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Introduction

Bacterial infections are a common source of morbidity and mortality around the world. The ability to treat these diseases with antimicrobial drugs has been one of the greatest public health triumphs of the last century. Yet because antimicrobial resistance (AMR) is a natural adaptive response among bacteria, antimicrobial drug innovation remains necessary to ensure that effective new drugs exist for future patients. In one recent report, the World Health Organization (WHO) concluded that the antibiotic clinical pipeline is “insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.”¹ If properly used, new antibiotics treating resistant infections will naturally have small patient populations, at least at first. This is often one reason claimed by many for-profit pharmaceutical companies for exiting the antimicrobial innovation market. However, many such companies remain invested in targeted high-cost therapies for cancer and rare diseases.^2,3 In recent years, legislators around the world have sought new policy initiatives that promote innovation, access, conservation, and the prevention of infections to more effectively address the increasing threat of antimicrobial resistance and maintain a vibrant antimicrobial drug pipeline.⁵

The proposed bill would have the US Department of Health and Human Services grant up to $6 billion for contracts with manufacturers of new antibiotics lasting 5-10 years and ranging in value from $750 million to $3 billion.

The PASTEUR Act

One of the latest proposed pieces of legislation in the US addressing the challenge of AMR is the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act.⁵ Reintroduced to the Senate for the third time in 2023, the PASTEUR Act provides a large financial prize for antibiotic drug development, promotes the appropriate use of antibiotics, and seeks to safeguard drug availability in times of need. The legislation establishes its reward by creating a pool of funding for new antibiotic drugs that meet specific criteria through which to enter into “subscription contracts.” The proposed bill would have the US Department of Health and Human Services grant up to $6 billion for contracts with manufacturers of new antibiotics lasting 5-10 years and ranging in value from $750 million to $3 billion. Contracts may also be eligible for extension and an additional $1 billion.⁵ In exchange, the manufacturer agrees to ensure commercial availability of the drug, track resistance data, communicate with professionals about the appropriate use of the drug, register the drug overseas where it is needed, and complete post-approval studies requested by the Food and Drug Administration (FDA). The legislation thus provides a large pool of funding intended to reward successful global antimicrobial research and development, also known as a “pull” incentive.⁶ The goal is to entice manufacturers to pursue products in (or even re-enter) the space.

Though the bill’s goals are praiseworthy, improvements are still needed to achieve optimal results in promoting and protecting public health. For example, the bill’s current language does not sufficiently ensure that antibiotics qualifying for the subscription contract would require evidence of improving the clinical outcomes of patients with resistant infections. This is a particular concern because, in recent years, the FDA has approved many new antibiotics based on non-inferiority studies and using unvalidated surrogate measures of treatment effects like negative cultures rather than direct clinical patient endpoints (effects on how patients feel, function, or survive).⁷ Some of these drugs may have in vitro activity against resistant pathogens, but their clinical efficacy in reducing patient mortality from AMR was never demonstrated in a clinical trial. Thus, PASTEUR could guide subscription contracts towards new drugs with only potential benefits for resistant infections that have not yet clearly demonstrated real clinical benefits. This problem is not unique to PASTEUR—defining qualification standards for pull incentives has long proven a challenging task.⁸ But as public health stakeholders and the PASTEUR Act’s cosponsors agree, resources supporting antimicrobial innovation need to be directed towards better drugs, not just more drugs.⁹

While it is possible that an antibiotic with a novel mechanism of action successfully addresses AMR, the best way to demonstrate that would be in a clinical trial in which the new drug shows superiority over alternatives in treating antimicrobial-resistant infections on meaningful clinical direct patient outcomes.

In the PASTEUR Act, subscription contract values would depend on a number of considerations, such as whether the antibiotic treats infections for which new drug development is needed, whether the antibiotic has evidence that it addresses unmet medical needs for the treatment of a serious or life-threatening infection by improving patient outcomes, and whether the antibiotic is novel.⁵ While it is possible that an antibiotic with a novel mechanism of action successfully addresses AMR, the best way to demonstrate that would be in a clinical trial in which the new drug shows superiority over alternatives in treating antimicrobial-resistant infections on meaningful clinical direct patient outcomes. However, the FDA does not mandate such trials for regulatory approval, and the PASTEUR Act does not mandate such evidence to qualify for subscription contracts. If requiring proof of superiority is not possible, then an antimicrobial should demonstrate efficacy against WHO priority pathogens or an unmet need based on clinical study results. The addition of such a requirement could help PASTEUR more effectively address AMR and achieve its purpose.

Another important component of combatting AMR is antimicrobial stewardship—making sure that antibiotics are not overused, particularly new ones, since that can generate AMR.¹⁰ The PASTEUR Act includes support for a range of stewardship provisions. It provides for the creation of a grant program to support healthcare facilities in the judicious use of antimicrobials and participation in antimicrobial usage and infection monitoring and reporting programs. Manufacturers must track and report resistance data, submit use assessments, develop and implement education and communication strategies for appropriate use, and abide by manufacturing and environmental best practices.⁵ It would also be useful to track patient outcomes adjusted for co-morbidities to optimally understand the effects of new drugs and stewardship programs.

Other Promising Models and Proposals

As the US Congress considers the PASTEUR Act, other national and regional jurisdictions are currently having similar discussions regarding other types of incentives. The UK, for example, recently announced a major expansion to its subscription model for antimicrobials. The UK model began with a pilot program in England in 2019.¹¹ After a competitive process, it awarded subscription contracts to two companies. As a “test run”, one contract was awarded to Pfizer’s existing product ceftazidime/avibactam, and one contract to Shionogi’s new product cefiderocol.¹¹ The contracts were to last for three years, for up to £10 million per year and could be extended for up to ten years.¹¹ After its pilot, the model is now being expanded to the entirety of the UK, with more antibiotics and maximum contract values doubled to £20 million per year.¹²

The UK model expansion is further notable for introducing a new scoring system for determining contract values. The pilot program determined contract values by applying quantitative health economic analyses product by product.¹² The new system uses a multi-criteria decision analysis tool focused on values of relative effectiveness and unmet medical need, pharmacological benefit, and health system benefit.¹² Points are assigned based on various considerations in these value categories.¹² These include, for example, whether an antibacterial shows activity against WHO priority pathogens, absence of cross-resistance, and any adverse events.¹² The UK’s scoring system is interesting but remains unvalidated; multi-criteria decision analysis often includes numerous non-data-driven factors as inputs that make it hard to replicate. Adding a quantitative component to multi-criteria decision analysis is particularly challenging given its inherently qualitative nature.¹³

The best new programs for combatting AMR around the world are those that are implemented in ways that ensure maximum impact on patient outcomes.

Other countries are similarly developing their programs. Japan is developing a revenue guarantee program, and Canada pledged to “secure new antimicrobials for Canadians” and is examining options for a pull incentive.¹⁴ In the EU, the European Commission is supporting member states to set up the new One Health AMR Candidate Partnership, expected in 2025, and is considering pull incentives, such as much debated transferable exclusivity vouchers.¹⁴ Sweden recently concluded a pilot program for its subscription model, and Germany has been engaging in newly revised pricing and reimbursement laws through its DART (Deutsch Antibiotic Resistance) strategy.¹⁴ France has continued to renegotiate prices for medicines at risk of shortage, while Italy has committed funds to implement recommendations made in its National Action Plan.¹⁴ Many countries also continue to invest in public-private partnerships to support work in this area, like CARB-X, that provides reactive funding for pre-clinical to phase 1 research and development and the AMR Action Fund that invests in  companies that are developing urgently needed therapeutics.¹⁴           

Conclusion

Greater government support is always a welcome development for new interventions that improve patient outcomes. In the US, the PASTEUR Act model of a subscription contract could benefit from further refining to ensure that these contracts are directed towards the most deserving new products. The best new programs for combatting AMR around the world are those that are implemented in ways that ensure maximum impact on patient outcomes.

Funding: The work was supported by the Collaborative Research Program for Biomedical Innovation Law (the CeBIL program), which is a scientifically independent collaborative research program supported by a Novo Nordisk Foundation Grant (Grant number NNF17SA0027784). Dr. Kesselheim’s work is also supported by Arnold Ventures. The funders had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.

References

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