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9 January 2023

20 Pages

Landscape of Push Funding in Antibiotic Research: Current Status and Way Forward

,
,
and
1
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
2
Principal Advisor India Strategy Development, Global Antibiotics Research and Development Partnership (GARDP), New Delhi 110016, India
*
Author to whom correspondence should be addressed.
Biology2023, 12(1), 101;https://doi.org/10.3390/biology12010101
This article belongs to the Section Infection Biology
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Simple Summary

Antibiotic resistance has become one of the biggest threats to global health. The occurrence of resistance is a natural phenomenon of bacterial evolution, but their inappropriate use in humans and the environment is hastening the process at a reckless speed. The speed of developing resistance is at par or, in fact, more than the speed of novel antibiotic development. Most of the big pharmaceutical companies have left antibiotic research due to the high risk of failure and poor return on investment. Antibiotic research is mostly carried out by academic institutes and small- and medium-sized enterprises. However, they lack sufficient funds to take the compounds from early-and-mid-stage to clinical trials and market. To make this possible, several government and non-government organizations worldwide have come forward to incentivize research through push funding mechanisms. The positive impact of these mechanisms, which started around a decade ago, is now visible, with fair improvements in research pipelines in the last five years. However, a large landscape of push incentives across the globe and staggered funding across different stages of development make the process complex. Efforts in various forms are now being implemented and proposed to streamline and smoothen push funding mechanisms for reinvigorating antibiotic research.

Abstract

The growing need for effective antibiotics is attributed to the intrinsic ability of bacteria to develop survival mechanisms. The speed at which pathogens develop resistance is at par or even faster than the discovery of newer agents. Due to the enormous cost of developing an antibiotic and poor return on investment, big pharmaceutical companies are stepping out of the antibiotic research field, and the world is now heading towards the silent pandemic of antibiotic resistance. Lack of investment in research has further led to the anemic antibiotic pipeline. To overcome these challenges, various organizations have come forward with push funding to financially assist antibiotic developers. Although push funding has somewhat reinvigorated the dwindled field of antibiotic development by bearing the financial risks of failure, the landscape is still large and staggered. Most of the funding is funneled towards the early stages; however, to carry the promising compounds forward, equal or more funding is required formid- and late-stage research. To some extent, the complexity associated with accessing the funding mechanisms has led to their underutilization. In the present review, we discuss several major push funding mechanisms, issues in their effective utilization, recent strategies adopted, and a way forward to streamline funding in antibiotic research.

1. Introduction

Antibiotic resistance is an evolutionary process in which bacteria develop novel survival mechanisms to evade antibiotics. In 2019, antibiotic resistance led to 1.27 million global deaths and is expected to kill approximately 10 million people annually by 2050 [1]. To mitigate the risk of drug-resistant infections, there is a continual need for an optimal and sustainable arsenal of effective antibiotics. Despite antibiotic resistance being the biggest threat to global health, the antibiotic research pipeline remains dry due to various scientific, economic, and regulatory challenges. To tackle these challenges, commendable efforts have been made by various government and non-government organizations in the form of grants and incentives in the last few years. Although, to reinvigorate the antibiotic pipeline, several preclinical and clinical research and development (R&D) programs in the form of push and pull incentives are in place; however, these efforts remain inadequate to address the global health needs. Funding in the form of push incentives to assist in the R&D of antibiotics and pull incentives to facilitate adequate market revenue for novel antibiotic developers are being proposed and implemented. In the present review, we discuss the current status of antibiotic R&D and the trends in push funding. We also discuss the issues with the current push funding mechanisms, recent strategies adopted, and a way forward to effectively utilize these incentives in a targeted and coordinated approach.

2. Current Status of Antibiotic Research and Development

The discussion over the early blooming era of antibiotics cannot be completed without mentioning Paul Ehrlich and Alexander Fleming. Ehrlich’s idea of magic bullets for syphilis in the form of salvarsan and Fleming’s serendipitous discovery of penicillin were prototypical, as they set a way forward for the discovery of many newer antibiotics. This led to the beginning of the golden era of antibiotics between the 1950s and the 1970s, when a large number of novel classes of antibiotics were discovered [2]. Simultaneously, resistance to these new antibiotics also started developing. However, the development of novel antibiotics after that period slowed down as the existing arsenal of antibiotics was effective, and by the early 1980s, the focus of pharmaceutical companies, based on public health needs, shifted towards more lucrative fields such as cancer and lifestyle diseases. The discovery void started to appear from early 2000 to 2010, when the majority of the big pharmaceuticals left the antibiotic market.
Since then, the scientific community in academia, small companies, and a few large pharmaceutical companies have been putting their efforts into the R&D of novel antibiotics. However, the investment is no longer sufficient to move the compounds from the early stages to approval. Further, after approval, the market potential is small due to low net present value (NPV, a value calculated based on ultimate costs and revenue) since, in most cases, the antibiotics are prescribed for a short duration with the best possible use of alternative generic antibiotics. Therefore, despite the high societal monetary benefits of new antibiotics (ranging from 486 million USD to 12 billion USD), the NPV of novel antibiotics remains low (negative) with an average of −50 million USD, in contrast to +1.15 billion USD for a new musculoskeletal drug [3]. Hence, many big pharmaceutical companies have left and are leaving the field of antibiotic research to invest in other lucrative areas. Recent examples are the exit of Novartis and Sanofi in 2018 from antibiotic R&D, and as of now, only six, including Pfizer, Roche, Otsuka, Merck, Shionogi, and GlaxoSmithKline have visible programs [4]. Until September 2021, there were 217 antibacterial products or programs in preclinical phases, with 84% of the research activities being carried out by micro-, small- and medium-sized developers and only 16% by large developers [5].
This disconnect between costly antibiotic development and low NPV stresses the need for financial incentives that can either decrease the cost of R&D or increase the market revenues. Therefore, several global organizations have put forward funding strategies to lower the cost of developing an antibiotic, directly or indirectly, by cutting down the risk of failures, as they cover both successful and unsuccessful projects. Of the major financial incentives in the field of antibiotic R&D, 71% are strictly push incentives funding the development of novel antibiotics [6]. For instance, the flourishing preclinical antibiotic pipeline in Europe (52%) and America (35%) can be attributed to the proactive approach of government and non-government philanthropic organizations in these continents [5]. Although these strategies showed a positive impact on NPV, they are insufficient as they do not cover the revenue generation after antibiotic approval and are inadequate alone to recuperate the dried antibiotic arena [6]. Therefore, equal attention to market sustainability through pull incentives is needed after antibiotic approval to mitigate the market failure challenges, as evidenced by the bankruptcy of Achaogen, an SME that developed plazomicin. Achaogen was unable to sustain the market of plazomicin despite being push funded from initial stages to clinical trials by Wellcome Trust, the National Institute of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA) [7,8]. In the following sections, we review the trends of push funding across various countries.

4. Challenges and the Way Forward

The efforts put globally in the form of push incentives to boost and furnish the antibiotic R&D pipeline are commendable and valuable. Governments and regulatory bodies of big economies started many initiatives, mostly in the last decade (Table 1). A huge amount of funding for antibiotic R&D have now been floated through various national and global initiatives.
Table 1. Summary of the major national and global push funding mechanisms adopted by the United States (US), European Union (EU), and United Kingdom (UK) to fund antibiotic research and development.
There is, nevertheless, an imbalance in the distribution of funds as a majority of the funding is funneled towards early-stage research, and various mechanisms of funding exist for academic and research institutes. Typically, if we look at the drug discovery pipeline, there are mainly three stages—early-stage carrying out basic science research including technology readiness levels (TRL) 1 and 2; mid-stage or preclinical research with TRL 3–5 (3: hit to lead identification, 4: lead optimization and 5: preclinical development) and late-stage or clinical stage with TRL 6–8 corresponding to Phase 1, Phase 2 and Phase 3 clinical trials [53]. In the field of antibiotic research, the early phase is primarily carried out by academic and research institutes. These are largely funded by public and philanthropic organizations, and they carry a high risk of failure. In the mid-stage, when there is a ray of hope, SMEs try to take the promising compounds forward from early-stage discovery to mid-stage and attempt to bring the compounds into clinical trials. Here the plethora of problems start as a lot of funds are required to run clinical trials, and even if the SMEs manage to accomplish this, they go into crisis at later stages in the market due to poor economic incentives. If we look at the antibacterial preclinical pipeline by WHO, as of September 2021, there were 217 compounds in preclinical stages, with more than 80% of the research carried out by SMEs in Europe and the US. More than 85% of compounds are in mid-stage development in TRL 4 & 5 and only 1% at the Investigational New Drug (IND) stage [5,75]. A lot of funding agencies are now streamlining their funds toward mid-stage development. However, on the contrary, SMEs receive only 20% of the public funding and eventually run out of business [76]. The reason for the difficulty in the outreach of funding to SMEs can be attributed to the complex and lengthy process of application and a lack of clarity on the ownership of intellectual property rights. This is the point of attrition when most of the potential compounds lose their future. Nevertheless, early-stage funding is important for replenishing the anemic pipeline as the success rate at this stage is low, but it is equally important to appropriately allocate funds to SMEs for transitioning towards clinical trial phases.
To address these issues of SMEs, the EU launched Biotech companies from Europe innovating in Anti-Microbial resistance research (BEAM) Alliance in 2015 to raise the voice of SMEs involved in innovative antibiotic research. Currently, the BEAM alliance is a group of 69 SMEs spanned across 16 European countries with 84 products in preclinical research, 26 in clinical development, and two in the market [77]. The BEAM Alliance maintains and promotes awareness about innovation driven by SMEs and sensitizes policy makers to incentivize these SMEs in simple and accessible ways to make R&D sustainable [78]. Currently, amongst non-dilutive funding, the Eureka Eurostars programme, European Innovation Council (EIC) Pathfinder, and EIC Accelerator Open is supporting SMEs, and amongst long-term engaging institutions and programs, BARDA, CARB-X, IDFF, GARDP, and AMR Action Fund are playing key roles. Despite these efforts, there are still issues in getting funding as SMEs are small, widely distributed, and resource-limited and usually have no public affairs departments for communication with funding agencies. Therefore, the funding mechanisms are required to be simplified, and the governing body should clearly identify the beneficiary and make funding readily available and accessible.
Another issue is the staggered funding mechanisms that can lead to a significant increase in the risk of effort duplication. There should be a global consortium of researchers as well as funding mechanisms to look after antibiotic R&D. As rightly mentioned by Ardal et al. (2018), there is a need for a Grant Incentives Framework to address the scientific and economic bottlenecks of antibiotic R&D [53]. All the existing funding mechanisms should be channeled in such a way that they could be effectively utilized to create a robust pipeline. These authors suggested categorization of funding into early-stage, mid-stage, and clinical-stage grants of 3–5 years duration. Early-stage grants could focus on basic science research, mainly in academic and research institutes, with a broad scope covering research on priority pathogens as well as in other areas of the antibiotic field. The mid-stage grants could be focused on priority pathogens and majorlycover SMEs to help them in taking their products forward toward later stages. The funding for clinical trials could be towards SMEs and other developers in a way that public health needs are appropriately targeted, and the large investment risks in clinical trials would be reduced. They also proposed ‘Priority grants’ that would strictly focus on WHO and CDC priority pathogens responsible for emerging or immediate threats. These grants are aimed toward long-term funding along the whole drug discovery pipeline, starting from TRL1 to TRL8. In this way, the present push incentives may focus antibiotic R&D toward unmet health needs [53].
GARDP, a pipeline coordinator, has put praiseworthy efforts into developing novel treatments from scratch that is from basic science research to late-stage trials to regulatory approvals and making them accessible globally. Similarly, ND4BB’s eight programs coordinate research activities from early-stage research to clinical trials, as well as making them accessible through its DRIVE-AB project. CARB-X is another strategic initiative to fund early- and mid-stage research, which after graduation are considered by BARDA for further funding of clinical trials. One of the examples under the CARB-X-BARDA portfolio is the development of VE303, a live biotherapeutic product of the Vedanta Biosciences being developed for treating patients at high risk of recurrent Clostridioides difficile infections. The early development support was provided by CARB-X with a research grant of 5.4 million USD in 2017, and later, the BARDA’s advanced development support funded a contract of up to 76.9 million USD in 2020 to support Phase 3 trials [79,80].
Despite all these efforts, a need for a single global governing entity that could look after and coordinate various national and international efforts was felt. The G20 leaders called for “a new international R&D Collaboration Hub to maximize the impact of existing and new antimicrobial basic and clinical research initiatives” at a 2017 G20 summit in Hamburg, Germany. This led to the launch of the Global Antimicrobial Resistance (AMR) Research and Development (R&D) Hub in 2018 [81,82]. The Global AMR R&D hub is not a funding mechanism but is a central platform that continuously collects and presents information on global investments in antibiotic R&D to help inform government and non-government funders in priority settings and decision-making for resource allocation [83]. This hub is open to all government and non-government funding agencies in G20 as well as non-G20 countries investing in antibiotic R&D. Its Dynamic Dashboard continuously updates information on AMR R&D investments and activities across One Health continuum and currently presents information of more than 12,000 projects funded by 222 funders with an investment of more than 10 billion USD [84]. This initiative is a major step in establishing internationally agreed priorities and will help in coordinating and streamlining existing as well as new initiatives.
Similar to the Global AMR R&D hub, we propose to the policymakers the consideration of a country-wise centralized database that should have information on completed and ongoing research projects in various institutions of the country. There should be a centralized funding mechanism, and it will be better to have a single funding agency looking after the antibiotic research being conducted in the entire country. For example, if we talk about India, multiple funding agencies such as DST, DBT, ICMR, etc., fund research in different domains. Instead, there could be a single central platform for antibiotic research funding (it could be named Department of Antibiotic Research or Indian Antibiotic Research Platform or any other), where only antibiotic research-based projects would be funded. In this way, the allocation of funds would be appropriately channelized, and duplication of efforts would be avoided. The unique platform should have different portals for early-, mid-, and late-stage funding. The research team working on early-stage research should enter into an early-stage portal and submit a proposal for funding. All country-wise platforms may be connected to a global platform. Moreover, similar to the clinical trial registry platform, there could be an antibiotic research registry platform, where it should be encouraged to register preclinical and clinical studies before execution. This may help in generating a centralized antibiotic research database that could make the antibiotic R&D status transparent.
In this review, we tried to cover the major push funding mechanisms. However, a lot more exists beyond these at various country levels. We apologize to the push funders for not comprehensively covering all the mechanisms, as it is too vast to cover all in a review. Needless to say, along with push incentives, equal attention is needed towards pull incentives to sustain the approved antibiotics in the market. Currently, more than two-thirds of the funding is towards push incentives which alone will not be able to suffice the pipeline. The discussion over pull incentives is out of the scope of this article, but replenishing the antibiotic R&D pipeline will not be possible without adequate pull incentives. Hence, there is a necessity to address the economic incentive needs of the developers; otherwise, the faintly appeared silver lining in the antibiotic research clouds may again darken.

5. Conclusions

Antibiotic resistance is a silent pandemic and a growing threat to public health. Revitalizing the antibiotic pipeline through financial assistance in the form of push funding and uniting the scientific community can bring back the lost art of discovery. Various push funding mechanisms in the last decade have tried to narrow the discovery void that occurred after the lucrative 1980s era of antibiotic development. However, despite numerous funding mechanisms, the pace of development is still slow, and the antibiotic market is unattractive for the big pharmaceuticals. Alongwith push funding, there is a need to incentivize antibiotic developers after regulatory approval to sustain the market.
The concern of exorbitant early-stage funding and little funding for SMEs struggling for mid- and late-stage developments are now being handled by several new mechanisms such as CARB-X, GARDP, ND4BB, etc. Further, to raise the voice of SMEs, the launch of the BEAM Alliance in 2015 by the EU is commendable. Another achievement is the foundation of the Global AMR R&D hub in 2018,which is helping to make the funding mechanisms and priorities transparent through its dynamic dashboard. Similar to the Global AMR R&D hub, a country-wise centralized database along with a central funding mechanism to appropriately channel the allocation of funds and to avoid efforts duplication can be considered for antibiotic research. Additionally, the formation of an antibiotic research registry platform can be considered, where it should be encouraged to register preclinical and clinical studies before execution to generate a centralized antibiotic research database.
The development of REVIVE platform by GARDP is another step in the right direction to bring the scientific community and experts in the antibiotic research field together, as many researchers in the field have retired, and a majority of the budding researchers are moving towards other lucrative fields, leading to little knowledge dissemination. REVIVE may revive back the scientific curiosity and vigor in the antibiotic R&D field. Now, the time has come to streamline the efforts and existing funding mechanisms in a coordinated and transparent way, along with a global collaboration to tackle this silently heading pandemic.

Author Contributions

Conceptualization, H.W. and K.H.R.; formal analysis, D.S., Y.K.G. and K.H.R.; writing—original draft preparation, H.W.; writing—review and editing, H.W., D.S., Y.K.G. and K.H.R.; supervision, Y.K.G. and K.H.R.; project administration, H.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AHRC: Arts and Humanities Research Council, AMR: Antimicrobial Resistance, AMRFF: AMR Funders’ Forum, AR Isolate Bank: Antibiotic Resistance Isolate Bank, ARLG: Antibacterial Resistance Leadership Group, BARDA: Biomedical Advanced Research and Development Authority, BBSRC: Biotechnology & Biological Sciences Research Council, BEAM: Biotech companies from Europe innovating in Anti-Microbial resistance research, BEI: Biodefense and Emerging Infections Research, BEIS: Department for Business, Energy and Industrial Strategy, CARB: Combating Antibiotic-Resistant Bacteria, CARB-X: Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, CBRN: Chemical, Biological, Radiological And Nuclear, CDC: Center for Disease Control and Prevention, CDI: Clostridium difficile infection, CO-ADD: Community for Open Antimicrobial Drug Discovery, CRE: Carbapenem-resistant enterobacteriaceae, DFID: Department for International Development, DHHS: Department of Health and Human Services, DHSC: Department of Health and Social Care, DNDi: Drugs for Neglected Diseases initiative, DOD: Department of Defense, EC: European Commission, EDCTP: European & Developing Countries Clinical Trials Partnership, EFPIA: European Federation of Pharmaceutical Industries and Associations, EIC: European Innovation Council, ETP: European Technology Platform, EU: European Union, FDA: Food and Drug Administration, FIND: Foundation for Innovative New Diagnostics, FP7: EU’s Seventh Framework Programme, GAMRIF: Global AMR Innovation Fund, GARDP: Global Antibiotic Research and Development Partnership, GCRF: Global Challenge Research Funds, GH EDCTP3 JU: Global Health EDCTP3 Joint Undertaking, Global AMR R&D Hub: Global Antimicrobial Resistance (AMR) Research and Development (R&D) Hub, IDFF: Innovfin Infectious Disease Facility, IFPMA: International Federation of Pharmaceutical Manufacturers & Associations, IMI: Innovative Medicine Initiative, IMI-ND4BB: Innovative Medicine Initiative-New Drugs for Bad Bugs, IND: Investigational New Drug, JPIAMR: Joint Programming Initiative on Antimicrobial Resistance, MRC: Medical Research Council, MVP: Meningitis Vaccine Project, ND4BB: New Drugs for Bad Bugs, NHS: National Health Service, NIAID: National Institute of Allergy and Infectious Diseases, NIH: National Institute of Health, NIHR: National Institute for Health and Care Research, NPV: Net Present Value, ODA: Official Development Assistance, OTA: Other Transaction Authority, PAHPA: Pandemic and All-Hazards Preparedness Act, R&D: Research and Development, REPAIR: Replenishing and Enabling the Pipeline for Anti-Infective Resistance, SAP: Stewardship and Access Plan, SBIR: Small Business Innovative Research, SME:Small and medium size enterprises, STTR: Small Business Technology Transfer, TRL: Technology Readiness Levels, UK: United Kingdom, UKRI: UK Research and Innovation councils, US: United States of America, WHO: World Health Organization.

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