A global challenge

Antibiotic resistance is a leading cause of mortality internationally, and urgent action is needed to tackle this growing threat to public health. It has been estimated that, in 2019, antibiotic resistance was directly responsible for 1.27 million deaths globally. The health burden of antibiotic resistance in the EU/EEA is comparable to that of influenza, tuberculosis and HIV/AIDS combined. It has also been estimated that antibiotic resistance costs about €1.1 billion annually to the healthcare systems of European Union (EU)/European Economic Area (EEA) countries.

Reinvigorating the antibiotic pipeline

Only a handful of new antibiotics have been developed and launched over the last few decades, and almost none have any innovative characteristics such as a new mechanism of action or chemical class. They are therefore vulnerable to rapidly emerging cross-resistance with existing antibiotics. In 2022, the World Health Organization (WHO) described these new antibiotics and those in clinical development as “insufficient” to tackle the challenge of increasing emergence and spread of antibiotic resistance.

Despite intensified international efforts, major scientific, economic and structural barriers to stimulating antibiotic research and development (R&D) persist. Most large pharmaceutical companies have withdrawn from antibiotic R&D because scientific challenges mean there is a high risk of failure for research projects and clinical trials, and antibiotics are less profitable than other therapeutic areas due to small volumes of sales and low prices.

Antibiotics R&D is now driven by academia and small and medium-sized enterprises (SMEs), many of whom become bankrupt or experience significant economic losses when launching new antibiotics. Due to recent push incentives, the WHO has found that the preclinical pipeline is “innovative and includes a large number of non-traditional approaches”. Yet, SMEs still experience difficulties in securing funding for preclinical and early-stage clinical trials, when the risk of failure is particularly high compared to later-stage clinical development. SMEs are advocating for solutions that will give them the predictability and will encourage private investors (e.g., venture capitalists and larger pharmaceutical companies) to allocate adequate budget for research into new molecules at an early stage.

A holistic incentive package for antibiotic R&D must address public health, market and implementation factors. Public health factors include targeting high-priority medical needs, ensuring antibiotic sustainability, promoting patient access, and protecting environmental health. Market factors include improving the return on investment from developing and commercializing a new antibiotic, and making market participation feasible for SMEs. Implementation factors include the size of the incentive, timing of incentive delivery, governance of the incentive package, and international coordination.

Increased investment in push incentives, such as direct funding and grants, across all stages of antibiotic R&D is still required. There is a particular unmet need for funding during the preclinical phase of development. This bottleneck in funding means that many antibiotic candidates cannot overcome what has been termed the “valleys of death”, transitioning between early drug discovery and preclinical research, and between preclinical and early clinical development research. There are benefits in distributing this funding through a designated global antibiotic pipeline coordinator. There are some organizations already playing this role at different stages of antibiotic R&D, but a more comprehensive mechanism is still needed.

Developing and implementing pull incentives are essential to creating a viable market for antibiotics. Many options exist, including direct financial pull incentives, such as prospective purchase agreements (i.e., de-linked or partially de-linked subscription payments) and market entry rewards, and indirect financial pull incentives, such as transferable exclusivity extensions and market exclusivity extensions. Each option has its benefits and drawbacks, although prospective purchase agreements (i.e., subscription payments) are most suited to encouraging compliance with antibiotic sustainability, patient access and environmental health manufacturing standards. However, prospective purchase agreements can also be combined with other pull incentives, such as market entry rewards or exclusivity extensions.

Milestone payments can be considered to support SMEs. Milestone payments are a type of push incentive that involve granting funding to developers at specific stages of antibiotic development. This funding is then used to fund subsequent stages of development. They can help to support SMEs, which drive most antibiotic R&D, and to overcome the aforementioned “valleys of death”, which result in the failure of so many antibiotic candidates during preclinical and early clinical development.

Mechanisms to share risk in antibiotic R&D can also secure return on investment for public funds. For example, the Options Model for Antibiotics (OMA) provides a mechanism for public investors to prospectively purchase options to procure new antibiotics at discounted prices, and can provide additional financial support through multiple stages of development.

Ensuring access to new and existing antibiotics

Many existing antibiotics, including generics, are unavailable in several countries. Several factors can influence the availability of an antibiotic in a given country, including whether manufacturers have brought their product to that market and kept it there, as well as whether there is sufficient supply of the antibiotic overall. Financial considerations, and in particular the expectation of insufficient revenues, are cited as the main reason for decisions to not launch or withdraw, while the fragility of the antibiotics supply chain often leads to short- or longer-term shortages.

Shortages of antibiotics are a major issue for all Member States in Europe. In 2019, there were over 1,300 notifications of antibiotic shortages across the EU. These antibiotic shortages have important implications for patients and health systems as they can lead to use of suboptimal antibiotics, prolonged bacterial infections, and spread of antibiotic resistance. WHO classifies antibiotics according to their potential for resistance development in three categories: ‘Access’, ‘Watch’ and ‘Reserve’. In primary care, 90% of common infections can be treated with ‘Access’ antibiotics, which have the lowest risk of resistance development. Shortages of many commonly used ‘Access’ antibiotics, such as amoxicillin and clindamycin, are frequently reported by Member States. In 2020, 8 Member States did not meet the WHO target that at least 60% of human antibiotics used at the country level should be ‘Access’ antibiotics. Addressing antibiotic shortages, along with improved antibiotic stewardship and infection prevention and control, are key to meeting this target.

Limited access to both new and pre-existing antibiotics puts patients at risk, raises costs and contributes to driving increases in antibiotic resistance. This can impact resistance development in several ways. First, use of less effective antibiotics can lead to prolonged infections and greater risk for resistance to emerge. Second, when narrow-spectrum antibiotics are not available physicians often need to prescribe suboptimal broad-spectrum antibiotics that have higher potential for resistance development. Third, insufficient supply of existing antibiotics can attract unserious players to supply substandard and falsified antibiotics that are less effective and boost resistance.

To counteract the financial unattractiveness of bringing new or keeping older antibiotics on the market, options such as reducing or waiving annual registration fees and amending sunset clauses could be considered to reduce costs for antibiotics manufacturers. Optimizing procurement terms (for example, avoiding race-to-the-bottom tendering by ensuring that more than one supplier is contracted, and offering contracts that are of sufficient duration and minimum order amounts to attract adequate bids and improve predictability), and also considering delivery security as a factor that will determine whether a tender is awarded, are important considerations and may not require substantial disruption to implement. Joint purchasing approaches can enhance expected revenues by increasing target populations, while subscription payments (or annual revenue guarantees) can contribute to maintaining production and availability.

The limited number of actors involved in the antibiotics production and supply chain, in conjunction with the fact that demand can be difficult to forecast and anticipate, are important contributors to shortages. Despite the overall lack of transparency about where raw materials are procured and where the producers of reaction intermediaries, active pharmaceutical ingredients (API) and finished dosage forms (FDF) are located, it is clear that these activities largely take place outside the EU. A first step towards addressing the fragility of the supply chain could entail a European pharmaceutical production capacity mapping database of all industrial entities that make up the pharmaceutical supply chain. Such a mapping would facilitate efforts to spread risks at procurement and help to identify alternative producers when shortages occur. Additionally, EU-level facilitated exchange between Member States to identify and compare which antibiotic formulations are available in different settings, and which would be the best options for existing medical needs according to best available evidence, could help to identify which products should be the focus of supply efforts. EU action towards strengthening manufacturing capacities along these lines within (and potentially outside) the EU could be further considered to provide long-term solutions. Given the substantial infrastructure and investment requirements, such action should align with national initiatives. Finally, different stockpiling options should be considered, not focusing solely on the final products.

A global solution

Antibiotic resistance is one of the most important global health challenges, and lack of access to appropriate and effective antibiotics is a threat to global health security. Indeed, lack of access to effective antibiotics as a driver of excess mortality is particularly felt in low-income and middle-income settings, which also most acutely experience antibiotic shortages and would experience larger drops in economic growth with an increasing AMR burden. The EU’s 2022 Global Health Strategy recognizes AMR as one of the key challenges needing to be addressed in the coming years and commits to a range of actions towards intensifying efforts to do so, including a commitment to support the development of new antibiotics, and the future pandemic agreement provides a unique opportunity to make progress in tackling AMR at the global level. Crucially, the EU can build on its relationships with international institutions, such as the UN Quadripartite, in conjunction with its G7 and G20 membership, and act as a facilitator in the global space towards advancing shared objectives and ensuring synergies among existing structures. Finally, the EU could increase its efforts in communicating both within and outside its confines what the cost of inaction in the face of antibiotic resistance could entail and in actively supporting related national and regional efforts.