The antibiotic subscription model: fostering innovation or repackaging old drugs?

Abstract

Antimicrobial resistance was associated with 4·95 million deaths worldwide in 2019.1Antimicrobial Resistance CollaboratorsGlobal burden of bacterial antimicrobial resistance in 2019: a systematic analysis.Lancet. 2022; 399: 629-655Summary Full Text Full Text PDF PubMed Scopus (2717) Google Scholar Although broadening access to affordable health care and sanitation are the most promising means to reduce morbidity and mortality associated with antimicrobial resistance, novel classes of antibiotics are urgently needed.2Kirchhelle C Atkinson P Broom A et al.Setting the standard: multidisciplinary hallmarks for structural, equitable and tracked antibiotic policy.BMJ Glob Health. 2020; 5e003091Crossref PubMed Scopus (35) Google Scholar However, low profitability means that most large pharmaceutical companies have withdrawn from antibiotic research and development. Meanwhile, reviews of compounds that remain in the research and development pipeline note that many such compounds are modifications of existing drug classes and do not constitute the molecular innovation needed to stay ahead of antimicrobial resistance.3WHOWHO antibacterial preclinical pipeline review.https://www.who.int/observatories/global-observatory-on-health-research-and-development/monitoring/who-antibacterial-preclinical-pipeline-reviewDate: June, 2022Date accessed: August 10, 2022Google Scholar Although some commentators have proposed non-market-based solutions, others emphasise the role of taxpayer-financed pull mechanisms to attract larger companies back into antibiotic research and development.4Rex J G7 Health Ministers: pull incentives to support stewardship, access, and innovation.https://amr.solutions/2022/05/21/g7-health-ministers-pull-incentives-to-support-stewardship-access-and-innovation/Date: May 21, 2022Date accessed: August 10, 2022Google Scholar, 5Glover RE Singer AC Roberts AP Kirchhelle C NIMble innovation—a networked model for public antibiotic trials.Lancet Microbe. 2021; 2: e637-e644Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar But will paying more for existing antibiotics promote molecular innovation, and if so, at what cost? Details from one of the largest pull-oriented policy experiments are emerging from the UK. In the UK, reports and policies on antimicrobial resistance have promoted a so-called subscription model to stimulate the antibiotic pipeline for the past decade.6UK Health Security AgencyEnglish surveillance programme for antimicrobial utilisation and resistance (ESPAUR): report 2020 to 2021.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1069632/espaur-report-2020-to-2021-16-Nov-FINAL-v2.pdfDate: November, 2021Date accessed: August 10, 2022Google Scholar, 7Glover RE Manton J Willcocks S Stabler RA Subscription model for antibiotic development.BMJ. 2019; 366l5364PubMed Google Scholar This model pays one flat-rate price to a company per year—a subscription—for an antibiotic used by a country's health system. The aim is two-fold: to avoid antibiotic overuse, and to guarantee a viable market for pharmaceutical companies even if their drugs are reserved as antibiotics of last resort. A subscription scheme is seen to be most useful to promote availability of high-value, low-use antibiotics, such as novel compounds that target multidrug resistant and priority ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This policy experiment was put into place in June, 2020, and the first two drugs to be financed by the new UK subscription model were announced in April, 2022: ceftazidime–avibactam and cefiderocol. Both drugs had commercially launched before the subscription model even existed. Originally developed by AstraZeneca, ceftazidime–avibactam was approved in the EU in 2016 and subsequently sold to Pfizer, who launched it in the UK in 2017. Cefiderocol, which was developed by Shionogi, was approved by the US Food and Drug Administration in November, 2019, and by the UK in April, 2020. Both drugs are part of the cephalosporin family, of which the first member, cephalosporin C, was discovered in 1953; molecular modification of this drug has been one of the backbones of 20th century antimicrobial development. In hospitals, ceftazidime-avibactam and cefiderocol are used intravenously to treat multidrug-resistant pathogens—usually carbapenem-resistant Gram-negative infections (although ceftazidime–avibactam is not effective against class B-type beta-lactamases). Proponents of this model highlight that paying a flat-rate, delinked to use, for current drugs will prove that the UK National Health Services is committed to derisking research and development and to supporting markets for future drugs. However, despite the UK's official aim to incentivise investment in antimicrobial research and development,8HM GovernmentTackling antimicrobial resistance 2019–2024: the UK's five-year national action plan.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/784894/UK_AMR_5_year_national_action_plan.pdfDate: Jan 24, 2019Date accessed: August 10, 2022Google Scholar, 9Department of Health and Department for EnvironmentFood & Rural AffairsUK five year antimicrobial resistance strategy: 2013 to 2018.https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/244058/20130902_UK_5_year_AMR_strategy.pdfDate: September, 2013Date accessed: August 10, 2022Google Scholar the current subscription funding does not convincingly reward innovative research into new chemical space, a field that many small and medium-sized enterprises are struggling to attract funding for. Instead, the annual price of £10 million per drug will support the antibiotic portfolios of two large pharmaceutical companies. Whether the volume of funding will be sufficient to lure companies of this size back into antibiotic investment is unclear.10Wouters OJ McKee M Luyten J Estimated research and development investment needed to bring a new medicine to market, 2009–2018.JAMA. 2020; 323: 844-853Crossref PubMed Scopus (511) Google Scholar Little exists in the fine-print to prevent companies from further derisking existing development pipelines by lobbying for reimbursement hikes or focusing on so-called me-too updates of old formulations.11uefranceamrhttps://uefranceamr.advancecom.live/video_replay/1Date: 2022Date accessed: June 28, 2022Google Scholar Rather than supporting a resilient, innovative, commercial antibiotic ecosystem, there seems to be a marked risk that the UK subscription model could fall prey to what is termed the folly of rewarding A when hoping for B.12Kerr S On the folly of rewarding A, while hoping for B.Acad Manag J. 1975; 18: 15Crossref Scopus (941) Google Scholar Because the subscription pilot is currently being rolled out only in England, domestic stewardship misalignment—in which the same two drugs remain available at lower costs in the National Health Services of Scotland, Wales, and Northern Ireland—is also a risk. According to current plans, the pilot will add two to three drugs every year. If the policy lasts 5 years, and all drugs are licensed or contracted for the maximum 10 years, then this scales up to a committed cost of £1 billion split across ten drugs. This is substantial public funding. Greater transparency regarding decision making and more public debate on the ultimate goals of this process are needed. Adding safeguards, such as ringfenced funding for truly new drugs and robust and regularly published trackers of the effects of subscriptions on antibiotic research and development for novel drug candidates, could help to mitigate some of the identified risks. Ultimately, providing financial incentives is not the same as creating a functioning investment ecosystem for urgently needed antibiotic innovation.8HM GovernmentTackling antimicrobial resistance 2019–2024: the UK's five-year national action plan.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/784894/UK_AMR_5_year_national_action_plan.pdfDate: Jan 24, 2019Date accessed: August 10, 2022Google Scholar, 13Perkins M Glover D How the ‘NHS model’ to tackle antimicrobial resistance (AMR) can set a global standard.https://www.england.nhs.uk/blog/how-the-nhs-model-to-tackle-antimicrobial-resistance-amr-can-set-a-global-standard/Date: Dec 18, 2020Date accessed: August 10, 2022Google Scholar REG reports consultancy fees from ICF and the Health Foundation, and support from the London School of Hygiene and Tropical Medicine Antimicrobial Resistance Centre. CK reports a Wellcome Trust University Award and support from the AHRC/IRC Digital Humanities Scheme. APR reports consultancy fees from Pfizer. ACS declares no competing interests.

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