resistance. In 2015, the World Health Assembly, the decision-making body of the World Health Organization (WHO), adopted the Global Action Plan on Antimicrobial Resistance. The following year, to deliver on this plan, WHO and the Drugs for Neglected Diseases initiative created GARDP. In 2018, the GARDP Foundation was legally established as an independent entity.
Since then, GARDP Foundation has developed a portfolio of antibiotic treatments that targets WHO priority pathogens, priority diseases and key populations/regions that are especially affected by drug resistance. It is also pioneering new access initiatives with innovator, manufacturing and distribution partners.
As of 2024, the GARDP team consists of about 100 people who collectively share extensive cross-sector R&D and access experience. They work with the key public and private sector stakeholders and partners, such as the research and development community, donors, industry and implementing countries.
PROJECT BACKGROUND & PURPOSE OF THE RFP
Background to project
Carbapenem-resistant (CR) Gram-negative bacterial infections caused by Acinetobacter baumannii (CRAB) and Enterobacterales (CRE), and Pseudomonas aeruginosa (CRPA), are listed in the WHO critical and high priority groups, respectively, requiring novel antibiotics for successful treatment1. CRAB is often resistant due to OXA-type β-lactamases, CRPA due to metallo-β-lactamases (MBL) and CRE due to OXA-type β-lactamases, although many carbapenamases exist, and therefore antibiotics are needed that have activity against a range of different types. CRAB and CRE show an increasing trend in at least 1-3 WHO regions and have a medium-high level of transmissibility. CR bacteria are difficult to prevent and treat, lead to high mortality, and rely on countries having access to the few last line antibiotics. Third-generation cephalosporin-resistant Enterobacterales (3GCRE) are also in the critical group, highlighting the need for new antibiotics to treat those infections too.
Despite the fact that CR and 3GCRE bacteria pose a major public health issue, with limited treatment options and high mortality rates, in many low- and middle- income countries (LMICs) treatment is limited and countries may have inadequate access to safe and effective antibiotics
that cover local resistance patterns.2 Further, CR may also be driven by increasing carbapenem use, including to combat increasingly prevalent infections caused by 3GCRE, suggesting that carbapenem-sparing strategies may be needed to treat 3GCRE.
There are only two approved antibiotics with activity against CRAB, cefiderocol and sulbactam-durlobactam3, which leaves few options, given that GLASS has reported Acinetobacter spp. isolates with over 50% carbapenem resistance4. Furthermore, only cefiderocol is also active against CRPA and CRE. Cefiderocol is the first clinically available siderophore cephalosporin and has been approved in the USA for the treatment of complicated urinary tract infections (cUTI), and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP), and in Europe for the treatment of infections caused by aerobic Gram-negative bacteria in adults with limited treatment options. Aztreonam-avibactam was also recently approved in Europe for the treatment of Gram-negative bacteria, including MBL-producing multidrug-resistant pathogens (especially CRE) for which there are limited or no treatment options, and is awaiting FDA approval. Cefiderocol is on the Model List of Essential Medicines (EML) and is recommended as a Reserve antibiotic in the WHO AWaRe antibiotic book, primarily for the treatment of infections caused by MBL-producing CRE and CRPA in adolescents and adults, depending on the type of carbapenemase produced and the resistance mechanism5. It can be used as monotherapy or potentially with other antibiotics (e.g. to treat CRAB).
While cefiderocol and other Reserve antibiotics are on the market, further evidence of their potential public health value and cost-effectiveness across different settings and use cases is needed to support both pricing and roll-out strategies, for which modelling can be helpful.
Purpose of RFP
The aim is to develop a model using a scenario analysis to better understand the key drivers of the public health value (e.g. deaths, disability-adjusted life-years (DALYs), and health sector costs) and cost-effectiveness of using Reserve antibiotics, like cefiderocol, to treat aerobic Gram-negative infections with limited treatment options across different settings and patient groups. While the primary focus is on Reserve antibiotics for the treatment of CR infections, a secondary focus is on a scenario analysis for using carbapenem-sparing regimens (of one or more antibiotics) to treat infections caused by 3GCRE.
Models should be designed to maximise clinical outcomes and equitable use across countries and include situations where cefiderocol is not available so that the current standard of care comparator is a different antibiotic. Comparators should also include non-antibiotic variables and the cost-effectiveness threshold per modular scenario should be established to inform price-thresholds for affordability.
In order to facilitate geographical applicability and involvement from local actors, in-country partners should be included. To maximise the likelihood that the results will be translated into normative recommendations and local policy decision-making, the target audience should include policymakers, clinicians and health managers in LMICs, and international organizations like the World Health Organization (WHO). Ideally, the model should include at least two countries with different epidemiological and health system contexts. The model should be transparently published to allow others to use and employ the same methodology, and so that it can be repurposed for other antibiotics beyond cefiderocol that are effective against select CR and ESBL-producing bacterial infections.
SCOPE OF WORK
Primarily, the modelling work should establish plausible, archetypal country scenarios for the use of Reserve antibiotics, using cefiderocol as an example, that would generate the most optimal and feasible use case(s) that maximise patient outcomes, minimise rate of resistance development and optimise cost-effectiveness, and that allows a plausible price range for cefiderocol in different scenarios to be established. This should include differences in prevalence of CR, access to essential antibiotics, diagnostic and antibiotic stewardship, and income level/resources. One of the scenarios should include availability of antibiotic susceptibility testing (AST) for cefiderocol, which is not currently part of existing automated or manual platforms. Additionally, while we expect that bacteriology will be needed for surveillance, stewardship and patient management, a scenario where cefiderocol is used as empiric therapy in specific situations where there are very high rates of CR/MBLs, and also where combinations are used for CRAB, should be included (GARDP will soon have some data on real world use of cefiderocol in the USA and Europe and could use the combos that are being used in this survey, as well as in vitro work done by Shionogi, the originator, to inform this modelling work).
Secondarily, country scenarios for the use of carbapenem-sparing regimens should be established for the treatment of 3GCRE that would, as described above, generate the most optimal and feasible use case(s) that maximise patient outcomes, minimise rate of resistance development and optimise cost-effectiveness.
Thirdly, a scenario analysis should be included for the addition of rapid tests to the existing standard of care bacteriology testing to model whether quicker results that inform a more rapid treatment switch to a more appropriate antibiotic add public health value and are cost-effective (including antigen lateral flow, biochemical, growth-based, and molecular tests measuring AST or carbapenemases and 3GCRE or ESBL production).
Non-antibiotic variables should be included in the modelling with varying levels of implementation, such as: (i) infection prevention and control (IPC) measures in health facilities, (ii) availability of relevant diagnostic testing and the use of a cumulative antibiogram, (iii) existence of an antimicrobial stewardship programme, and (iv) routine immunization (for example, using PCV, HiB, RSV, influenza, rotavirus, RTS,S, typhoid, and GBS vaccines)6. Finally, the model should be informed and validated by in-country experts and the WHO AMR Division.
DELIVERABLES
Expected Outcomes:
- Scoping review of available data in a range of countries (e.g. aetiology of resistant infections, transmission, disease burden, antibiotic use and adherence to protocols on prescribing antibiotics and the effectiveness of IPC) and expert consultation to inform the development of country scenarios (i.e., archetypes) and the model structure, published as a research paper in a scientific journal.
- A model or set of modular models to analyse the different scenarios outlined in terms of the public health value, cost-effectiveness and price thresholds (e.g. deaths, DALYs, and health sector costs) of (i) Reserve antibiotics / cefiderocol for the treatment of CR bacteria, (ii) carbapenem-sparing regimens for treatment of 3GCRE, and (iii) the addition of rapid diagnostic tests for AST, carbapenamases and 3GCRE. At least two articles should be published, with the methodology, as research papers in scientific journals, and available as an open-source online tool.
- Powerpoint presentation summarising the project and results.
If you are interested to participate, please send a request to: RFP_Procurement@gardp.org to receive complete documentation of this RFP
Due/closing date: December 9th 2024
1 WHO Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance. Geneva: World Health Organization; 2024
2 Jean, S. S., Harnod, D., & Hsueh, P. R. (2022). Global Threat of Carbapenem-Resistant Gram-Negative Bacteria. Front Cell Infect Microbiol, 12, 823684. https://doi.org/10.3389/fcimb.2022.823684
3 2023 Antibacterial agents in clinical and preclinical development: an overview and analysis. Geneva:
World Health Organization; 2024
4 Global antimicrobial resistance and use surveillance system (GLASS) report 2022. Geneva: World
Health Organization; 2022
5 The WHO AWaRe (Access, Watch, Reserve) antibiotic book. Geneva: World Health Organization; 2022
6 Lewnard, J. A., Charani, E., Gleason, A. et al. (2024). Burden of bacterial antimicrobial resistance in low-income and middle-income countries avertible by existing interventions: an evidence review and modelling analysis. The Lancet, 403(10442), 2439–2454. https://doi.org/10.1016/S0140-6736(24)00862-6