Antimicrobials have revolutionised medical care. However, most will eventually become obsolete as pathogens develop resistance. Read about the situation and how the AMRB Benchmark stimulates pharmaceutical companies to ensure effective antimicrobials remain available.
Where is action by pharmaceutical companies most critical?
Antimicrobial medicines, and in particular antibacterials (commonly known as antibiotics), are essential life-saving medicines that have revolutionised medical care as we know today. Over time, however, most bacteria and fungi, among other pathogens, develop resistance to medicines, hampering the treatment of infections. Eventually, most pathogens will become resistant to antimicrobials, making it extremely difficult and, in many cases, impossible to treat infections. This scenario is all the more worrying considering that aging populations and climate change are expected to further drive up the burden of infectious diseases in the future.
Antimicrobial resistance (AMR) is now widely recognised as having a significant impact on human health and the global economy. It has been on the agenda of the G20 and the United Nations General Assembly since 2016. A range of advocacy- and policy-oriented organisations and initiatives have been prominent in driving AMR up the political agenda, including the Alliance for the Prudent Use of Antibiotics (APUA), Doctors without Borders (MSF), the Global Antibiotic Resistance Partnership (GARP), ReAct and the World Alliance Against Antibiotic Resistance (WAAR), as has the Ministerial Alliance of Champions against AMR, which includes 14 countries. The most recent political milestone is the inclusion of AMR in the 2017 G20 Leader’s Declaration, in which the G20 Heads of State and global leaders made a historic commitment to combatting AMR. The Declaration acknowledges that AMR can only be tackled by taking shared responsibility, including by international agencies, governments, the pharmaceutical industry, health workers, farmers, veterinarians and the general public.
To follow up on these political commitments, global AMR strategies are now being developed by international agencies, such as the World Health Organization (WHO), the UN Interagency Coordination Group on Antimicrobial Resistance and others, to research and develop new antimicrobials to replace those that are losing effectiveness, and to conserve those that still work through stewardship. Global AMR strategies must address access and stewardship issues in tandem. People living in less developed and resource-limited settings are on the frontlines for AMR – they generally face higher rates of resistance and infectious diseases. They are more likely to receive poor healthcare advice and often struggle to access appropriate antimicrobials when they need them, which can drive up rates of resistance. Efforts to increase access must include measures to limit resistance, while efforts to curb resistance must also include measures to enable appropriate access. The pharmaceutical industry has a key role to play in these different areas.
AMR threatens all countries
In recent decades, AMR has become widespread, irrespective of national income levels. In Europe, drug-resistant bacteria are responsible for more than 670,000 infections and 33,000 deaths annually, costing EUR 1 billion in annual healthcare expenditure. Each year in the US, at least 2 million people get an antibacterial-resistant infection leading to at least 23,000 deaths. This costs over USD 20 billion in direct healthcare costs and as much as USD 35 billion in lost productivity. There is less data available generally on AMR in low- and middle income countries (LMICs), due to, for example, the absence of local disease surveillance systems. Nevertheless, cost estimates of AMR for Thailand, which do exist, can be assumed to apply to many LMICs: the total economic cost of AMR due to five key pathogens in Thailand is estimated at USD 0.5 billion.
Local disease surveillance systems are critical for monitoring and preventing the rise and spread of diseases. For instance, information on antibacterial consumption, resistance levels and transmission patterns is still scarce or completely absent in many countries. Nevertheless, we know that mortality rates due to bacterial infections, such as untreated pneumonia and sepsis/meningitis, continue to be a public health problem in LMICs due to poor and/or limited access to relevant medicines, especially in children under five years of age. To address gaps in surveillance, WHO and the Wellcome Trust are now supporting programmes that aim to advance global surveillance, including the Global Antimicrobial Resistance Surveillance System (GLASS) and the AMR Register.
Multiple factors influence AMR
AMR affects human health when infections become difficult to treat or life threatening, and the appropriate medicines either do not exist, are unavailable, are of poor quality or come at a prohibitively high cost to individuals and society.The exact impact of AMR on people and their communities depends on an interplay of factors including the distribution of pathogens such as bacteria and fungi, the prevalence of resistance to each and the availability of economic and healthcare delivery resources.
Weaknesses in healthcare delivery systems can limit access to antimicrobial medicines while also promoting their overuse. The issues of limited access and overuse are closely interlinked. Measures to increase access can lead to overuse, which leads in turn to greater resistance. As resistance increases, demand for second- and third-line treatments also increases. These products are often more expensive than first-line treatments, and thus harder to access. The need for new strategies and programmes to appropriately increase access to antimicrobial medicines remains particularly acute in LMICs, where healthcare delivery systems are generally weaker.
Weaknesses in regulatory oversight can also promote overuse. They can lead to easy over-the-counter access to antimicrobial medicines and to the widespread availability of poor-quality antimicrobials with subtherapeutic levels of the active ingredient. Over-the-counter access encourages self-diagnosis and self-medication, leading to overuse. Exposure to subtherapeutic levels of an active ingredient can promote the development of resistant bacterial strains and increased virulence, which leads to the threat of deadlier infections.
Globally, the burden of non-communicable diseases (NCDs) is increasing, including for cardiovascular disease and cancer. At the same time, the infections that now persist in higher-income countries tend to occur among sicker and often older patients in challenging settings such as hospital intensive care units and nursing homes. The resistant pathogens that emerge in such settings are not as common as the underlying conditions and invasive procedures that set the stage for their presence, yet the consequences of such infections for those with otherwise treatable conditions are life-threatening. Unless addressed early, the probability of a dramatic increase in high-risk infections in aging populations is substantial.
Growing but varied demand
The antibacterial market is expected to grow to USD 55.8 billion by 2023 (up from USD 38.3 billion in 2018). This is in step with the growing demand for generic antibacterials from emerging markets. Human consumption of antibacterials is growing primarily in LMICs (e.g., China and India) where antibacterials are often accessed over-the-counter rather than by prescription. The growing demand coupled with poor surveillance and stewardship is likely to drive the emergence of resistant strains.
The majority of antibacterials are generic; only a small number remain on patent, with small profit margins. In general, new antibacterials are developed by either large research-based pharmaceutical companies or smaller biotechnology companies. Some larger research-based pharmaceutical companies have generic medicine divisions while some generic medicine manufacturers also invest in R&D.
Need for new products, low market promise
Appropriate access to antimicrobials is needed more urgently than ever by communities around the world, and the pharmaceutical industry has a critical role to play here. There is an evolutionary arms race occurring between pathogens and the medicines we use against them. This means novel products must be developed at at least the same rate as the existing ones are becoming obsolete due to resistance. New antibacterials in particular are urgently needed. Yet, antibacterials offer low profit margins, their R&D is risky and expensive and growth in demand comes mainly from the poorest. Plus, new antibacterials must be used conservatively, as part of stewardship strategies, in order to limit resistance. This makes high-volume, high-return markets unlikely to develop. These factors have contributed to several companies, including large research-based pharmaceutical companies and smaller companies, leaving this market since 2000, halting their production and engagement in R&D.
The result is a drying up of the global antibacterial pipeline; only 15 new antibacterials have been approved since 2000, compared to 63 that were put to clinical use between 1980 and 2000. Only 16 new antibacterial candidates targeting priority pathogens (those that pose the highest public health risk from AMR) are now in development. Nevertheless, a core group of companies remain committed with dedicated antimicrobial R&D divisions, and a growing number of smaller biopharmaceutical companies demonstrate a strong focus on antimicrobial R&D.
Incentives for antimicrobial R&D
To incentivise pharmaceutical companies to invest in R&D for new antimicrobial medicines and vaccines, the global AMR community established “push” incentives that share R&D costs between partners to reduce the costs of necessary inputs for developers. These push incentives include research grants (e.g., from the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB X), the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), and the AMR Accelerator Programme), as well as tax incentives, public private partnerships (such as GARDP) and data-sharing initiatives.
On its own, push funding is not enough to create a functioning antimicrobials market, particularly for antibacterials. The call for “pull’ funding has become louder in recent years. Pull mechanisms guarantee or increase the revenue generated by a new antibacterial either by: 1) accelerating the regulatory pathway; 2) extending market exclusivity; or 3) offering premium pricing. For instance, the United States’ Generating Antibiotic Incentives Now (GAIN) Act grants an additional five years of market exclusivity to companies developing antibacterials that target a selected group of qualifying pathogens. Many different ideas for pull mechanisms have recently been discussed in various fora around the world and consensus is emerging that a mix of incentives could provide a sustainable long term outcome. To demonstrate the viability of the approach, governments and pharmaceutical companies now need to collaborate on designing concrete pull incentives.
Ultimately, novel and existing antimicrobial medicines need to be affordably priced and prudently used. The challenge will be to ensure affordable, sufficient and appropriate access to these medicines while also advancing antimicrobial stewardship – and all within a viable business model. Successfully limiting AMR requires a consolidated, concerted effort by multiple stakeholders, including governments, pharmaceutical companies, international health organisations and academic institutions, to name a few. AMR is a public health issue that impacts not only human health, but animal health and the agricultural industry as well. Addressing AMR requires a “One Health” approach that stimulates increased access and affordability and ensures stewardship to limit overuse, as well as innovative R&D in next generation medicines and a higher level of environmental care in the management of antibacterial manufacturing and discharge.
Pharmaceutical companies are critical players in the innovation of new and improved medicines and vaccines, in the safe manufacturing of high-quality products and in ensuring appropriate access to and stewardship of their products. The role they play in these different areas can have a profound effect on the usage of antimicrobials and, ultimately, on resistance.
Benchmark deepens pharmaceutical industry engagement in AMR
The goal of the Antimicrobial Resistance (AMR) Benchmark is to guide and incentivise pharmaceutical companies to limit AMR. It is published every two years and tracks how a cross-section of the industry is responding to AMR by benchmarking them against the consensus view on where they can and should be making progress.
Identifying the consensus view
Before each new iteration of the Benchmark, the Foundation conducts a methodology review to refine the scopes and analytical framework that form the basis of this research. The Foundation conducts this review following its proven process for building consensus on the role of pharmaceutical companies in tackling global health priorities. The review draws on input and feedback from a variety of stakeholders, including governments, non-governmental organisations (NGOs), academia and research organisations, pharmaceutical companies and industry associations, investors, product development partnerships (PDPs) and relevant international organisations. The methodology is finalised in consultation with global experts on AMR. This report describes the 2019 methodology review and its outcomes.
The first AMR Benchmark report was published in January 2018. It was the first independent assessment of pharmaceutical company action on AMR. The Benchmark gives companies, governments, investors, NGOs and others a tool for deepening industry engagement in global efforts to curb AMR. The Benchmark metrics and analyses highlight where good practice and progress are expected and can be expanded upon, and where companies and other stakeholders can take action together, while pointing towards where new ideas are needed.
The second Benchmark report will be published early in 2020, and will provide an updated, refined map of how 30 pharmaceutical companies are responding to the global threat of AMR in three key areas: R&D, responsible manufacturing, and appropriate access and stewardship.
For a full list of references, please see the Methodology 2020 AMR Benchmark