Consensus on Antimicrobial resistance (AMR) call to action
Antimicrobial resistance (AMR) is a threat to our way of life. At the moment, it kills over 700,000 people each year globally (O’Neill 2016). However, it is the future threat that is truly existential: some estimates suggest that as many as 50 million people could die due to AMR each year by 2050 (O’Neill 2016). The threat comes both from the direct issue of contracting infections that cannot be treated with antimicrobials because they are resistant to the current arsenal, and from the wider impact on health and care systems. The potentially greater risk comes from all the healthcare activities that are reliant on access to effective antimicrobials, such as chemotherapy for cancer, caesarean section births or elective joint replacements. It would be very difficult, if not impossible, to provide the same level of healthcare that we currently enjoy without functioning antimicrobials.
Pathogens don’t carry passports
Innovation and development are the key to preventing this catastrophe. Humans and microbes are locked in an arms race that humans can never win definitively. What we can do is keep creating new solutions by outwitting and out-innovating our opponents. COVID-19 has shown the devastating impact of infectious diseases for the entire global population, through direct effects of mortality and morbidity, as well as forgone medical treatment, restrictions impacting mental health and social wellbeing and the economic damage that is likely to be felt for decades, all leading to enormous opportunity costs. AMR presents the potential for a slower burning, but ultimately more damaging, healthcare crisis that could undo many of the healthcare advances of the 20th and 21st centuries.
Where we are now
At the moment there are few incentives for companies to develop an antimicrobial. In most markets across the world, the primary way in which drugs are paid for is by volume, to reward companies via return on investment – the more units sold, the more money is received by the company. This model does not work well in antimicrobial development, as they are often developed to be used after all other avenues have been exhausted; to be saved until the need is dire, rather than to be used as a first or early choice. This restricts the market available to companies seeking to develop an antimicrobial within the current global commercial framework and disincentivises innovation in antimicrobial development.
Compounding these difficulties is a lack of reliable, rapid diagnostics that are available at point of care and are appropriately reimbursed. These are crucial for the appropriate use of broad-spectrum and narrow-spectrum antibiotics. At the moment, doctors are often faced with a difficult clinical decision – whether to treat a patient presenting with a severe problem (e.g. sepsis or pneumonia) with a broad-spectrum antibiotic, which is likely to work because it encompasses a wide range of potential pathogens, or to wait for a more specific microbiological diagnosis, which can take 48 hours or sometimes longer. Even when diagnostics are fairly rapid (12 hours or less), doctors often make a clinical decision to initiate treatment with a broad-spectrum antibiotic in order to avoid patients’ deterioration. In order to maximise the use of narrow spectrum antimicrobials, there is a pressing need for the development and implementation of widespread rapid diagnostics capable of distinguishing between pathogens quickly enough to inform clinical decision-making. There is an unfortunate chicken-and-egg situation with narrow-spectrum antimicrobial and diagnostic development – the development of narrow-spectrum antimicrobials requires rapid, accurate diagnostics, while the economically viable development of diagnostics rely on having effective treatments available to choose from that will affect the treatment pathway that are reimbursed fairly within the healthcare system. This dichotomy needs to be resolved through industry collaboration, with the support of governmental bodies and research institutions. There is also often a disparity in sizes of companies, with drug development often done by companies many magnitudes in size larger than diagnostics developers. As diagnostics are relatively inexpensive to develop compared with drugs, there is often less incentive for larger companies to do so. There is also an unwillingness to pay high sums for diagnostics once developed which is compounded by the cost of developing both the antimicrobial and the companion diagnostic. These factors mean that companies developing antimicrobial therapeutics may not also invest in developing diagnostic tests that would optimise their use. There may be a lack of knowledge and capacity around market access for smaller diagnostics companies, as well as a lack of willingness by larger drug developers to prioritise development in these areas. Taking advantage of these differences, rather than being seen as a weakness, would permit a more agile approach to targeted diagnostics development. Creating pull incentives around adoption and implementation of diagnostics would also relieve some industry tension associated with investment in this area.
There are two commonly understood types of incentives for encouraging the development of antimicrobials – ‘push’ incentives and ‘pull’ incentives (as referred to above). Push incentives are those that reward inputs, including research grants, tax incentives and public-private initiatives designed to stimulate research. Pull incentives are those that reward outputs and are arguably more important for creating market stability while also being more difficult to implement.
The UK has pioneered a new approach for England through its Models for the evaluation and purchase of antimicrobials project. This project selected two antimicrobials for evaluation and subsequent reimbursement through a ‘delinked’ payment model. The National Institute for Health and Care Excellence (NICE) conducted a full health technology assessment (HTA) evaluation to understand the full value of these two antimicrobials to the NHS. This value assessment is now being used to inform negotiations between the companies and NHS England and Improvement (NHSE&I), which will lead to an annual payment of up to £10m per product for an initial three years, with a possibility of extension to five or 10 years.
Sweden has also led an initiative to improve antimicrobial access through a delinked payment model for existing antimicrobials. This initiative differs from the UK project in two important ways – it is designed to ensure access for Sweden to existing antimicrobials where the population is too small to support traditional procurement procedures rather than to stimulate company investment in new antimicrobials, and does not contain an HTA evaluation as the basis for decision-making. However, it provides an excellent example of where political will can affect antimicrobial policy in a positive way, providing much better patient access than would have been available otherwise, without reliance on technically demanding HTA processes or difficult procurement processes. There are other global initiatives also seeking to implement pull incentives, such as DRIVE-AB, part of New Drugs 4 Bad Bugs (ND4BB) and the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), but these have not been adopted by national governments yet. A new report from TATFAR is expected in late 2021, which may affect future policy in the US and internationally. The Pasteur Act may be signed into law, which would also support the principle of fixed payments for antimicrobial drugs. The UK is planning to use its presidency of the G7 to drive forward the AMR agenda, as well (https://www.gov.uk/government/speeches/reinvigorating-our-system-for-international-health).
Call to action
While these projects are an excellent start, there is a pressing need to extend pull incentives. The UK AMR project is designed to test the concept of a delinked payment model in England, and the full initial evaluation of the project outcomes and success will not be ready until 2025. This will be almost 10 years after the inception of the project. Rather than wait for this report to explore all of the ramifications of the UK project, it is critical to understand the important learnings from the project that are available now: it is already possible to decide to pay for antimicrobials in a delinked model and to decide criteria on which to select them. The HTA element of the UK project is invaluable in quantifying the value of the products and this understanding will be useful in forward planning nationally and internationally. However, it is possible to estimate the minimum value that an antimicrobial should bring to an individual country’s market in order to make its development worthwhile, irrespective of the precise number of Quality Adjusted Life Years (QALY) gained during its implementation. After all, this is the basis on which the maximum cap of £10m per annum per antimicrobial was decided in the UK project. It is possible to extrapolate from the estimate from O’Neill (2016) of $0.8bn to $1.3bn total required reward for an antimicrobial to understand the proportion required from each country, based on volume of antimicrobial sales annually. This is not a complex calculation and does not require sophisticated and uncertain QALY calculations. It requires political will to implement an evidence-based policy that will have direct consequences for future global health.
Six-point action plan
We are at a critical fulcrum point, where we must take advantage of the momentum generated by the UK, Swedish and global AMR projects to develop and test different types of pull incentives to a pipeline of effective antimicrobials for the future. These are concrete actions for stakeholders engaged in this area to take, in order to drive forward the AMR consensus agenda.
· Industry and government stakeholders to engage with international governments to discuss pull incentives, particularly based on an O’Neill calculation of drug development costs spread proportionately, based on drug spend per annum and/or GDP considerations
· Use learning from the UK project to anticipate and diffuse issues around legal, bureaucratic and scientific challenges for agreement and implementation of pull incentives
· Create an international consensus on meaningful minimum clinical efficacy standards for a new antimicrobial, and use this to inform both trial development plans and reimbursement criteria
· Determine roll-out strategy for UK project to England and the devolved nations on a shorter timeframe than three+ years after the HTA-informed negotiations by NHSE and the companies, in order to keep momentum going in the UK
· Commit to developing and funding the entire treatment pathway associated with antimicrobials, from diagnosis, to prescription of antimicrobials through to follow-up
· Develop cross-industry collaborations between developers of antimicrobials and diagnostics companies (particularly when there is a disparity in the size of the companies) and commit to meaningful incentives for diagnostic development
HM Government, Tackling antimicrobial resistance 2019–2024: The UK’s five-year national action plan, available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/784894/UK_AMR_5_year_national_action_plan.pdf
O’Neill, J, Tackling drug-resistant infections globally: final report and recommendations, May 2016, available at: https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf
New Drugs 4 Bad Bugs project, available at: http://www.nd4bb.eu/index.php
DRIVE-AB, Revitalising the antibiotic pipeline, March 2019, available at: http://drive-ab.eu/wp-content/uploads/2018/01/CHHJ5467-Drive-AB-Main-Report-180319-WEB.pdf
Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), available at: https://www.cdc.gov/drugresistance/tatfar/index.html