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Shionogi AMR Position Paper


Antimicrobial resistance (AMR) is a global threat with potentially devastating consequences to those infected with resistant pathogens and high direct and indirect cost to society. In the future, lack of effective antibiotics could make routine medical interventions extremely dangerous and make other more complex interventions and procedures impossible. For these reasons, AMR must be regarded as a global, regional, and national priority for health organizations and governments.

Shionogi is a co-signatory of the January 2016 Davos Declaration. This document, signed by >100 companies and trade associations, called for collective action to create a sustainable and predictable market for antibiotics, vaccines, and diagnostics whilst emphasising the need for conservation of new and existing treatments. Together with 12 other leading companies, Shionogi has gone further, signing an Industry Roadmap that includes action plans for antibiotic research and science, appropriate use, access, and manufacturing and environmental actions to achieve this goal.

Successfully addressing AMR requires coordinated action by all stakeholders, including governments and international organizations, the pharmaceutical industry, and prescribers and users of antibiotic products. Shionogi believes that the following actions are required:

  1. Create a predictable and sustainable market for AMR products through economic incentives, such as pull incentives and new value assessments for reimbursement
  2. Harmonize global regulations for development and approval of new antibiotics
  3. Establish clinical trial networks to help execute clinical studies more efficiently
  4. Ensure appropriate use of antibiotics through regulation of animal use, stewardship, and timely surveillance of resistance epidemiology
  5. Make effective medicines available for patients in need directly or via alliance partners
  6. Reduce environmental impact from manufacture of antibiotics

We are proud of our on-going commitment to the research and development of new antimicrobial therapies, and we are working hard to ensure that both individual patients and society as a whole will continue to benefit from effective AMR drugs. We call on all stakeholders to join the fight against AMR.


A significant unmet need: ‘Time is running out’

Antimicrobial resistance (AMR) is a real and immediate global threat. The damaging effects caused by resistant bacteria are already responsible for an estimated 700,000 deaths every year globally,1 with 33,110 lives lost per year in Europe2 and 23,000 in the United States.3 The impact in other areas of the world is estimated to be even more profound.1 Future projections of the impact of unresolved AMR have been as high as 10 million additional deaths per year by 2050, a figure that surpasses projected number of deaths caused by cancer (8.2 million).1 The European Commission reports that combined direct and indirect costs due to AMR amount to €1.5 billion in the EU.4 In the United States, some estimates have ranged as high as $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year.3, By 2050, the world is at risk of losing up to 3.8% of its annual gross domestic product (GDP), with an annual shortfall of up to US$3.4 trillion by 2030, a figure on par with the losses provoked by the 2008 global financial crisis.5 The cumulative cost to the global economy could be as high as US$100 trillion (UK£ 64 trillion).1 Moreover, as life-threatening infections can arise after many medical procedures, such as surgery or cancer treatment, the rise of AMR threatens to make routine medical interventions extremely dangerous or even impossible in the future.1 For these reasons, AMR is a global, regional, and national priority for many organizations and governments. There have been calls for collaborative, multisectoral, and transdisciplinary ‘One Health’ approaches to combat AMR with the goal of achieving optimal health outcomes and recognizing the interconnection between people, animals, and plants and their shared environment.6

Development of resistance to antibiotics is an evolutionary process driven by natural selection and occurring either through spontaneous mutations within the bacterial genome or by the acquisition of exogenous genetic material from other pathogens in the wider environment. Proliferation of resistance genes has in part been driven by overall antibiotic consumption; over the past decades, this problem has been accelerated by inappropriate prescribing, poor infection control practices, incomplete surveillance, and non-human use of antibiotics. More recent antibiotic stewardship initiatives that aim to rationalise the use of antibiotics and slow the rate of resistance development have focussed on restricting the use of new antibiotics and targeting their use to instances in which treatment options are limited. While it is rational to take steps to ensure the appropriate use of new antibiotics, they have the unintended consequence of making the commercial viability of developing new antibiotics highly uncertain. The uncertainty around market size, combined with the increasingly challenging task of discovering and developing novel antibiotics, has led many large manufacturers to exit, deprioritise, and scale back their antibiotic development programmes to focus development activities on more predictable therapeutic areas.

1 O’Neill J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf.

2 Cassini A. et al. ‘Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis’ https://doi.org/10.1016/S1473-3099(18)30605-4

3 CDC. ‘Antibiotic Threats in the United States’, 2013. https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

4 EU Commission. ‘EU Action on Antimicrobial Resistance’, http://ec.europa.eu/health/amr/antimicrobial-resistance_en

5 World Bank. Final Report Drug Resistant Infections: A Threat to Our Economic Future. Mar 2017. http://documents.worldbank.org/curated/en/323311493396993758/pdf/114679-REVISED-v2-Drug-Resistant-Infections-Final-Report.pdf.

6 CDC. ‘One Health’. https://www.cdc.gov/onehealth/index.html.

Carbapenem-resistant Gram-negative pathogens: New antibiotics are urgently needed

Carbapenems have been the workhorse for treating difficult Gram-negative infections, but resistance to carbapenems is increasing at an alarming rate. Gram-negative bacteria resistant to carbapenems, a class of β-lactam antibiotics with a broad spectrum of activity, frequently carry multiple resistance mechanisms, limiting their susceptibility to treatment with many different antimicrobial classes. As a result, they have been classified as the highest ‘critical’ priority in the World Health Organization (WHO) global-priority pathogens list. Specifically, these pathogens include carbapenem-resistant strains of Acinetobacter baumannii (CRAB), Pseudomonas aeruginosa (CRPA), and Enterobacteriaceae (CRE).7 These pathogens have been described as ‘nightmare’ bacteria8 and are considered ‘urgent and serious’ threats by the US Centers for Disease Control and Prevention (CDC).9

Infections caused by carbapenem-resistant Gram-negative bacteria are associated with higher mortality rates compared with those involving susceptible strains. However, this varies depending on pathogen species and infection site. For example, mortality rates for CRE have been reported to be about 30% for non-bacteraemia cases but can reach up to 70% for bacteraemia or liver transplant patients.10 Furthermore, the current treatment options available for these patients may address only a subset of resistance mechanisms and/or may be associated with severe adverse events; the polymixin antibiotic colistin, which was until recently considered a ‘last-resort’ drug used in this context, is associated with reports of nephrotoxicity in up to 60% of patients11 and was reintroduced to address these resistance issues after withdrawal from the market due to safety concerns.12 More concerning is the fact that even the utility of colistin is under threat because of the recent emergence and worldwide spread of a colistin-resistance genes (mcr-1).13,14

In terms of economic burden to patients and society, carbapenem-resistant infections are associated with long hospital stays (up to 63 days, depending on pathogen and infection site).15 In the United States, the increases in direct and indirect costs have been estimated to be as high as US$65,815 and US$48,106 per carbapenem-resistant infection, respectively.16 Therefore, there exists a significant unmet need in improving the efficacy, safety, and resource use for carbapenem-resistant infections from both clinical and societal perspectives.

7 WHO. ‘Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics’. http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf.

8 CDC. ‘Tracking the MCR Gene’. https://www.cdc.gov/drugresistance/tracking-mcr1.html.

9 CDC. ‘Antibiotic/Antimicrobial Resistance: Biggest Threats’.https://www.cdc.gov/drugresistance/biggest_threats.html.

10 Perez, F. and Van Duin, D. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr 2013 ; 80(4): 225–33.

11 Morill, H., et al. ‘Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections’. Open Forum Infect Dis. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462593.

12 Falagas ME., et al. ‘Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections.’ Clin Infect Dis. 2006 Jun 15;42(12):1819 https://www.ncbi.nlm.nih.gov/pubmed/15825037

13 Hu Y., et al. ‘Dissemination of the MCR-1 Colistin Resistance Gene’. Lancet Infect Dis. Feb 2016; 16(2): 146–7. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00533-2/fulltext.

14 Oikonomou, O., et.al. ‘Rapid Dissemination of Colistin and Carbapenem Resistant Acinetobacter Baumannii in Central Greece: Mechanisms of Resistance, Molecular Identification and Epidemiological Data’. BMC Infectious Diseases. 2015; 15:559. https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-015-1297-x.

15 Eberle BM., et al. ‘The Impact of Acinetobacter Baumannii Infections on Outcome in Trauma Patients: A Matched Cohort Study’. Crit Care Med. 2010; 38, 2133–38.

16 Bartsch SM., et al. ‘Potential Economic Burden of Carbapenem-Resistant Enterobacteriaceae (CRE) in the United States’. Clin Microbiol Infect. 2017; 23, 48 e9-48 e16.

Delay in appropriate therapy: The importance of early diagnosis

Appropriate therapy can be defined as the timely prescription of an antibiotic to which the pathogen is susceptible. Any prolonged delays in receiving appropriate therapy can therefore have a detrimental impact on the patient’s clinical outcome. This is particularly true of fragile or severely ill patients, such as those with sepsis, in whom delays in effective therapy have been associated with higher mortality rates, increased resource usage, and increased length of hospital stay. Currently, there is often a delay in accurate diagnosis of infections, especially when infections are caused by resistant organisms, and hence a delay in time to effective therapy.17 Therefore, to improve patient outcomes, there is a clear need to encourage and facilitate rapid identification of a resistant pathogen and its resistance mechanism to ensure that appropriate antibiotic therapy is initiated as early as possible.

17 Lodise T., et al. ‘Carbapenem-Resistant Enterobacteriaceae (CRE) or Delayed Appropriate Therapy (DAT): Does One Affect Outcomes More than the Other among Patients With Serious Infections Due to Enterobacteriaceae?’ Open Forum Infect Dis. 2017 Fall; 4(Suppl 1): S14. Published online 2017 Oct 4..

Shionogi’s long-term commitment to improving research and development to provide treatments for infectious disease18

Shionogi is a global pharmaceutical company established more than 140 years ago in Osaka, Japan. Shionogi has been developing antimicrobial therapies for more than 50 years, both by itself and through innovative alliances. In a recent Antimicrobial Resistance Benchmark 201818 survey, Shionogi was found to invest a greater proportion of revenue in antimicrobial research and development (R&D) than all other companies evaluated. The development of antibiotics is expensive, at about USD 1 billion19 per new antibiotic, and only 5 of the top 50 pharmaceutical companies currently have an antibiotics pipeline.20 According to a Pew Charitable Trust report, only approximately 1 in 4 antibiotics belong to a completely new class or have a novel mechanism of action, and only 1 in 5 of the infectious disease drugs in phase 1 clinical testing will ultimately be commercialized.21 We are committed to putting patients first and recognise the importance of investing in infectious disease research despite the uncertainties surrounding returns on investment.

Milestones in the Shionogi history of development of antibiotics include the following:22

  • 1959: sulfamethoxazole, the first sulfonamide antibiotic drug discovered and developed by Shionogi
  • 1982: moxalactam, the world’s first oxacephem antibiotic
  • 1988 and 1997: flomoxef, the world’s second oxacephem antibiotic
  • 1992 and 1997: ceftibuten and cefcapene, new oral cephem antibiotics
  • 2005: doripenem, a new carbapenem antibiotic

Other anti-infectives that Shionogi has developed include baloxavir marboxil (Xofluza®) for influenza A/B infections, and dolutegravir (Tivicay®) for the treatment of HIV/AIDS.23

Building on our legacy, Shionogi is currently developing several infectious disease drug candidates discovered in our in-house R&D programme, including cefiderocol (phase 3), the first of a new class of siderophore-cephalosporin antibiotics with activity against multi–drug-resistant Gram-negative bacteria potentiated by its novel mechanism of cell entry.23

18 Access to Medicine Foundation. Antimicrobial Resistance Benchmark. 2018. https://amrbenchmark.org/wp-content/uploads/2018/01/Antimicrobial-Resistance-Benchmark-2018.pdf.

19 DRIVE-AB. Revitalizing the Antibiotic Pipeline. Final Report. 2018. http://drive-ab.eu/wp-content/uploads/2018/01/DRIVE-AB-Final-Report-Jan2018.pdf.

20 Pew Charitable Trusts. Antibiotics currently in global clinical development, September 2017. Retrieved from http://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development

21 Pew Charitable Trusts. Talkington K., et al.,The World Is Running Out of Antibiotics, December 2017. http://www.pewtrusts.org/en/research-and-analysis/articles/2017/12/21/the-world-is-running-out-of-antibiotics

22 Shionogi History http://www.shionogi.co.jp/en/company/outline/history/history.html

23 Shionogi Pipeline. http://www.shionogi.co.jp/en/company/pmrltj0000000u4v-att/e_kaihatsu.pdf.

Shionogi’s positions and strategies

Davos Declaration/AMR industry roadmap and Shionogi AMR positions

Shionogi is a leader in anti-infective development within the pharmaceutical industry and supports various global and regional initiatives and recommendations, such as the declaration on addressing antibiotic resistance by the G7,24 G20,25 countries in the United Nations,26 the Global Action Plan by WHO,27 and the AMR Review on Antimicrobial Resistance (also known as the O’Neill Report).1 We also strongly believe in the importance of continuing to address the AMR issue and support pragmatic action at the country level to address immediate needs while global frameworks are established.

Shionogi is a co-signatory of the Davos Declaration (January 2016),28 together with more than 100 companies and trade associations. The declaration called for collective action to create a sustainable and predictable market for antibiotics, vaccines, and diagnostics, simultaneously emphasising the need for conservation of new and existing treatments. Based on this declaration, Shionogi, together with 12 leading companies, has signed an Industry Roadmap outlining action plans to achieve this goal.29 We believe in consolidated action and have joined with other stakeholders to progress initiatives through the AMR Industry Alliance, an initiative sponsored by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).30

To address the complex, global AMR issue, we believe that a combination of actions is required:

  1. Create a predictable and sustainable market for AMR products through economic incentives, such as pull incentives and new value assessments for reimbursement
  2. Harmonize global regulations for development and approval of new antibiotics
  3. Establish clinical trial networks to help execute clinical studies more efficiently
  4. Ensure appropriate use of antibiotics through regulation of animal use, stewardship, and timely surveillance of resistance epidemiology
  5. Make effective medicines available for patients in need directly or via alliance partners
  6. Reduce environmental impact from manufacture of antibiotics

24 G7 Health Ministers. Declaration of Health Ministers. 2015. https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/G/G7/G7_Health_Ministers_Declaration_AMR_and_EBOLA.pdf.

25 G20. Leaders’ Declaration. 2017. https://www.g20.org/profiles/g20/modules/custom/g20_beverly/img/timeline/Germany/G20-leaders-declaration.pdf.

26 General Assembly of the United Nations. ‘High-Level Meeting on Antimicrobial Resistance’. UN event. 2016. https://www.un.org/pga/71/event-latest/high-level-meeting-on-antimicrobial-resistance/.

27 WHO. Global Action Plan on Antimicrobial Resistance. 2015. http://apps.who.int/iris/bitstream/10665/193736/1/9789241509763_eng.pdf?ua=1.

28 AMR Review. Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance. https://amr-review.org/sites/default/files/Industry_Declaration_on_Combating_Antimicrobial_Resistance_UPDATED%20SIGNATORIES_MAY_2016.pdf.

29 IFPMA. AMR Industry Roadmap. https://www.ifpma.org/wp-content/uploads/2016/09/Roadmap-for-Progress-on-AMR-FINAL.pdf.

30 IFPMA. AMR Industry Alliance. https://www.ifpma.org/partners-2/declaration-by-the-pharmaceutical-biotechnology-and-diagnostics-industries-on-combating-antimicrobial-resistance-amr/.

1. Create a predictable and sustainable market for AMR products through economic incentives, such as pull incentives and new value assessments for reimbursement

Economic incentives

As pathogens continually evolve their response to antibiotic therapies, there is a need for R&D to develop new molecules to outpace the development of resistance. Shionogi strongly supports the introduction of new incentives, funding, and reimbursement models to restore and maintain R&D, innovation, and excitement in this critical field.

Measures to support the widespread implementation of antibiotic stewardship are of vital importance in combating AMR and prolonging the utility of antibiotics. Shionogi therefore supports the delinking of sales volume from revenue reward; this will support more appropriate use over the long term, leading to better outcomes for patients and improved antibiotic sustainability. Addressing the economic model for antibiotic development and commercialization is critical. We advocate for a mix of ‘push’ (e.g., subsidies for R&D) and ‘pull’ (e.g., financial rewards on market entry) incentives to stimulate continued development and commercialization of novel antimicrobial agents.31

Shionogi is excited to see the visible progress in R&D collaborations as a part of ‘push’ incentives, for example, BARDA’s32 Broad Spectrum Antimicrobials Program, CARB-X,33 GARDP,34 the IMI’s35 ND4BB36 programme, and JPIAMR,37 and we are the first Japanese company to partner with CARB-X.38 We have been working with partners across various parts of the health sector to find workable solutions to the numerous unmet needs in infectious disease. Since its inception in 2013, Shionogi has participated in the GHIT, Japan’s first public-private partnership fund39 created to advance the research and development of innovative medicines for the treatment of infectious diseases in the developing world. In addition, we have started a screening program for new anti-tuberculosis compounds with the Global Alliance for Tuberculosis Drug Development.

While ‘push’ funding is important, ‘pull’ incentives are critical to ensure that new antibiotics are made available to consumers. To date, there has been much discussion but little tangible action in terms of pull incentives. We recognise that pull incentives have to fit country and regional situations and therefore support implementation of a suite of pull incentives, such as partially delinked or fully delinked market-entry rewards, transferable exclusivity vouchers, and government purchases, in addition to value-based pricing and reimbursement initiatives. Shionogi appreciates the ongoing discussion of pull incentives by governments and other organizations and strongly advocates for quickly moving from discussion to implementation.

31Mossialos E., et al. Policies and Incentives for Promoting Innovation in Antibiotic Research, European Observatory on Health Systems and Policies. 2010. ISBN 9789289042130. http://www.lse.ac.uk/LSEHealthAndSocialCare/impacts/LSEHealthNews/News%20Attachments/Policies%20and%20incentives%20report.pdf.

32 US Department of Health and Human Services. Public Health Emergency. ‘Biomedical Advanced Research and Development Authority’. https://www.phe.gov/about/barda/Pages/default.aspx

33 US Department of Health and Human Services. Public Health Emergency. ‘Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator’. https://www.phe.gov/about/barda/CARB-X/Pages/default.aspx

34 Global Antibiotic Research and Development Partnership. https://www.gardp.org/

35 Innovative Medicines Initiative. http://www.imi.europa.eu/

36 New Drugs for Bad Bugs. http://nd4bb.eu/

37 Joint Programming Initiative on Antimicrobial Resistance. https://www.jpiamr.eu/

38 CARB-X. Press Release, 22 Mar 2018.’ CARB-X partners with Shionogi to develop an antibiotic to treat infections caused by the life-threatening CRE superbug’. http://www.carb-x.org/press/shionogi_2018

39 Global Health Innovative Technology Fund. https://www.ghitfund.org/

New value assessment of antibiotics for reimbursement and health technology assessment (HTA)

In relation to implementing economic incentives, there is an urgent need for new approaches to assessment and payment for new antibiotics, including recognition of societal value, such as avoidance of the spread of infection to the wider population.40 Measures designed to assess wider public benefits (e.g., the values associated with a reduction in transmission, ensuring the availability of treatment, adding to the diversity of options, unique mechanism of action with wider benefits, enabling other treatments, providing narrow spectrum targeting, etc) of new antibiotics should be included, as recommended in reports by DRIVE-AB,41 the Duke Margolis Center for Health Policy,42 and the Office of Health Economics.40 In addition, budget constraints resulting from imposed bundle payment systems, such as the Diagnosis-Related Group-based (DRG) hospital reimbursement system, should be addressed where they create hurdles for use of the most appropriate antibiotic.40 In the short to medium term, while a global framework is maturing, Shionogi proposes to explore new valuation and reimbursement models with national healthcare systems.

40 Karlsberg Schaffer S., et al. Assessing the Value of New Antibiotics: Additional Elements of Value for Health Technology Assessment Decisions. Office of Health Economics. 2017

41 DRIVE-AB. Revitalizing the Antibiotic Pipeline. Final Report. 2018. http://drive-ab.eu/wp-content/uploads/2018/01/DRIVE-AB-Final-Report-Jan2018.pdf.

42 Daniel GW., et al. Value-Based Strategies for Encouraging New Development of Antimicrobial Drugs. Duke Margolis Center for Helath Policy. https://healthpolicy.duke.edu/sites/default/files/atoms/files/value-based_strategies_for_encouraging_new_development_of_antimicrobial_drugs.pdf.

Risk-sharing scheme in manufacturing

Shionogi has made a significant investment in manufacturing facilities, in part because some antibiotics require dedicated manufacturing equipment, and plant capacity must be prepared in advance of need. Adoption of appropriate use policies make it likely that many new MDR antibiotics will be manufactured in low volume. Further, planning for future demand is complicated by our inability to predict future resistance patterns. Together, these issues drive up the cost of goods and thereby exacerbate access issues. Shionogi supports implementation of measures that address manufacturing issues as part of the overall development and commercialization need.

2. Harmonize global regulations for development and approval of new antibiotics

The introduction of clearer and more streamlined regulatory approaches and guidelines by the European Medicines Agency (EMA; PRIME43, Adaptive Pathways44) and US Food and Drug Administration (FDA; GAIN45, LPAD46 in the 21st Century Cures Act), which may allow faster development, expedited review processes, and eventually earlier access for patients, have been well received. We believe that further harmonization of the clinical trial requirements across regions, beginning with parallel tripartite meetings among the EMA, FDA, and Pharmaceuticals and Medical Devices Agency47 would further support faster access to new antibiotics globally.

43 EMA. ‘PRIME: Priority Medicines’. http://www.ema.europa.eu/ema/index.jsp%3Fcurl%3Dpages/regulation/general/general_content_000660.jsp%26mid%3DWC0b01ac058096f643.

44 European Medicines Agency. ‘Adaptive Pathways’. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp.

45 The Pew Charitable Trusts. ‘GAIN: How a New Law is Stimulating the Development of Antibiotics’. 2013. http://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics.

46 The Pew Charitable Trusts. ‘LPAD: A Regulatory Pathway to Develop Antibiotics and Fight Drug-Resistant Infections’. 2015. http://www.pewtrusts.org/en/research-and-analysis/q-and-a/2015/06/lpad-a-regulatory-pathway-to-develop-antibiotics-and-fight-drug-resistant-infections.

47 EMA. Minutes, 17 Nov 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/11/WC500238496.pdf.

3. Establish clinical trial networks to help execute clinical studies more efficiently

One of the biggest challenges for developing new antibiotics addressing MDR bacterial infections is the generation of comparative data from target patients with resistant infections. Usually, clinical trials for resistant infections are conducted in a non-resistant patient population using a non-inferiority study design,40 since it would be unethical to study patients with resistant infections with a comparator agent that is already known to be resistant. If patients with resistant infections are studied with a comparator drug or best available therapy, underlying complexities such as heterogeneity in the epidemiology, underlying conditions, and causal pathogens make not only a superiority design but also statistical powering of the study challenging. Shionogi believes that creation of a clinical network focused on antibiotic studies would allow for more efficient and cost-effective study execution. Shionogi has collaborated with COMBACTE-NET, a part of the EU New Drugs for Bad Bugs programme, for microbiology support for the cefiderocol development program and will look for opportunities to participate in more extensive network opportunities.

4. Ensure appropriate use of antibiotics through regulation of animal use, stewardship, and timely surveillance of resistance epidemiology

The use and misuse of antibiotics accelerates the emergence of drug-resistant strains.48 To maintain the efficacy of currently available antibiotics, inappropriate antibiotic use should be minimized.

Antibiotic use in animals exceeds use in humans (e.g., 72.5% animal vs 27.5% human in the United States).1 Therefore, addressing AMR requires a significant emphasis on appropriate use in agriculture. Shionogi welcomes the changes introduced in some countries to ban last-resort antibiotic use in animals (e.g., colistin ban in China)49 and welcomes retail and food chain efforts to reduce antibiotic use in food production (e.g., Marks & Spencer, McDonald’s).50,51

For human use, as a first step, Shionogi believes that the regulatory label for anti-infective products should reflect patient need and guide physicians appropriately. This points to the need for pathogen-focused labels with a focus on ensuring efficacy against the specific bacterial infection rather than traditional labels based only on sites of infection. Regulatory agencies have already made progress with respect to harmonizing both clinical development requirements and product labels, and we encourage further progress.

Treatment should be appropriate for the bacteria causing the infection, using the correct dosage for the correct length of time. We support the implementation of financial stewardship incentives, such as financial penalties/rewards along the healthcare value chain. We participate in educational programmes for healthcare professionals to raise awareness of issues around AMR stewardship, and we do not remunerate sales staff based on sales volume of antibiotics.20 In addition, we fully support efforts to promote rapid microbiological diagnosis and antimicrobial susceptibility testing, as quick initiation of appropriate therapy is critical both to patient outcomes and to ensuring the appropriate use of antibiotics. Incentives for the use of rapid diagnosis could limit the empirical use of anti-infectives, support the transition to targeted antibiotic therapy, and improve patient outcomes.

In addition to aligning incentives for appropriate antibiotic use, we also support global and national action plans to conduct more timely and coordinated surveillance for resistant infections. Timely and well-coordinated surveillance activities to understand the epidemiology and emergence of resistant bacteria are critical, for both front-line physicians and healthcare stakeholders setting strategies to address AMR. For clinicians, this provides supportive information, enabling them to choose the most appropriate therapy when susceptibility information is limited. For healthcare stakeholders, the timely understanding of the issue is fundamental to target the most critical priorities. Shionogi has been conducting global surveillance of Gram-negative infections to support the cefiderocol development program and would be willing to participate in initiatives designed to share surveillance data.

48 WHO. ‘Antimicrobial Resistance’, fact sheet N194. 2018. http://www.who.int/mediacentre/factsheets/fs194/en/

49 Newton Fund. ‘Antibiotic colistin now banned as feed additive for animals in China’, https://www.newtonfund.ac.uk/news/success-stories/antibiotic-colistin-now-banned-as-feed-additive-for-animals-in-china/

50 The Guardian. ‘Marks & Spencer is first supermarket to publish data on antibiotics in supply chain’ https://www.theguardian.com/environment/2017/dec/20/marks-spencer-is-first-supermarket-to-publish-data-on-antibiotics-in-supply-chain

51 Reuters. Aug 23 2017, ‘McDonald's to cut global antibiotic use in chickens’ https://www.reuters.com/article/us-mcdonalds-antibiotics/mcdonalds-to-cut-global-antibiotic-use-in-chickens-idUSKCN1B321V

5. Make effective medicines available for patients in need directly or through alliance partners

To improve global access to medicines, exploring and establishing new business models with other stakeholders is essential. Shionogi has been working to improve access to our innovative medicines through alliances and licensing partnerships with other global companies. For example, we have established collaborations for novel drugs originated by Shionogi that treat HIV/AIDS and influenza. Contributing to our core business model of commercialization of R&D innovation through alliances and licensing, we recognize the importance of considering access provisions in possible future partnership agreements related to AMR.

6. Reduce environmental impact from manufacture of antibiotics

It is crucial for antibiotics manufacturers to implement measures to reduce the environmental impact from production. Shionogi has been engaged in the development, manufacture, and sale of antimicrobials for many years and has always strictly controlled the release of antimicrobials into the environment. We have committed to environmental impact control strategies52 and will work together with other pharmaceutical companies on environmental risk management through the Pharmaceutical Supply Chain Initiative (PSCI) and implementation of Industry Roadmap commitments.

52 Shionogi. Environment, Health and Safety Report. 2018. http://www.shionogi.co.jp/en/ir/pdf/ehs_2018_e.pdf.


Shionogi recognises that establishing pull incentives, introducing new value assessments/reimbursement systems, and implementing other initiatives to address AMR will take time, stakeholder engagement, and political goodwill at national and global levels. Even if effective appropriate use measures are deployed globally, the emergence of microbial resistance can only be slowed. Given the long time frame required to develop new medicines, society now needs a strategy to incentivise development and commercialization of new antibiotics. While many pharmaceutical companies have moved away from infectious disease R&D, we are proud to be committed to ensure that both individual patients and society as a whole will benefit from new antibiotics and will take a leadership role in ensuring access and appropriate use.

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