Authored by BresMed, now part of Lumanity

In this piece, Renu and Matthew break down why the market has failed to tackle antimicrobial resistance and look into some of the initiatives created to deal with the problem. Focusing on England’s novel payment evaluation and purchasing frameworks, they investigate how the new ‘de-linked’ approach could impact the development of future treatments.

It is undeniable that antimicrobial resistance (AMR) is a major and growing threat to global public health. Every year, an estimated 700,000 people die globally due to drug-resistant infections. With pathogenic bacteria inevitably becoming more resistant to the existing array of antimicrobials, it has been estimated that if significant action is not taken, 10 million lives could be lost each year by 2050 due to AMR.1 In addition to this large loss of life, there is also an economic cost – a projected loss of up to 3.8% of the global annual GDP between 2016 and 2050.

Several key market failures have made tackling AMR hugely challenging. Investment in novel antimicrobials is commercially unattractive; the high R&D costs and low potential returns have led to a lack of interest, funding and research into new antimicrobials, with some larger pharmaceutical companies leaving the market entirely.1-3

Why has the market failed to face up to AMR?

  • It is very difficult to predict how resistance will evolve over time. This makes it hard for a pharmaceutical company to know how many people will need its new antimicrobial in the future and, therefore, its potential for financial reward – undermining the company’s economic case for investing
  • Any new products that could potentially be valuable as part of ‘cycling’ stewardship schemes tend not to be used due to their high cost compared with existing products, many of which are low-cost generics1, 2
  • New antimicrobials are likely to be ‘held back’ until strictly necessary to reduce emergence of AMR (stewardship), which reduces the number of patients receiving treatment and thus the pharmaceutical company’s financial reward. Further, by the time a new antimicrobial is more widely used due to emerging resistance to existing products the patent life will have been reduced, limiting the time available for the pharmaceutical company to reap rewards

In recognition of the global threat of AMR and the market failures associated with tackling it, a number of international initiatives are ongoing, including a global action plan from the WHO, a call to action from the UN and the creation of a transatlantic taskforce on AMR (TATFAR).4-6

A new approach to evaluating and funding antimicrobials

In January 2019, the UK government set out a 20-year vision for AMR and pledged to drive innovation to support the development and sustainable supply of new antimicrobials, as well as a 5-year national action plan. One of the key commitments was to ‘develop and test new models for national purchasing arrangements that de-link the price paid for antimicrobials from the volumes sold, using a NICE led healthcare technology assessment to support robust stewardship’.7, 8

To support the government’s AMR ambition, NHS England has set up a ‘subscription-style’ payment model for antimicrobials, in collaboration with NICE and the Department of Health and Social Care (DHSC).9 As the two treatments face evaluation in upcoming NICE appraisals (Shionogi’s cefiderocol and Pfizer’s ceftazidime with avibactam), we consider some of the key issues to look out for.

How will the evaluation of antimicrobials differ from that for other drugs?

A broader definition of value

If there’s one thing that is certain, it is that the concept of value will be broadened.

When considering the arsenal of antimicrobials available to a health system, there is a benefit in having additional products available (diversity value) and in replacing broad-spectrum antimicrobials with narrow-spectrum antimicrobials, where appropriate (spectrum value). Both of these reduce the reliance on and use of existing products in order to slow the emergence of resistance. Through fighting infection, an antimicrobial reduces transmission to others (transmission value) and can enable other treatments and procedures to take place, such as chemotherapy and surgery (enablement value). In addition, it is vital to prevent the unlikely (but highly damaging) scenario where widespread resistance to all other products renders an antimicrobial as the only available treatment option (insurance value).

It will be interesting to see how these other elements of value are included in the evaluations.

The use of a stewardship strategy

It is widely understood that an antimicrobial stewardship strategy (essentially a strategy to promote and monitor judicious use of antimicrobials to preserve their future effectiveness) will be needed for any new antimicrobials so as to slow the emergence of resistance to them and prolong their usefulness.1  This is very different to what happens in other therapeutic areas, where a breakthrough product will most likely enter the market as the new ‘first-choice’ treatment for a disease, capturing substantial market share and maximizing sales during the early years of the product’s life when it is still on patent and its developer is shielded from competition.1

When assessing a new product, the evaluation may need to incorporate how the drug is likely to be used in practice – i.e. incorporating the ‘stewardship strategy’ – not just the value compared with existing products. We will have to see from the appraisal the approach NICE ends up taking on dealing with this issue.

There are also a number of specific technical and methodological issues that will be of particular interest to those responsible for conducting and reviewing health economic evaluations. These include: the use of structured elicitation, economic modelling approaches and the use of in-vitro data; these are detailed in boxes 1, 2 and 3 respectively.

How will manufacturers be paid for new antimicrobials?

An insurance-based, de-linked ‘Netflix-style’ model to reward innovation

NHS England’s purchasing framework is likely to involve a one-off or series of ‘insurance’ payments made to reward innovation, with the aim of ‘de-linking’ revenue from the volume of antimicrobials sold. This will hopefully avoid the contradiction in wanting manufacturers to produce a new drug that will be used as little as possible. Therefore, instead of the volume of use, this model would potentially be based on a payment that reflects the expected value of a new product to the NHS over a specified period. There will also be the possible addition of ‘cap and collar’ arrangements to meet an agreed maximum and minimum payment, respectively, to share risk and unexpected variations in use.

The precise specification of the UK insurance-based delinked model is yet to be determined, but it is likely to be specific to each antimicrobial’s profile of risk and its expected pattern of resistance over time.

A payment that considers the total expected population net health benefit

The output of the value assessment framework for new antimicrobials is an estimate of the total expected population net health benefit for each of the alternative strategies regarding usage of new and existing antimicrobials, considering the projections of AMR over the modelled time horizon. The population health benefit calculations will be used to inform fixed payment levels for access, to incentivize the successful development of antimicrobials.

How might the new evaluation and payment framework affect HTA in other settings?

As a manufacturer it will be important to start to think about how the AMR evaluation and purchasing frameworks will affect appraisal, market access and evidence generation plans for products – not just for antimicrobial drugs, but potentially in other settings (such as vaccines), as well as other commercially unattractive but high-priority government health concerns. It will be interesting to see the use and acceptance of in vitro studies in AMR, and how this use and acceptance might translate to other areas where the ability to use data from randomized controlled trials is restricted.

Similarly, the acceptance and use of subscription models will be watched with interest. Subscription models provide certainty to both manufacturers and payers – a fixed payment mitigates risks, but it remains to be seen if this will be an incentive to invest for manufacturers. Subscription models are not a new concept in medicine pricing and reimbursement; they have been floated as a payment mechanism for gene

therapies and have been tried and tested in other areas, notably hepatitis C. However, a significant difference is that previously, such mechanisms have been proposed and adopted as a way to address issues of affordability and uncertainty in budget impact and long-term outcomes, rather than ‘market failure’ as is the case here.10

As a payer there will a focus on measuring how effective these strategies are in both incentivizing investments, reducing burden, and facilitating patient access; if successful, other countries may wish to leverage lessons or build upon their ideas from the UK experience.

For patients and the public at large, these innovations could potentially lead to not just a UK, but a truly global, concerted, effort to develop new products and avoid a potential AMR crisis.

Once the appraisals of the new antimicrobial products have concluded, it will be interesting to evaluate the decision-making process to see whether the framework is set up for success long-term.

For more information, please contact us.

develop and test new models for national purchasing arrangements that de-link the price paid for antimicrobials from the volumes sold, using a NICE led healthcare technology assessment to support robust stewardship.7, 8

1: Evidence collection and the use of structured expert elicitation

  • Evidence and data needed to inform any analysis are likely to be complex and wide ranging for antimicrobials
  • Traditional approaches may not be suitable, and common parameters may not be matched. A more pragmatic and adaptable approach to evidence generation is likely to be needed, including:
    • loosening of the rigid requirements for literature reviews
    • formal expert elicitation exercises to quantify expert opinion more robustly (for parameters like transmission rates and fitness costs)

2: Economic modelling methods

  • More complex health economic modelling methods (such as dynamic transmission modelling) will potentially need to be used, to capture and quantify the costs and benefits associated with products beyond the cohort of infected patients
  • Evaluations are likely to need high levels of stratification to capture the value across different settings as patterns of resistance are likely to be highly localized
  • The high uncertainty in evaluating the benefits quantitatively may mean that outcome estimates may need to be expressed as intervals rather than as central estimates (i.e. with incremental cost-effectiveness ratio [ICER] intervals rather than point estimates)

3: A reliance on in vitro data to interpret clinical results

  • It will be difficult to use clinical trial data for economic evaluation in the field of AMR:
    • Due to the life-threatening nature of acute systemic bacterial infections, the efficacy of antimicrobials cannot be compared against placebo
    • It is unethical to enrol patients with bacterial infections that are known or suspected to be resistant to the comparator drug in a trial
  • If only patients with susceptible infections can be recruited for clinical trials, this would not generate reliable estimates of the likely clinical impact of a new antimicrobial
  • In vitro data are, therefore, likely to be of critical importance in the appraisal


  1. O’Neill J. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. 2016. Available at: Accessed: 6 August 2021.
  2. National Institute for Health and Care Excellence (NICE), National Health Service (NHS) and Department of Health & Social Care (DHSC). Antimicrobial Resistance: Developing and testing innovative models for the evaluation and purchase of antimicrobials. 2021. Available at: Accessed: 6 August 2021.
  3. Batista PHD, Byrski D, Lamping M and Romandini R. IP-Based Incentives Against Antimicrobial Crisis: A European Perspective. IIC – International Review of Intellectual Property and Competition Law. 2019; 50(1):30-76.nt.
  4. World Health Organization (WHO). Global action plan on antimicrobial resistance. 2016. Available at: Accessed: 6 August 2021.
  5. United Nations (UN). Call to action on antimicrobial resistance. 2021. Available at: Accessed: 6 August 2021.
  6. Centers for Disease Control and Prevention (CDC). Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). Available at: Accessed: 23 August 2021.
  7. HM Government. Contained and controlled: The UK’s 20-year vision for antimicrobial resistance. 2019. Available at: Accessed: 6 August 2021.
  8. HM Government. Tackling antimicrobial resistance 2019–2024: The UK’s five-year national action plan. 2019. Available at: Accessed: 6 August 2021.
  9. Perkins M and Glover D. How the ‘NHS model’ to tackle antimicrobial resistance (AMR) can set a global standard. 2020. Available at: Accessed: 13 August 2020.
  10. Irwin J. World’s first ‘subscription-style’ antibiotic payment model passes landmark. 2021. Available at: Accessed: 9 August 2021.