Antimicrobial resistance (AMR) affects millions of people globally, but addressing AMR poses a unique challenge – as encouraging and promoting manufacturers to invest in research and development of new antibiotics while simultaneously restricting the use and sale of existing and new antibiotics creates a less lucrative market. In recent years, countries have finally started to spring into action to fight this global threat. But what impact are these initiatives having?

A global AMR surveillance report incorporating data of resistant infections in 144 countries, published by the World Health Organization (WHO) in 2014, documented resistance across different microorganisms. This gave us our first real glimpse into the magnitude of the direct and indirect impacts of AMR on the global health landscape. A lack of action, coupled with a slow response to report findings, allowed the rampant spread of AMR. Chronic misuse and overuse of existing antibiotics, combined with a lack of stringent laws to curb inappropriate utilisation/prescription, resulted in widespread resistance to most, if not all, antibiotics/antimicrobials. WHO has since declared it one of the top ten threats to global health.

In 2020, drug-resistant infections were found to contribute to at least 700,000 deaths per year globally. If no mitigatory actions are taken, as per the World Bank project, this may increase to 10 million per year by 2050.

When it comes to indirect effects, AMR leads to an increase in the cost of treatments and a loss of productivity, as drug-resistant infections take a long time to resolve. It is estimated that in the EU alone, AMR is associated with EUR 1.5 billion annually in healthcare costs and productivity losses.

The problem of emerging resistance to antibiotics is exacerbated by the lack of discovery and development of new antibiotics. In 2021, there were only 27 antibiotics in clinical development against priority pathogens, down from 31 in 2017. Between 2017 and 2021, only 12 new antibiotics entered the market.

Manufacturers have limited incentives to invest in R&D in this field due to several challenges:

• Developing a new antibiotic is a time-consuming process. It takes approximately ten to 15 years to progress an antibiotic candidate from preclinical to clinical stages
• The cost of developing a new drug can range from hundreds of millions to billions of dollars and antibiotics yield limited returns because:
  - They are generally prescribed for short periods of time, which limits the financial returns for pharmaceutical companies compared to drugs for chronic diseases such as diabetes, hypertension, or cancer
  - The market for antibiotics is also relatively small compared to other classes of drugs such as insulin for diabetes
  - One of WHO’s AMR Global Action Plan’s strategic objectives is to optimise the use of antimicrobial medicines, which includes rationing the use of existing antibiotics and restricting the sale and use of new antibiotics. These restrictions further limit the market size
• The regulatory pathway for new antibiotics is complex and challenging due to the need to demonstrate that a new antibiotic has value against drug-resistant infections. This requires extensive clinical trials that are difficult to design and execute
• Current Health Technology Assessment (HTA) frameworks and processes do not capture and assess the true value of antimicrobials that can address resistance.

To address these challenges, policymakers are looking for ways to incentivise manufacturers to invest in developing new antimicrobials. Payers have noted that many different actions are being taken to address AMR at national, physician and patient levels. Overall, they recognise that these steps are helping to address AMR, but they are clear that there is still room for improvement.

In the UK, an innovative reimbursement model was launched in 2020, according to which one flat price per year – a subscription – is paid to pharmaceutical companies for any new antibiotic used by the UK’s health system. This model aims to avoid antibiotic overuse and guarantee a viable market for manufacturers, even if their drugs are reserved for later lines of therapy.

Germany’s approach was to implement exceptions in G-BA’s value assessment for new reserve antibiotics. In 2020, new legislation called the Fair Statutory Health Insurance Law was passed, exempting reserve antibiotics from the full scope of regular benefit assessment. They are assumed to have added therapeutic benefit in the value assessment that forms the basis of the subsequent pricing and reimbursement negotiations. This means price is determined not based on added benefit but instead on the ability to act against multi-resistant bacteria and other pathogens.

On average, payers rate innovative reimbursement models as being slightly more impactful than amending HTA pathways at addressing AMR. Payers perceived that the UK’s subscription model may have a high impact in addressing AMR since it ensures an income for the manufacturer and thus encourages development of new antibiotics while also restricting their usage.

One payer based in the UK remarked: “[The UK subscription model] hopefully means we can restrict use without detriment to development.” Another said: “I personally think that restricting use whilst encouraging innovation is the way to go – but it’s hard to achieve and therefore financial input is necessary to encourage innovation.”

In Germany, the country’s exemption of novel antibiotics from the full scope of regular benefit assessment was considered slightly less impactful by payers overall, despite its recognised advantages such as immediate coverage and the ability to obtain full list price for the six months post launch. A German payer said: “The most effective way to address AMR is a rational and restrictive use of antibiotics and not to use them in a scattergun approach, even for viral infections.”

The physicians that took part consider emerging resistance to antibiotics to have the second highest impact on patients’ health after air pollution and climate change (Figure 1) out of the reasons listed. Although different mitigatory actions are being taken by countries to address AMR at several levels, physicians are of the opinion that they have a key role to play in the quest to address AMR, ranking improving physicians’ knowledge and appropriate prescription practices as the most impactful action countries can take to tackle AMR (Figure 2).

AMR is a multifaceted global phenomenon that will have devastating impacts on millions of lives unless urgent actions are taken to address it. Under WHO’s guidance, European countries are taking steps to address AMR, such as encouraging optimal use of antimicrobials by training physicians to restrict prescribing antimicrobials and educating the public on the consequences of not completing the prescribed dose.

However, research and development into new antimicrobials is necessary to combat AMR. Policy intervention is required to create viable market conditions to encourage manufacturers to invest in this area and enable patients to access these new drugs more quickly. Payers recognise value in the approaches adopted by the UK and Germany, suggesting that moving away from the standard pricing and reimbursement frameworks for antimicrobials and exploring innovative contracting models that incentivise manufacturers to invest in this area could have a positive impact if applied elsewhere.

AMR is a global issue and manufacturers’ efforts are shaped by the global market, which means effectively tackling AMR will necessitate more than a siloed country-by-country approach, with the combined efforts of policymakers, prescribers, public and pharmaceutical companies being vital in the fight against AMR.

As part of the author’s research, she reached out to payers from a global network as well as physicians responsible for treating infectious diseases across Europe to identify the initiatives underway to address the challenge of AMR and understand payers’ perceptions on their impact.

‘Antimicrobial resistance in Europe: Which policies will prove most effective in tackling this issue?’ is now available to download from the Research Partnership website. The white paper includes data collected from ten payers and 178 physicians treating infectious diseases in France, Germany, Italy, Spain and the UK.

References are available on request.

Kavyashree Satish is a Senior Analyst at Research Partnership