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This is a cross-post from a guest article written for the European Public Health Alliance.
The importance of antimicrobial medicines in the modern world cannot be overstated, with some studies estimating they have increased average human life expectancy by up to 23 years. However, the emergence of antimicrobial resistance (AMR) threatens to reverse this progress, undermining modern medicine and potentially making infections that are currently easily treated once again life-threatening.
Recent trends highlight this risk with outbreaks of highly drug-resistant hypervirulent Klebsiella Pneumoniae in Italy, cases of E. Coli resistant to last line antibiotics treatments rising from almost zero to over 300 cases per year in Denmark in less than 10 years and the war in Ukraine driving resistance which then spreads to the rest of Europe. Without swift, coordinated action, the 35,000 deaths annually in the EU will just be the start of a pandemic of drug-resistant infections.
The Need for New Drugs
As our current antimicrobial drugs lose effectiveness, developing new ones that can overcome existing and future resistance patterns is crucial for tackling AMR globally. However, an essential element of preserving the effectiveness of new antimicrobials is that we only use them sparingly. This leads to low sales volumes, combined with short treatment courses, generic competition, and a lack of clinical evidence, making it difficult for developers to recoup their investment. Essentially, in many cases the cost of developing a new antimicrobial exceeds expected revenue throughout the product lifecycle! This has led many large pharmaceutical companies to leave the field and left over 80% of antimicrobial assets in the hands of SMEs, who often struggle to secure sufficient funding to advance their projects.
To address this, national governments and the European Commission have funded non-profit development partnerships such as CARB-X and GARDP and the private sector has set-up the AMR Action Fund to support antimicrobial development. These initiatives are essential for sustaining and strengthening the antimicrobial research and development ecosystem but need to be accompanied by a fix of the underlying market failure.
Market shaping “Pull incentives” offer a promising and well supported mechanism for resolving this issue and can be designed to reward public health value of a drug regardless of sales volume, a concept known as “de-linkage”. The UK leads the way on this approach and has recently expanded its antimicrobial “subscription model” to cover all drugs meeting specific criteria, rewarding activity against WHO priority pathogens, existing resistance mechanisms, chemical novelty and other key properties. Eligible drugs receive annual payouts of between £5 – 20 million for up to 15 years regardless of sales volumes. This is sized to reflect the UK’s “fair share” of a total global reward for developing a new antimicrobial.
Similar models are currently being considered in Europe and beyond:
EU: The EU is exploring various incentives for developing new antimicrobials, including transferable exclusivity extensions, joint procurement, subscription models, and milestone payments.
France and Germany: These countries alter or exempt certain antimicrobials from health technology assessment (HTA) processes to allow higher pricing.
Sweden: Completed a pilot offering minimum revenue guarantees to antibiotic producers for secure supply, focusing on access rather than innovation.
Switzerland: The Swiss Roundtable on Antibiotics has proposed a model similar to the UK subscription model to their parliament.
US: The PASTEUR Act, reintroduced to Congress in 2023, proposes a model similar to the UK subscription model.
Canada: An expert committee has proposed a similar scheme to the UK’s, still early in development.
Japan: The Antimicrobial Securement Project and Cooperative Fund has a pilot to top-up sales shortfalls due to stewardship, focusing on existing drugs.
Europe is central to antimicrobial R&D, but recent years have seen an exodus of experienced researchers and developers. It is imperative that schemes to support antimicrobial R&D are developed and deployed quickly and are of a sufficient size to attract investment back to the field. They must also emphasise meeting public health needs, including those of LMICs, and ensure that they support global access and stewardship once drugs reach the market.
Access to existing
Shortages of essential medicines have now become commonplace in Europe and antibiotic shortages are the most frequent and widespread, with 100% of respondent countries reporting shortages in the PGEU Medicines Shortages Report 2023). These shortages can exacerbate AMR as physicians resort to less appropriate treatments when preferred options are unavailable.
To combat these shortages, several strategies are being explored. The recently established Critical Medicines Alliance aims to strengthen EU manufacturing capacity and strengthen/diversify supply chains. The European Commission is currently developing an multi-country revenue guarantee scheme which would see the commission top-up sales volumes to a guaranteed minimum in return for making the select drug(s) available in participating member states. The pilot for this is planned to begin next year.
Norway, Iceland and Denmark have recently run a joint tendering procedure which includes 10 antimicrobials and compliance with antibiotic manufacturing standards as part of the tender.
Expanding the use of joint procurement and revenue guarantee schemes should be complemented by other initiatives such as improved demand forecasting and reducing registration barriers, such as lowering registration fees and mutual recognition of registration of old antibiotics. Each new version of these schemes offers an opportunity to develop knowledge, try new ideas and iteratively improve.
Beyond Europe, the SECURE initiative, a collaboration between GARDP and the WHO, aims to enhance access to antimicrobials globally through tools such as pooled procurement, revenue/volume guarantees, strategic stockpiling and catalytic financing.
Conclusion
Developing new antimicrobials and ensuring access to existing ones are top public health priorities. Despite frequent commitments from EU and G7, including an EU commitment to pilot a pull incentive scheme in 2021, meaningful action has lagged. With the UNGA High-Level Meeting on AMR in September, it is time to move past discussions and deliver tangible progress against AMR.