Regulatory Rapporteur
September 2024 | Volume 21 | No.8
Abstract
It is estimated that there were 1.27 million deaths globally directly attributed to antibacterial resistance in 2019. The WHO have declared that antimicrobial resistance (AMR) is one of the biggest threats to global health.[1] Research has highlighted that there is a strong link between antibiotics consumption and the development of bacterial resistance.[2] Beyond this, populations affected by antimicrobial resistance can develop life-threatening fungial, viral and protozoa infections.
There is a global focus to address this critical issue, both through preventative measures to mitigate the risk of development of resistant strains and by improving the availability and accessibility of new antimicrobial agents. Different strategies to combat antimicrobial resistance include new technologies such as phage therapy, bacterial vaccines and microbiome science. Regulatory challenges arise when development falls beyond the scope of current guidelines, such as the European Medicines Agency (EMA) guidelines for the development of new antibiotics adopted in 2022.[3] This article looks at current and future prospects for the regulation of antimicrobial agents and how policy and regulation aim to boost research, development and innovation in antimicrobial resistance (AMR) in human and animal health.
Introduction
The World Health Organization (WHO) has described antimicrobial resistance (AMR) as “one of the top global public health and development threats”.[1] In 2022, the EU declared it to be one of the top three priority health threats. In 2019 alone, AMR is estimated to have contributed to almost five million deaths, with 1.3 million directly attributed to it. Without a global response to AMR, it is projected that by 2050, 10 million people will die annually due to drug-resistant infections.[3]
Several factors accelerate resistance, including the misuse of antimicrobials in humans, animals and crops, poor infection control practices, global trade and travel, and climate change. Despite widespread concern and recognition among international bodies regarding the seriousness of AMR, it remains a global health challenge. Poor stewardship continues to drive the problem: a reported one in ten EU citizens are taking antibiotics without a prescription and results from a 2022 Eurobarometer showed that only half of those questioned were aware that antibiotics are ineffective against viruses.[4] A comprehensive and coordinated global response is needed to address the multifaceted causes of AMR and curb its spread.
Health policy
The need to work together across nations and sectors to tackle AMR as a health priority is slowly being recognised by world leaders. In five years, the G7 leaders have moved from identifying gaps in efforts to mitigate the threat to developing incentives. The G20 has included AMR research and development (R&D) within its goals. The UN General Assembly High-level Meetings of the 79th Session this month (September 2024) aim to define targets for UN member states, with proposed collaborative action. These commitments for action aim to incentivise innovation, enhance data sharing and strengthen surveillance.
Ambitious global targets by 2030 have been recommended by the Global Leaders Group (GLG) on AMR and include:
- a 10 per cent reduction in global deaths attributed to bacterial AMR
- a 20 per cent reduction in human antibiotic consumption
- at least a 30 per cent reduction in antimicrobials use in agrifood systems
- the elimination of the use of antimicrobials for humans in animals for non-veterinary purposes and agrifood systems for phytosanitary purposes.
National strategies to meet these recommended targets involve cross-sector collaboration in human health, animal health and environmental ecosystems, especially harmonised surveillance systems which can create an integrated global surveillance across sectors.[5] These recommendations from the GLG build on initiatives such as the One Health framework, which is an integrated approach balancing the health of humans, animals and ecosystems aiming to prevent, detect and respond to global public health threats including antimicrobial resistance.
The global ministerial meetings like the UN General Assembly High-level Meeting are raising the profile of AMR among policymakers and highlight the urgent need to address the barriers to antimicrobial R&D. The conventional model for pharmaceutical R&D does not incentivise antibiotic development and there is an need to kickstart the R&D pipeline; one way of doing this is to use push and pull incentives (see Figure 1).
Push incentives aim to support R&D by lowering the cost of development. The objective is for funding organisations to work with private pharmaceutical companies to lower the risks of development in exchange for rights to low- and middle-income countries (LMICs); LMICs are disproportionally affected by AMR.[6] Push incentives implemented include the early stage financing for R&D targeting the Bacterial Priority Pathogen List, such as the Combating Antibiotic-Resistant Bacteria Fund (CARB-X), the Global Antibiotic Research and Development Partnership (GARDP) and the Antimicrobial Resistance Action Fund (AMR Action fund). However, these incentives have had limited success.[7] Drug reimbursement volume-driven models and the drive for antibiotic stewardship have meant low volume production, which makes for unsustainable returns. Simulation of these types of push funding incentives demonstrate that they can be complemented by pull incentives.[8]
Pull incentives aim to improve the commercial viability for development by reducing the risk of low revenues, such as new costing models. These strategies are needed alongside enhanced funding to reward development. Policymakers need to consider new costing models, including market entry rewards, delinking pricing from volumes sold, market exclusivity and options for expedited regulatory approval pathways. Some countries are putting together new pull incentives to encourage market entry and to protect the supply of off-patent antibiotics. For example, in July 2023, Germany enacted a law to combat supply shortages through revised pricing for reserve antibiotics allowing the company to set the sales price if first launched before 2031, rather than be influenced by reference pricing.[9] Another recent development in the UK includes a subscription model pricing for new antimicrobial agents, where the price is not linked to the sales volume.[10] It is too early to say how effective these measures will be to both improve supply of existing reserve antibiotics and encourage future novel antimicrobials.
Figure 1: Push and pull incentives to encourage development of antimicrobials
The antimicrobial pipeline
The development of new antimicrobial agents is crucial in tackling AMR, specifically agents targeting the WHO priority pathogens. New classes of traditional direct-acting small molecule antimicrobials and even non-traditional agents are considered a great solution as they can target microbes in novel ways, avoiding resistance mechanisms found with older antibiotics.[11] A summary of non-traditional agents is provided in Table 1 below.
Table 1: Summary of non-traditional agents
| Category | Function explained |
|---|---|
|
Antibodies |
These can be monoclonal antibodies designed to target virulence factors, or toxin on the pathogen, and inactivate or neutralise the pathogen. Seven are in the clinical pipeline. |
|
Antivirulence |
These interfere with bacterial virulence factors but are neither bacteriostatic nor bactericidal. Three are in the clinical pipeline. |
|
Immunomodulating agents |
These change the body’s immune response. Pathogen-specific immunomodulators include antibody re-agents and vaccines. Non-specific examples include cytokines, antimicrobial peptides, certain antimicrobial drugs and microbes such as probiotics. Two are in the clinical pipeline. |
|
Microbiome-modulating agents |
These modify the microbiome to eliminate or prevent carriage of pathogenic bacteria. They includes live biotherapeutics. Nine are in the clinical pipeline. |
|
Bacteriophages |
These are viruses that can cause direct lysis of target bacteria.13 are in the clinical pipeline. |
|
Miscellaneous agents |
These do not fit any of the above categories. Four are in the clinical pipeline. |
The development of new antimicrobial agents presents regulatory challenges, due to the limited amount of published guidance. Between 2017 and 2023, there have been 16 new antibacterials approved by the Food and Drug Administration (FDA), the EMA and other regulatory authorities to treat priority pathogens.[12] Only two were new chemical classes of traditional agents and three were non-traditional agents; all were live biotherapeutics. Oral formulations are preferred to facilitate outpatient treatments, but there has been a reduced volume in the pipeline during this period in favour of intravenous formulations. Small biotech companies are leading antibacterial development, but often receive less funding than other pharmaceutical endeavours.
International collaboration between regulatory agencies
Clinical studies for antimicrobial agents are expensive and challenging: large numbers of patients are required, especially when targeting resistant pathogens, and global studies need to balance the requirements of different territories. In addition, diagnostic confidence becomes even more important in confirmatory clinical trials, but appropriate testing methods are not always available.
There is recognition that these requirements present barriers and competent authorities have released additional guidelines to support specific aspects of development. The EMA has recently released a guideline to support the clinical evaluation of vaccines, addressing common issues that have been noted during scientific advice procedures.[13] In addition, their guideline on the use of pharmacokinetics (PK) and pharmacodynamics (PD) in antimicrobial agent development begins to address the common challenges with the PK and minimum inhibitory concentration (MIC) variability in patient subgroups due to resistant strains.[14] The FDA has adopted indication-specific guidance to support the development of drugs which treat diabetic foot infections, tuberculosis and infections with Clostridioides difficile.[15],[16],[17]
The EMA, the FDA and the Pharmaceutical and Medical Devices Agency (PMDA) initiated a series of tripartite talks focused on AMR in 2016.[18] Since then, guidelines have been released in an attempt to streamline aspects of their respective requirements and stimulate the global development of new treatments to combat AMR. Examples of these include the EMA’s guideline on the evaluation of human medicines for the treatment of bacterial infections and the FDA’s Q&A on antibacterial therapies for patients with an unmet medical need for the treatment of serious bacterial diseases.[19],[20] Further international regulatory collaboration comes from groups such as the International Coalition of Medicines Regulatory Authorities (ICMRA), which highlights successful regulatory and non-regulatory interventions used in different countries.[21]
Other international collaborative efforts aim to improve stewardship. Regionally, the EMA has its own guidelines on the prudent use of antimicrobials for human and animal health but, as a member of the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), the EMA exchanges information with its support partners, for example, the WHO, in developing standards for surveillance and modelling transmission of antimicrobial-resistant pathogens and diagnostic stewardship.[22],[23],[24]
Completion of large clinical studies for antimicrobial products is slow and so an increase in licensing speed is important for these much-needed products. The FDA’s Qualified Infectious Disease Product (QIDP) designation allows fast-track designation and a five-year exclusivity extension for certain antibacterial and antifungal products. While the EMA does not have a specific fast-track procedure for antimicrobials beyond a health emergency, the scope of the agency’s Opening Procedures at EMA to Non-EU authorities (OPEN) framework was widened in 2023 to include medicines intended to help combat AMR, allowing closer collaboration with those international partner agencies which have the intent to share expertise and speed patient access.
A holistic approach to AMR regulation in the EU
Consistent with the European Commission’s ‘One Health’ action plan against AMR, there is a heavy emphasis on measures to tackle AMR in the proposed update to the European pharmaceutical legislation.[5] As well as an overall goal to simplify the regulatory authorisation system and make it more competitive, the proposed regulation is holistic, with a combination of incentives and additional responsibilities for developers:[25],[26]
- Transferrable data exclusivity vouchers (TEVs) are planned to promote the development of priority antimicrobials. An additional year of regulatory data protection (RDP) will be granted to the developer of a ‘priority antimicrobial’, which the developer will be able to use, either for any product in their own product portfolio or to sell to another marketing authorisation holder. Strict conditions accompany the granting, use and sale of the vouchers. To qualify as a ‘priority antimicrobial’, nonclinical and clinical data must show a significant clinical benefit with respect to AMR (taking into account the WHO priority pathogens list) and the product must also have one of the following characteristics:
- represent a new class of antimicrobials
- have a distinctly different mechanism of action from any authorised antimicrobial
- contain a new active substance that addresses a multi-drug-resistant organism and serious or life-threatening infection.
- Developers must demonstrate the capacity to supply the antimicrobial in sufficient quantities to meet the expected needs of the EU.
- Developers must provide information, to be made public, on all direct financial support received for research related to the development of the priority antimicrobial.
- A voucher may only be used once, within the first four years of regulatory data protection (RDP) and only if the marketing authorisation has not been withdrawn. If sold to another marketing authorisation holder, it may not be transferred further. The transfer value must be declared to the EMA and will be made public.
- A maximum of ten vouchers may be issued within a 15-year period, after which time the scheme as a whole will be reviewed.
- Measures for prudent use mean that antimicrobials will be subject to medical prescription throughout the EU, with member states free to add further conditions such as special or restricted prescription, the imposition of limits to the amounts prescribed and/or the mandatory use of diagnostic tests prior to prescription. Pack sizes will have to correspond to the usual posology and duration of treatment and information on AMR and the appropriate use and disposal of antimicrobials will have to be added to the patient leaflet.
- Stewardship plans for AMR will be introduced, requiring information on risk mitigation measures to limit AMR development, and monitoring and reporting to the competent authority information about resistance to the medicinal product.
- Environmental risk assessments (ERAs) for antimicrobials will need to address the risk of AMR selection in the environment, due to the entire manufacturing, use and disposal lifecycle of such products.
The current EU legislation does not provide sufficient incentives to manage the threat of antimicrobial resistance. A European Commission study published in 2022 reported that only 25.8 per cent of the 93 developers of AMR medical products surveyed intended to submit for initial marketing authorisation to the EMA, compared with 66.7 per cent who intended to submit to the FDA.[27] Individual national pricing and access requirements in the EU and a slower, less straightforward regulatory approval process were among the reasons cited. However, there is a focus in the proposed legislation on the development of products for unmet medical need. Together with shorter review timelines and an emphasis on support for SMEs and not-for-profit enterprises, measures to make the EU a more competitive environment and encourage innovation in the fight against AMR are evidently at the forefront of the EMA’s current and future priorities.
The proposed changes to pharmaceutical legislation are a long way from implementation; at the time of writing, the proposed legislation awaits the European Council’s first reading position and, in the interim, developers need to be aware of the mechanisms for early engagement with regulators, tailored regulatory support for SMEs and incentives for the development of products for unmet medical need. As of June 2024, only six products out of 78 in the PRIME scheme were in the anti-infective therapy area, of which four were being developed by SMEs and none were treatments targeting organisms on the WHO list of priority bacterial pathogens.[7]
Conclusion
There are signs of the direct impact of interventions to stimulate innovation in this field. The recent winners of the UK’s Longitude Prize were originally developing their technology to answer basic science questions. It was awareness of the AMR prize that prompted the developers to re-think their direction and apply their technology to the field of rapid antibody susceptibility detection.[28]
AMR is rising higher on the public agenda. In June 2024, the leaders of the G7 group of nations reiterated their commitment to address AMR, with a focus on the needs of LMICs and a broad approach involving the implementation of push and pull incentives, support for partnerships between public and private bodies and the exploration of innovative instruments to accelerate the R&D of new antimicrobials, their alternatives and microbial diagnostics.[29] The UN GLG is seeking agreement of global and national targets to combat resistance at the UN General Assembly High-level Meeting on AMR in September; in its words, the commitment to tackling AMR must be “personal, local, national and global”.[5]
In the EU, progress is being made towards targets relating to improved stewardship and prudent use. The EC reported that antibiotic use reached a record low in 2021, with only 23 per cent of Europeans taking oral antibiotics that year, the lowest number since 2009.[4] As new antimicrobials enter the market, manufacturers, prescribers and patients will be better informed and supported to prevent the cure for infectious diseases becoming the cause once more. Behind all of this, however, sits the absolute need for the development of new antimicrobial agents. Financial incentives will drive this, but innovation and agile drug regulation will be at the heart of any efforts to address this evolving health crisis.
References
[1] World Health Organization (2023) ‘Antimicrobial resistance’.
[2] European Centre for Disease Prevention and Control (ECDC), European Food Safety Authority (EFSA), European Medicines Agency (EMA) (2021) ‘Third joint inter‐agency report on integrated analysis of consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food‐producing animals in the EU/EEA’, EFSA Journal, 19(6):6712 pp. 164.
[3] Jonas O et al. (2017) ‘Drug-Resistant Infections: A Threat to Our Economic Future (Volume 2)’. World Bank Group.
[4] The European Commission (2022) ‘Antimicrobial Resistance’ Special Eurobarometer 522.
[5] Global Leaders Group on Antimicrobial Resistance (2024) ‘GLG report: Towards specific commitments and action in the response to antimicrobial resistance’.
[6] The Global Antimicrobial Resistance Research & Development Hub (2023) ‘Incentivising the development of new antibacterial treatments Progress Report’.
[7] World Health Organization (2024) ‘WHO Bacterial Priority Pathogens List, 2024: bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance’.
[8] European Commission, European Health and Digital Executive Agency (2023) ‘Study on bringing AMR medical countermeasures to the market’.
[9] Federal Ministry of Health (2023) ‘Pharmaceutical Shortage Control and Supply Improvement Act’ or ‘Arzneimittel-Lieferengpassbekämpfungs- und Versorgungsverbesserungsgesetz (ALBVVG)’.
[10] NHS England (May 2024) ‘Antimicrobial products subscription model Guidance on commercial arrangements’.
[11] Coates AR, Halls G, Hu Y (2011) ‘Novel classes of antibiotics or more of the same?’ British Journal of Pharmacoly 163:1 pp.184–194. doi: 10.1111/j.1476-5381.2011.01250.x
[12] World Health Organization (2023) ‘Antibacterial agents in clinical and preclinical development: an overview and analysis’.
[13] European Medicines Agency (2023) ‘Guideline on clinical evaluation of vaccines’.
[14] European Medicines Agency (2016) ‘Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antimicrobial medicinal products’.
[15] US Food and Drug Administration (2024) ‘Diabetic Foot Infections: Developing Drugs for Treatment Guidance for Industry’.
[16] US Food and Drug Administration (2024) ‘Pulmonary Tuberculosis: Developing Drugs for Treatment Guidance for Industry’.
[17] US Food and Drug Administration (2024) ‘Clostridioides difficile Infection: Developing Drugs for Treatment, Reduction of Recurrence, and Prevention Guidance for Industry’.
[18] European Medicines Agency, Japanese Pharmaceuticals and Medical Devices Agency and US Food and Drug Administration (2016) ‘Tripartite meeting held between the EMA, FDA and PMDA at the EMA, London, on 1-2 September 2016 to discuss regulatory approaches for the evaluation of antibacterial agents Meeting Summary’.
[19] European Medicines Agency (2022) ‘Guideline on the evaluation of medicinal products indicated for treatment of bacterial infections’.
[20] US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (2022) ‘Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases – Questions and Answers (Revision 1): Guidance for Industry’.
[21] International Coalition of Medicines Regulatory Authorities (2022) ‘Antimicrobial Resistance Best Practices: Working Group Report and Case Studies’.
[22] European Commission (2017) ‘EU Guidelines for the prudent use of antimicrobials in human health’. Official Journal of the European Union.
[23] European Commission (2017) ‘Guidelines for the prudent use of antimicrobials in veterinary medicine’. Official Journal of the European Union.
[24] US Centers for Disease Control and Prevention as Secretariat for the Transatlantic Taskforce on Antimicrobial Resistance (2021) ‘TATFAR Progress Report’.
[25] European Commission (2023) ‘Proposal for a Regulation of the European Parliament and of the Council laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006’. Official Journal of the European Union.
[26] European Commission (2023) ‘Proposal for a Directive of the European Parliament and of the Council on the Union code relating to medicinal products for human use, and repealing Directive 2001/83/EC and Directive 2009/35/EC’. Official Journal of the European Union.
[27] European Commission (2023) ‘Council Recommendation on stepping up EU actions to combat antimicrobial resistance in a One Health approach’. Official Journal of the European Union.
[28] Price, K (2024) ‘Rapid UTI test wins £8m Longitude Prize on Antimicrobial Resistance’. The Pharmaceutical Journal. Vol 312, No 7986;312(7986). DOI:10.1211/PJ.2024.1.320238
[29] Leaders of the Group of Seven (2024) ‘G7 Apulia Leaders’ Communiqué’. The White House.
