Opinion Status and Issues of Antimicrobial Drug Development in Japan, Europe and the United States

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International Committee, Japan Pharmaceutical Manufacturers Association Akira Yuasa
Masao Yoshida, Senior Researcher, Pharmaceutical Industry Policy Institute, Japan
Yasunori Tawaraki, International Committee, Japan Pharmaceutical Manufacturers Association

It is no exaggeration to say that the pandemic of novel coronavirus infection (COVID-19) ¹⁾ in 2019 has drastically changed people's awareness of infectious diseases. Although novel coronavirus infection is caused by the SARS coronavirus2 (SARS-CoV-2) infecting ^humans2), infectious diseases are caused by infection with a variety of microorganisms in addition to ^viruses3). Among drugs for infectious diseases, the slowdown in the development of antimicrobial agents used to treat bacterial infections (systemic antibiotics, synthetic antimicrobial agents, and drugs used primarily for their antimicrobial action are referred to as "antimicrobial agents" in this ^paper4) has been discussed both in Japan and abroad in recent years, especially with regard to the development of new drugs for the treatment of infectious diseases. 4))), the slowdown in the development of antimicrobial agents has been discussed in Japan and abroad in recent years, and is now recognized as an important issue in Japan as well. However, there have been few new reports on the development of antimicrobial agents in Japan.

In this report, we report a survey of the development status of antimicrobial agents in Japan in three areas: 1) the number and percentage of antimicrobial agents approved in Japan over the past 20 years and the drug lag situation, 2) the development status of new antimicrobial agents approved overseas in Japan over the past 10 years, and 3) the development status of new antimicrobial agents in Japan, Europe, and the United States. The report will also cover issues related to antimicrobial drug development. We will also summarize and present issues related to antimicrobial drug development.

1. introduction

1-1. Infectious diseases and AMR

Infectious diseases are diseases that cause symptoms when pathogenic microorganisms invade the body, and pathogenic microorganisms are classified into bacteria, viruses, fungi, parasites, etc. according to size and structure ^.3 AMR (Antimicrobial Resistance) refers to the ineffectiveness of drugs used to eliminate these pathogenic microorganisms. AMR (Antimicrobial Resistance ⁾ refers to the ineffectiveness of drugs used to kill these pathogenic microorganisms, i.e., the acquisition of ^resistance5). An increase in the rate of drug resistance to existing antimicrobial agents leads to a decrease in clinical efficacy and an increase in the types of infections that become difficult to treat.

AMR is a significant public health crisis worldwide, with an estimated 700,000 deaths worldwide due to AMR each year in ²⁰¹⁶⁶⁾. While the 700,000 deaths in this estimate include deaths due to non-bacterial AMR such as human immunodeficiency virus and malaria, a paper published in ²⁰²²⁷⁾ estimated that in 2019 there were 1.27 million deaths directly attributable to bacterial AMR. The total annual number of deaths attributable to AMR in Japan is unknown, but a paper published in 2020 estimated that the number of deaths attributable to bloodstream infections caused by methicillin-resistant Staphylococcus aureus and fluoroquinolone-resistant E. coli was over 8,000 per ^year8).

8) The impact of AMR not only on clinical practice but also on health care economics has been reported. A report by the Organization for Economic Cooperation and Development (OECD) estimated that AMR incurred a total of US$3.5 billion in annual health care costs in the 33 countries ^analyzed9). ⁹⁾ Furthermore, a comparison of 2007 data for the EU/EEA (European Economic Area) countries and this report shows that the impact of AMR on the healthcare budgets of EU/EEA countries has increased by 60% in a little more than 10 ^years9). A Japanese study on the impact of an increase or decrease in AMR on the domestic healthcare economy reported that a 50% reduction in the drug resistance rate of Gram-negative bacteria (the three most frequently isolated major bacterial species) would reduce hospitalization costs by 2.5 to 6.4 billion yen (annually) ^.10)

This global sense of urgency has led to international efforts to address the AMR threat: in 2015, the World Health Organization (WHO) published a "Global action plan on antimicrobial resistance" that calls for immediate, harmonized action on a global scale ¹¹⁾. In 2016, the Japanese government announced the "Action Plan on Drug Resistance (AMR) " ¹²⁾ and has been working on its implementation. This Action Plan was expected to be revised at an early date, as the period covered by the Plan was until 2020.

Background of Antimicrobial Development in Japan and Overseas

Despite the growing awareness of the threat of AMR and the need for countermeasures, the slowdown in the development of new antimicrobial agents is a global ^challenge13).

In the United States, an initiative called "The 10x'20 ^{Initiative14)} was launched in 2010 with the goal of creating 10 new antimicrobial agents by 2020 through a joint effort by industry, academia, and government. According to a 2021 paper showing the number of FDA approvals of systemically active antimicrobial agents containing New Molecular Entity (NME) since 1980, there was a steady decline from 1980 to 2009, but a comparison between those years and the period from 2010 to 2019 shows an increase, albeit not sufficient (15). ⁽¹⁵⁾.

On the other hand, the number of antimicrobial agents approved in Japan from 2010 to 2019 was low compared to Europe and the United States, and the number of approved drugs was tied for the second worst among the 14 countries ^surveyed16). In addition, a report on the status of unapproved drugs in ^Japan17), which organized 265 unapproved drugs in Japan as of the end of December 2020 by drug class, found that the number of unapproved drugs tied for second place with 52 (20%) antineoplastics, followed by 32 (12%) gastrointestinal and metabolic agents and 32 (12%) systemic anti-infectives The number of approvals was the second highest in the industry.

One of the reasons for this low number of approvals may be due to the harsh environment surrounding the antimicrobial agent business. The details will be discussed later in this report.

Survey 1 (Number and percentage of antimicrobial agents approved in Japan and the drug lag situation) 3.

2-1. Methodology of Survey 1

We searched for NMEs approved in Japan between 1990 and 2019 that fell under the drug classification numbers ⁽¹⁸⁾ 61 (antibiotic drugs) and 62 (chemotherapeutic drugs) to determine the number of approvals and the percentage of all NMEs (drugs) approved during the same period. The "List of New Drugs ^Approved19)," "Pharmaceutical Affairs Public ^Relations20)," and "New Drugs of ^Tomorrow21) were used for the search. To ensure that the survey covered systemic antimicrobial agents for bacterial infections, those falling under Drug Classification Nos. 617 (mainly acting on molds) and 625 (antivirals) and topical agents were excluded from the survey. Drug lag was calculated as the difference between the earliest approval date in Japan, the U.S., and Europe and the approval date in Japan.

2-2. Results of Survey 1

The results are shown in Figure 1. The number of approved NMEs (antimicrobial agents) in Japan was divided into three chronological groups: 1990-1999, 2000-2009, and 2010-2019, showing a decrease of 27, 16, and 11 products, respectively. In addition, the percentages of NMEs (antimicrobials) as a percentage of all NMEs (drugs) also decreased, as did the number of approvals, to 8.5%, 6.2%, and 2.8%, respectively (see left figure). In addition, a comparison of the timing of approval in Japan, the U.S., and Europe for the 11 products approved between 2010 and 2019 showed that 7 products (64%) had a lag (delay) of 5 years or more after approval in the U.S. and Europe. (see figure on the right). In order to ensure the same number of target years, results were compiled through 2019, but it was confirmed that none of the target products were approved in 2020.

Survey 2 (Development status of new antimicrobial agents approved overseas in Japan) 4.

3-1. Methodology of Survey 2

The antimicrobial agents identified in the previous ^study16) were included in the survey, and their development status in Japan as of December 2021 was investigated using the information published in New Drugs for ^Tomorrow21).

New antimicrobial agents used in the previous study were defined as: 1) NMEs that fall under J01 (systemic antimicrobial agents) in the WHO Anatomical Therapeutic Chemistry Classification (ATC Classification), 2) NMEs that are not classified as generic drugs, topical drugs, drugs with other classification in the ATC Classification, or combination drugs containing no NMEs, and The EMA uses the term New Active Substance (NAS) for NMEs. (NAS) as the corresponding term for NME, but NME is used uniformly in this paper.

In the previous study, Bezlotoxumab (J06) and Fidaxomicin (A07), which are drugs for the treatment of Clostridioides difficile infection, were included in this study, even though they do not fall under J01, so they were treated in the same way.

In addition, the ^FDA22), ^EMA23), and the Pharmaceuticals and Medical Devices Agency (PMDA) ¹⁹⁾ websites were additionally searched for the same period (January 2010 to December 2021) to ensure that no omissions were made. In addition, the antimicrobial spectrum of the targeted antimicrobial agents was investigated, and the "List of Pathogens Targeted in AMR Drug Discovery Research (2021 Edition)" compiled by the Japan Agency for Medical Research and Development (AMED) ²⁴⁾ (AMED List), as indicated by the AMED Infectious Disease Drug Discovery Industry-Academia-Government Liaison Group Table 1 shows an excerpt from the AMED list.

Although the ^{WHO25) and the} U.S. Centers for Disease Control (CDC) ²⁶⁾ have issued such lists of pathogenic microorganisms that should be prioritized for development of new antimicrobial agents (Priority Pathogens List), the AMED list was created with more consideration given to issues in clinical practice in Japan. The AMED List also includes a list of pathogens that have been identified by the PTC. In the AMED List, Priority 1 is pathogens that are considered higher priority for AMR drug discovery research development, and antimicrobial agents with antimicrobial spectra against pathogens that fall under more than one Priority are classified in the higher Priority. Note that the antibacterial spectra estimated to be possessed by unapproved products in Japan were determined based on overseas approval information, etc., and may be different from those of the indicated organisms that will be approved in the future.

Results of Survey 2 4-1.

Results are shown in Tables 2 and 3. 18 products were included in the study, as in previous studies, based on additional searches of FDA, EMA, and PMDA websites.

Of the 18 products, 6 were approved in Japan as of December 2021 and 2 were currently under development in Japan. Four products had development history in Japan but were suspended or discontinued, and six products had no development history in Japan. The reasons for the suspension or discontinuation of the four products whose development was suspended or discontinued could not be confirmed from the publicly available information. Of the 10 products not yet developed in Japan, excluding the 6 products approved in Japan and the 2 products under development in Japan, a total of 9 products (4 and 5, respectively) fell under Priority 1 and Priority 2.

Survey 3 (Development status of new antimicrobial agents in Japan, Europe, and the United States) 5.

4-1. Methodology of Survey 3

The following three lists or websites were used to identify antimicrobial agents currently in development in Japan and overseas: 1) Antibiotics Currently in Global Clinical ^{Development27)} (at least one small molecule compound that acts systemically and has not been previously approved) 2) Nontraditional Products for Bacterial Infections in Clinical ^{Development28)} (a list of systemically acting non-small molecule modalities (e.g., antibodies and nucleic acid drugs) that have not been approved to date). ), 3) New Drugs for ^Tomorrow21), and 4) New Drugs for ^Tomorrow22).

The search definition of tomorrow's new drugs was defined by NME as those falling under Drug Classification Nos. 61 (antibiotics) and 62 (chemotherapeutics), and those falling under Drug Classification Nos. 617 (mainly acting against molds) and 625 (antivirals) and topical drugs were excluded from the survey. It should be noted that the search using tomorrow's new drugs was conducted in December 2021, so the information included in this survey is what was available on that website as of December 2021.

After merging the three lists, the following items were excluded: 1) items that were duplicated in the merged list, 2) items that were included in the "Development status of new antimicrobial agents approved overseas in Japan," which was shown in Survey 2, and items that were not included but were already approved in Japan, 3) items that mainly act on fungi or viruses, and 4) items that are not included in the list of new drugs approved in Japan. 3) those that act mainly on fungi or viruses, and 4) those that have not been developed in either Japan, the U.S., or Europe.

In addition, the development status and antibacterial spectrum of each of the developed products were investigated. The same method was used to sort the data as in Survey 2, but since Survey 3 covered products under development, a classification of "not applicable/unknown" was created by adding "unknown" to "not applicable". It should be noted that the antimicrobial spectrum that was determined to be possessed by the developed product was determined based on information available at the development stage (including the results of basic research) and may differ from the indicated strains for which approval will be obtained in the future.

Results of Survey 3

The results are shown in Table 4. Sixty products were identified according to the method. 51 of the 60 products had no development history in Japan. Of the 7 products with a development history identified in Japan, excluding the 2 products for which development was already discontinued, etc. (development suspended / development discontinued / approval withdrawn / no update of development information for more than 5 years), 1 product (solithromycin) was identified as having an application pending in Japan, but the public information after filing for approval in Japan in April 2019 was The status was not updated and the current status was unknown. In addition, this product was discontinued or suspended in the US and Europe after the application was submitted. Of the seven products, two (Gepotidacin and Nacubactam) were identified as being in Phase I studies in Japan, and the former was in Phase III studies in the US, while the latter's development in the US had been discontinued.

Of the 60 products, 2 and 11 were under submission and in Phase III trials in the U.S. and Europe, respectively. The development status in Japan for 13 of the 60 products was as follows: 11, 1, and 1 were not in development, development was discontinued, and Phase I trials were ongoing, respectively.

Table 5 shows the development status in the U.S. and Europe for the 51 products whose development history could not be confirmed in Japan. 17 products were also classified as discontinued in the U.S. and Europe. Of the remaining 34 products, 24 were either under regulatory review in the U.S. or Europe (1 product), in Phase 3 trials (10 products), or in Phase 2 trials (13 products). The antimicrobial spectrum of the one product under review and the 10 products in Phase III trials were confirmed to be potentially applicable to the AMED list, with five and six products in Priority 1 and 6 in Priority 2, respectively.

Summary of survey results and issues related to antimicrobial development

This paper presents the results of surveys on the number and percentage of antimicrobial agents approved in Japan (Survey 1), the status of development of new antimicrobial agents approved overseas in Japan (Survey 2), and the status of development of new antimicrobial agents in Japan, Europe, and the United States (Survey 3).

Survey 1 showed that the number of approved antimicrobial agents in Japan has decreased over time, and that more than 60% of those approved have a lag of five years or more after approval in Europe and the United States. Survey 2 showed that of the 18 new antimicrobial agents available in either Europe or the United States, only 6 are available in Japan as of December 2021. There are two aspects to the drug lag: one is "unapproved drugs" that are approved in other countries but not in Japan, and the other is "lag (delay)" in which drugs are also approved in Japan but the period required for approval is longer than in other ^countries17). The results of Surveys 1 and 2 indicate that both lags exist in antimicrobial drug development in Japan. Survey 3 showed that of the 60 products in development that have not been approved in all of Japan, the U.S., and Europe, 2 and 11 are under application and in Phase III trials, respectively, in the U.S. and Europe, while in Japan, only one product is under application and none were identified as being in Phase III trials.

There has been much discussion about the reasons for the difficulties in developing new antimicrobial agents. Many issues have been raised, including the difficulty in discovering antimicrobial agents with novel mechanisms of action and the difficulty in incorporating cases of AMR infection into clinical trials ^.) In this article, we will focus on "low profitability of antimicrobial agents" among these issues. The reason for this is that it is considered to be an important point as the reason why the development of antimicrobial agents in Japan lags behind that in Europe and the United States.

In general, antimicrobial agents, especially those with a broad antimicrobial spectrum and those expected to be effective against AMR, require more rigorous promotion of proper use than drugs in other disease areas. One of the reasons for this is that inappropriate use of antimicrobial agents is known to be one of the factors that promote an increase in ^AMR33). Given the mechanism by which AMR occurs and increases, it is essential that measures against AMR incorporate the concept of antimicrobial stewardship (AS), which supports the appropriate use of antimicrobial ^agents34), and that the patients to whom antimicrobial agents are administered, the amount used, and the duration of use are properly managed to maximize therapeutic efficacy. In other words, it is essential for pharmaceutical companies to provide broad-spectrum antimicrobials. In other words, even if a pharmaceutical company succeeds in the research and development of a new antimicrobial agent with a broad spectrum, the antimicrobial agent that is expected to be effective for AMR must be reserved for AMR infections, making it difficult to expect profits based on "usage or sales volume " ³⁵⁾.

In 2021, it was estimated that US$1.9 billion in annual global sales at peak would be required to make the development and marketing of antimicrobials a viable ^business35). However, only two antimicrobials launched after 2000 had peak global sales exceeding US$1 billion: Zyvox (US$1.353 billion in 2015; launched in April ²⁰⁰⁰³⁵ ) and Cubicin (US$1.312 billion in 2016; launched in November 2003 ^Launched35 )), indicating that it is not easy to achieve peak sales of US$1.9 billion.

Of the 60 products identified in Survey 3, 51 (85%, including 20 products whose development has already been discontinued or suspended in the U.S. and Europe) have no known development history in Japan, and when we checked the development companies for these 51 products, we found that most of them are not directly operating in Japan, but are biopharmaceutical companies that are not so-called "megapharma The majority of the 51 products were developed by bio-ventures or similar companies that are not "mega-pharma" and do not have direct operations in Japan. This point has been pointed out in previous analyses of unapproved drugs in ^Japan17). In order for such products to be developed directly in Japan by overseas development companies or introduced and developed in Japan by companies operating in Japan, a system to enhance the predictability of the antimicrobial drug business in Japan is required.

Typical economic support mechanisms to enhance the predictability of the antimicrobial drug business include "push-type incentives" until approval is obtained and "pull-type incentives" to provide support after approval is ^obtained35). There are a number of organizations overseas engaged in activities to raise the funds needed for push-type incentives and to promote antimicrobial R&D, primarily supporting antimicrobial drug research and development at university research institutes and bio-ventures. Push-type incentive activities are more active overseas than in Japan, and it is conceivable that this may have had a small impact on the difference in the number of antimicrobials developed between Japan and the West. However, in July 2020, the AMR Action ^Fund36) was established by more than 20 major pharmaceutical companies, including Japanese pharmaceutical companies, with the objective of commercializing and bringing two to four new antimicrobial agents to patients by 2030. The fund is an initiative of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), and the Japan Pharmaceutical Manufacturers Association has contributed to its establishment as an IFPMA member. It is expected that Japanese pharmaceutical companies and bio-ventures will use the Fund to promote research and development of antimicrobial agents in Japan.

On the other hand, the scale of the pull-type incentive amount is mentioned in ^{the proposal37)} compiled by the AMR Subcommittee of the Asia-Africa Consortium for Medical Innovation. Under the "Subscription Model (SM)," which is a system of continuous payment of a fixed amount that is separated from the revenue from sales, it is proposed that the amount required for Japan is about 2-8 billion yen per year per product, and the payment period is assumed to continue for 10 years after the product is launched. The payment period is assumed to continue for 10 years after the product is launched. Another method is the Market Entry Reward (MER). Under this system, pharmaceutical companies receive revenue based on the volume of antimicrobials sold, but in addition, they are guaranteed a certain amount of money for their investment in research and development of antimicrobials, and it is proposed that the amount should be 10 to 30 billion yen per product. The aforementioned ^paper35) reports that the world as a whole needs US$3.1-4.2 billion for SM (total for 10 years) and US$1.6-2.2 billion for MER (one-time payment). In the U.S. and the U.K., legislation to support antimicrobial drug development, including pull-type incentives, has been ^{proposed38, 39)} or introduced on a trial ^basis40), and discussions on the amount of money needed as pull-type incentives in their countries have already begun with the participation of their governments. Table 6 shows the status of efforts in the U.S. and the U.K.

Although it is difficult to estimate the number of antimicrobial agents that will be developed in Japan in the future from the results of this survey, at least the "4 products" shown in Survey 2 that are already approved in the U.S. and Europe but not developed in Japan and fall under Priority 1 of the AMED list and the "4 products" shown in Survey 3 that are under submission or in Phase III trials in the U.S. and Europe but not yet developed in Japan are included. Details of the nine products are shown in Table 7. Furthermore, the AMED list states that "AMR research requires breakthroughs at all times, so it is necessary for AMR research to support approaches from new perspectives, regardless of Priority. This means that support for development of innovative antimicrobial agents with unconventional mechanisms of action is required regardless of Priority, in addition to support for antimicrobial agents that act against Priority pathogens.

The survey results presented in this paper include the following limitation: First, the domestic and international development information was surveyed using public information and tomorrow's new drugs that cite public information, but there may be development information and products that companies have not disclosed publicly. As a result, in Survey 3, more products were counted as being in Phase 2 or Phase 3 trials than as being in preclinical or Phase 1 trials. Third, whether a developed product falls under the AMR treatment or AMED list is estimated based on information at the development stage (including the results of basic research), and if the product is developed and approved in Japan, the indications and bacterial species may differ. The development of drugs for the treatment of AMR infections is particularly important.

6. conclusion

The development of drugs for the treatment of AMR infections is a particularly urgent issue for Japan, and awareness of the need for economic incentives to stimulate the development of antimicrobial agents is growing in Japan. Although economic incentives require financial resources, the former is clearly less when compared to the economic impact and damage caused by infectious diseases, and COVID-19 has made us deeply aware of the importance of investing in advance and taking measures to treat AMR infections. The cost of antimicrobial drug development, including drugs, and the financial resources needed for economic incentives require a perspective that considers them as "investments in national security, not costs. On the other hand, since there are slight differences among countries in terms of the pathogens among AMR for which the development of therapeutic agents should be prioritized, Japan needs to be prepared accordingly in its own country.

It is hoped that the introduction of such an economic incentive system in Japan will promote the research, development, and marketing of new antimicrobial agents, and will help prepare the country for what is called a silent pandemic of AMR.

7. acknowledgements

In writing this paper, we received advice from Yusuke Ariyoshi and Yoshinori Yamano of the International Committee of the Japan Pharmaceutical Manufacturers Association (JPMA). We are deeply grateful for their cooperation.

(Added on March 7, 2022: The results of Survey 2 have been revised.)

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