March 24, 2021

Strengthening AMR Countermeasures to Respond to Health Crises
Recommendations to the Japanese Government on Establishing a Pull Incentive
System for the Antimicrobial Market: Creating an Ecosystem for Sustainable
Antimicrobial Development to Protect the Lives of the Public
Executive Summary
Nikkei FT Communicable Diseases Conference
Asia Medical Innovation Consortium (AMIC)AMR Consortium
Antimicrobial resistance (AMR) is an internationally recognized health crisis. It requires a strong policy response. To
promote such responses, the World Health Organization released a WHO policy package to combat antimicrobial
resistance1 in 2011. In 2015, the World Health Assembly endorsed the Global Action Plan on Antimicrobial Resistance.2
Following the release of these documents, Japan created its own National Action Plan on AMR 2016-20203 in 2016.

Despite these measures, the threat of AMR as a ‘silent pandemic’ is growing. In 2019, it was estimated that alreadyapproximately 8,000 deaths are occurring annually in Japan due to blood-stream infections attributable to just two
antimicrobial-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistantEscherichia coli (E. coli) (Figure 1).4 While the number of infections attributed to MRSA has been trending downward
since 2011, Japan still maintains a high number of infections compared with other countries. Meanwhile, the numberof fluoroquinolone-resistant E. coli infections is on the rise, 5 as are infections due to carbapenem-resistantEnterobacteriaceae (CRE) bacteremia, which is estimated to kill 20% to 40% of the people it infects.6 In the past, thenumber of domestic CRE infections was stable. Japan saw around 1,600 cases between 2015 and 2017.7 This number
suddenly jumped to 2,289 cases in 2018 (resulting in 71 deaths). This increase coincided with a rise in the percentage
of infections caused specifically by overseas strains of CRE, which rose from 1.4% in 2017 to 2.5% in 2018. At the sametime, Japan began to see a larger variety of prefectures reporting the appearance of these strains. In 2017, overseas
strains of CRE were reported in just six prefectures (with three prefectures reporting cases involving people with no or
unknown overseas travel history). By 2018, that figure rose to 16 prefectures, with 12 prefectures reporting cases
involving people with no or unknown overseas travel history (Figure 2).8 Although MRSA case numbers are currently
falling in Japan, increases are being seen overseas, and it is plausible that a spread of MRSA infections could spread fromabroad to Japan in the future. Rapid measures to deal with the AMR are urgently needed.91

https://www.who.int/bulletin/volumes/89/5/11-088435/en/
https://apps.who.int/iris/bitstream/handle/10665/193736/9789241509763_eng.pdf?sequence=1
https://www.mhlw.go.jp/file/06-Seisakujouhou-10900000-Kenkoukyoku/0000120769.pdf
4National trend of blood-stream infection attributable deaths caused by Staphylococcus aureus and Escherichia coli in Japan. https://www.sciencedirect.com/science/article/pii/S1341321X
19303356. Accessed September 16, 2020.
5
Nippon AMR One Health Report (NAOR) 2019. https://www.mhlw.go.jp/content/10900000/000571551.pdf. Accessed September 7, 2020.
6
Treating carbapenem-resistant Enterobacteriaceae infections. https://www.niid.go.jp/niid/ja/allarticles/surveillance/2439-iasr/related-articles/related-articles-468/8619-468r05.html. AccessedSeptember 7, 2020.
7
Notifications of carbapenem-resistant Enterobacteriaceae infections submitted according to the Infectious Diseases Control Act, 2018. https://www.niid.go.jp/niid/ja/cre-m/cre-idwrs/9781-cre191227.html. Accessed September 7, 2020.
8
Detected carbapenemase gene-positive strains originating from locations overseas in carbapenem-resistant Enterobacteriaceae (CRE) pathogen surveillance, 2017-2018.
https://www.niid.go.jp/niid/ja/cre-m/cre-iasrd/9125-475d02.html. Accessed September 7, 2020.
9
Fix the antibiotics pipeline. https://www.nature.com/articles/472032a.pdf. Accessed September 14, 2020.
23Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)

Figure 1: Estimated annual BSI deaths attributable to MRSA andFQREC
Figure 2: Regions reporting carbapenemase gene-positive
strains originating from overseas

That said, the number of new antimicrobials in development has been declining worldwide since the 1980s. In responseto this problem, “The 10×ʼ20 Initiative” was launched in the United States with the goal of encouraging the productionof ten new antimicrobials between 2010 to 2020. Following on the start of that initiative, in 2011, the U.S. Food andDrug Administration (FDA) passed the Generating Antibiotic Incentives Now Act (GAIN), which promotes thedevelopment of new antimicrobials to combat AMR by granting them accelerated FDA review and approvals, as well as
five-year extensions on market exclusivity upon approval. Financial support for antimicrobial development is also being
provided by the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Healthand Human Services (HHS), which grants public funds for basic research on AMR countermeasures, and Combating
Antibiotic-Resistant Bacteria (CARB-X), a public-private partnership (PPP) focused on addressing the threat of AMR.
CARB-X has announced it will invest up to US$500 million in AMR countermeasures in the United States and abroadfrom 2016 to 2021.10 With the support of these initiatives, twenty new antimicrobial agents were approved in the U.S.
between 2010 and 2020 (Table 1).11

However, not all of the new antimicrobials have been launched successfully. Shortly after the approval of Plazomicin in
2018, the biotech venture company that developed it, Achaogen, Inc., went bankrupt.12 That event highlighted themajor financial challenges that firms aiming to develop new antimicrobials face after obtaining approval. These include
issues related to maintaining sufficient funding to cover post-marketing costs, and expenses related to the creation of amanufacturing system in order to ensure the stable and continuous provision of antimicrobials to the market.13To help address these challenges, discussions have begun in the United States, the United Kingdom, and elsewhere toexamine the introduction of new pull incentives that could help companies secure continued funding for new
antimicrobials even after approval. The Pasteur Act, which calls for antimicrobial subscriptions, was submitted to the US
Congress in April 2004. In the United Kingdom, a pilot is underway that aims to test a delinked subscription model inwhich the prices paid for new antimicrobials selected by the National Health Service (NHS) will not depend on the10

CARB-X is a non-profit partnership. https://carb-x.org/partners/funding-partners/. Accessed September 7, 2020.
Current status and prospective of antibacterial agents regarding countermeasure against antimicrobial resistance (AMR). http://www.thcu.ac.jp/uploads/imgs/20191226090752.pdf. Accessed
September 7, 2020.
12https://www.nature.com/articles/d41573-019-00085-w. Accessed September 8, 2020.
13
The history and future prospects of antimicrobial drug development in Japan. http://journal.chemotherapy.or.jp/detail.php?-DB=jsc&-recid=5561&-action=browse. Accessed September 8, 2020.
11Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)

volume sold. Two antimicrobials were selected for this pilot in December 2020.14 Likewise, in Sweden, discussions on
the introduction of a delinked subscription model have been held since 2018, and a pilot study on the subject is currently
being carried out.15 Pull incentives will not succeed without collaboration and coordination within the international
community. Solving the problems of antimicrobial development will require pull incentives in a range of countries thatare designed to suit local healthcare systems and regulations.

AMR countermeasures must be built upon efforts supporting the appropriate use of antimicrobials. It is important toprovide antimicrobials only to the patients who need them and only during the periods they are needed, based on
testing. From a public health standpoint, the use of new antimicrobials must be carefully controlled. All of these points
have consequences for antimicrobial manufacturing. Because of the nature of antimicrobial stewardship requirements,
even if pharmaceutical manufacturers successfully develop new antimicrobials, they cannot expect profits based onhigh usage or sales volume, and it is impossible to predict revenue. There is an additional element to this issue in Japan,
in that compared to other countries, relatively few people have experienced antimicrobial-resistant infections
domestically. This, combined with pharmaceutical pricing issues, makes the prospect of developing and manufacturing
new antimicrobials unattractive for pharmaceutical companies in Japan. All of these issues have contributed to thecreation of a drug lag for antimicrobials in Japan. Among the twenty new antimicrobials developed as a result of the10x’20 Initiative in the U.S., only five have been approved for use in Japan. Furthermore, it took an average of 51.2
months for any one of those products to get approved in Japan compared to when they were first approved overseas(Figure 1). The Japanese Government must adopt policies to allow for the rapid and steady introduction of new
antimicrobials moving forward.

In 2020, the rapid spread of Coronavirus Disease 2019 (COVID-19) reminded societies around the world of theimportance of being prepared for infectious diseases. Worldwide efforts to develop vaccines and therapeutic agentsadvanced rapidly. Countries around the world, including Japan, are rushing to secure a share of the pharmaceuticals
developed. The world is racing against time to deliver the developed pharmaceuticals to their populations in order tosave as many lives from COVID-19 as possible.

AMR is at least as large of a threat as COVID-19. It is projected that if serious measures aren’t taken against AMR, by2050, as many as 10 million people could be dying each year from AMR-related causes.16 The WHO has recognized AMR
as a critical health issue.17 Japan too must recognize that infectious disease-related health crises are not limited tojust emerging and reemerging infectious diseases, but also include AMR, and as such, the Japanese Government
should increase support for AMR countermeasures as means of responding to future health crises.

14Mark Perkins, David Glover, “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-antimicrobialresistance-amr-can-set-a-global-standard/ Accessed: February 18, 2021
15
Public Health Agency of Sweden, “Availability of antibiotics.” https://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/communicable-disease-control/antibiotics-and-antimi
crobial-resistance/availability-of-antibiotics/ Accessed: March 17, 2021
16
TACKLING DRUG-RESISTANT INFECTIONS GLOBALLY: FINAL REPORT AND RECOMMENDATIONS. https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf. Accessed
September 14, 2020.
17
WHO, “10 Global Health Issues to Track in 2021” https://www.who.int/news-room/spotlight/10-global-health-issues-to-track-in-2021 Accessed: February 18, 2021
Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)In an effort to push AMR countermeasures forward, the WHO18 and the U.S. Centers for Disease Control and Prevention(CDC)19 created Priority Pathogens Lists (PPL) in 2017 and 2019, respectively. These lists catalogue the pathogens thateach organization considers to be the greatest threat to humanity. In Japan, the Agency for Medical Research andDevelopment (AMED), the chairman of the Japan Infectious Diseases Society, the chairman of the Japan Chemotherapy
Association, and members of the Japan Pharmaceutical Manufacturers Association have come together to form theAMED Industry-Academia-Government Liaison Committee for Infectious Disease Drug Discovery, which aims to developa Japanese PPL.20 Table 2 shows an updated version of the PPL, which was presented at the 13th joint meeting of Seven
Academic Societies21 and the Drug Discovery Promotion Review Committee in March 2021. This list will continue to berevised based on feedback from various sectors of society. The Japanese PPL should be the starting point for theselection of the antimicrobials that should be eligible for a pull incentive.

This proposal provides specific recommendations for ensuring that the few antimicrobials that are expected to be
developed globally in the coming decade reach the Japanese public. The measures in these recommendations will also
help to establish market conditions that allow domestic pharmaceutical makers to sustain continuous investment in
antimicrobial R&D. This document is a compilation of the opinions of experts from industry, government, academia, andcivil society who voluntarily lent their knowledge in support of the aforementioned goals. It is presented in the hope ofproviding useful information for future discussions on AMR countermeasures held within the Japanese Government
toward the protection of public health and strengthening of national security.

18

Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. https://www.who.int/medicines/publications/global-priority-list-antibioticresistant-bacteria/en/. Accessed September 14, 2020.
19
ANTIBIOTIC RESISTANCE THREATS IN THE UNITED STATES 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed September 14, 2020.
20
Study on the development of pharmaceuticals against infectious diseases and pathogens in Japan and overseas. https://www.amed.go.jp/content/000064113.pdf. Accessed September 8, 2020.
21
The seven academic societies are the Japanese Society of Chemotherapy, The Japanese Association for Infectious Diseases, the Japanese Society for Clinical Microbiology, the Japanese Society forBacteriology, the Japanese Society for Infection Prevention and Control, the Pharmaceutical Society of Japan, and the Japanese Society of Veterinary Science
Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)

Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)

Key Messages
 Antimicrobial Resistance (AMR) is a health crisis. Japan must deal with it
urgently.
 It has been estimated that AMR infections (MRSA and fluoroquinoloneresistant E. coli) already cause at least 8,000 deaths in Japan annually. Incomparison, COVID-19 has caused 8,227 deaths in Japan (as of March 7, 2021).
 Infections that are resistant to last-resort antimicrobials (such ascarbapenem) are on the rise, and the number of infections caused by bacterial
strains from outside of Japan is rapidly increasing (based on data from 2017 to2018).
 Antimicrobial development peaked in the 1980s. Only six antimicrobials havebeen approved in Japan since 2010 (compared to over 20 antimicrobials in theU.S.).
 To promote the development of new antimicrobial agents, we have developedspecific recommendations on the creation of a pull incentive
 There are three types of pull incentives that should be considered in Japan: Market entry rewards
 Delinked subscription model Profit guarantee scheme Budgetary scope:

Total costs per product depending on the model selected: 20 to 80billion yen (over a ten-year payment period, this equates to paymentsof 2 to 8 billion yen annually).

Nikkei FT Communicable Diseases Conference The AMR Consortium of Asia Africa Medical Innovation Consortium (AMIC)
Secretariat: AMR Alliance Japan (Health and Global Policy Institute)Tel: 03-4243-7156 Fax: 03-4243-7378 E-mail: info@hgpi.org (Contact: Matt McEnany, Tomohito Shibata, or Yui Kohno)