Policy Research Institute page Nationalities of patent generating organizations for NME-approved products in Japan, the U.S. and Europe Comparison of Approved Drugs Containing New Active Pharmaceutical Ingredients in Japan, the U.S., and Europe

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In a comparison of the nationalities of patent application organizations for global new molecular entities (NMEs) approved in Japan, the U.S., and Europe from 2013 to 2021, Japan was the second largest creator country in the world after the U.S. in terms of total number of patent applications. However, the number of patents created declined after 2016, and was overtaken by Switzerland for third place in the total number of patents created in the three-year period from 2019 to 2021. A breakdown of modalities in Japan shows that the number of small molecule drugs (small molecule drugs) created was less than one-third of the total after 2016. Non-low-molecule modalities increased; the share of breakthrough drugs (first-in-class, FIC) in NMEs did not decrease. The decline in NME creation in Japan was due to the decline in small molecules and the failure of the increase in other new modalities to compensate for this decline.

1. Introduction

In addition to this, the Institute for Policy Studies (IPS) has been continuously surveying and reporting on the companies that created drugs at the time of application for each of the top 100 pharmaceutical products in terms of global sales*1, and has also conducted a survey in Japan, the U.S., and Europe of companies that created drugs as New Molecular Entities (NME) to determine the actual creation of new drugs and overall trends. The results show that Japan is the second largest producer of NMEs approved in more than two regions, indicating that Japan is in a certain position in the world. 3 The results showed that Japan is the second largest creator of new drugs approved in two or more regions, indicating that Japan has a certain position in the world. On the other hand, it was also apparent that the number of drugs of Japanese origin and their share in the total number of drugs has been declining in recent years.

There are various stages before a drug is released into the world. These include the elucidation of disease mechanisms in basic research, the search for drug candidate seeds, the refinement of seeds in terms of efficacy and toxicity in applied research, clinical development, manufacturing, regulatory affairs, and licensing activities, among others, before a drug is approved. In this report, based on an update of the report*3 focusing on "new drug creation capabilities" in the initial basic research stage, we conducted a nationality survey of patent creation organizations for NME products approved in Japan, the U.S., and Europe, and extracted their characteristics and issues in Japan.

Survey Methodology

The survey covered items approved as NMEs in Japan, the U.S., and Europe during the nine-year period from 2013 to 2021, and items approved in two or more regions were defined as globally approved items. From 2020 onward, based on the latest status of new drug approvals, items identified as NMEs by each reviewing organization were selected, and basic patents were identified for each item according to the method described below. The year in which the NME was first approved was used as the approval year for that NME. The number of NMEs is different from that in the previous survey*3 because some NMEs that were approved in multipolar regions were added in this survey. NME information extracted from the Evaluate Pharma (R) database*5 was collected and supplemented.

The basic patents for each product were identified using Cortellis Competitive Intelligence of Clarivate Analytics, and the patents classified as "Product" and "Patent" for each product were used. The nationality of the patent generating organization was previously determined by a search*. The nationality of the patent generating organization was the nationality of the applicant/assignee listed in the above patents, as in previous surveys*2*3. In cases where there were multiple applicants and their nationalities spanned two countries, 0.5 was assigned for each (none for three or more countries).

Modalities were classified based on "Technology" in Cortellis Competitive Intelligence. The classification of drug efficacy was based on The Anatomical Therapeutic Chemical code (ATC code) of each item, referring to the "ATC/DDD Index 2023" *6 of the World Health Organization (WHO).

The drug's innovativeness was judged as a breakthrough drug (First-in-Class, FIC). The U.S. Food and Drug Administration (FDA) annually announces FICs for drugs approved in the U.S. that have a mode of action (MOA) that is different from that of existing drugs approved in the U.S. *7 Therefore, FDA-approved items were designated as FICs based on the FDA-approved items. For items approved by the Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA), FICs are those with the first MOA listed in the drug market in each country. Both were extracted from the Evaluate Pharma(R) database*5, and items determined to be FICs at either pole were designated as FIC products.

The founding years of the various institutions were extracted from Evaluate Pharma (R) *5, and those missing were checked on the company websites. Japan HQ companies were extracted from Pharmaprojects(R) /Citeline*8.

Results

3-1. NMEs approved in two or more regions (Japan, the U.S., and Europe)

Of the NMEs approved during the nine-year period from 2013 to 2021, 341 items were extracted from those approved in two or more regions (globally approved items), namely Japan, the U.S., and Europe ( Fig. 1 ). The U.S. was the leading country in terms of NMEs approved, accounting for 199 items, followed by Japan with 33.5 items, Switzerland with 23.5 items, the U.K. with 17 items, and Germany with 16 items.

The annual trend of the number and percentage of these 341 products approved in each country based on the year of approval is shown in the table below. Japan was second to the U.S. in the total number of approvals for the entire period, but the number of approvals by year was 18 (15%) from 2012 to 2015, 8 (7%) from 2016 to 2018, and 7.5 (7%) from 2019 to 2021, showing that both the number of products and their share of the total dropped by half in the latter half of the 2010s. In terms of country ranking by year, Japan was in second place from 2013 to 2015 and from 2016 to 2018, but in the three-year period from 2019 to 2021, it was overtaken by Switzerland, which doubled both the number of products and their share during this period, to take third place, confirming the decline in new drug creation capacity originating from Japan.

Figure 1: Nationalities and annual trends of globally approved items created
Note 1: Number is the number of items. When more than one organization is listed as an applicant, the number is divided equally by nationality.　　
Note 2: Items approved in two or more regions (Japan, the U.S., and Europe) and approved for the first time by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, and EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

3-2. modality characteristics of globally approved items

An examination of the modalities of all 341 drugs shows that the number of small molecule drugs approved was always the highest in the triennial tally from 2013 to 2021, but decreased over time (from 75 to 60 to 56 drugs) ( Figure 2 ). The percentage, on the other hand, decreased by 12 percentage points from 63% to 51% between 2013-2015 and 2016-2018, but increased by 3 percentage points to 54% in the following period, 2019-2021. More than 50% of the approved products were always small molecule drugs; the second largest category was monoclonal antibodies, with a three-year trend of 16 to 26 to 18 products and a percentage of 13% to 22% to 17%. We looked at the modalities that have attracted attention in recent years, such as antibody-drug conjugates (ADCs), nucleic acids, chimeric antigen receptor-T cells (CAR-T) and gene therapy ( Table 1 ), The number of ADCs began to increase after 2016, with a three-year trend of 1 to 2 to 5, nucleic acids from 1 to 3 to 4, CAR-T from 0 to 2 to 2, and gene therapy from 0 to 1 to 1.

Although the number of new modalities other than small molecules is increasing, small molecules accounted for more than half of the globally approved products.

Figure 2 Modality Yearly Trends
Note: Items approved in Japan, the U.S., and Europe in two or more regions and first approved by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

Table 1 Annual Trends in Various Modalities

3-3. Modality Trends by Nationality of Patent Generating Organization

For the top five countries in global approved product creation (U.S., Japan, Switzerland, U.K., and Germany), the number and percentage of products of each modality in each country were compiled as annual trends. Figure 3 shows the number of products of Japanese origin. 17 out of 18 products were small molecules in 2013-2015, but in the following three years, 2016-2018, the number of small molecules decreased to 5, less than a third of the number in the previous three years. 4.5 products did not increase in 2019-2021. For non-small molecule modalities, the number of drugs increased from one in 2013-2015 to three in 2016-2018 and three in 2019-2021. The percentage of small-molecule drugs went from 94% to 63% to 60%. In Japan, the number of small molecule modalities has decreased since 2016 and the number of non-small molecule modalities has increased, but not enough to compensate for the decrease in small molecule drugs in number, resulting in a decrease in the number of products to less than half since 2016. rate of 92%, data omitted), indicating that the 2013-2015 period was not a one-time increase, but a decline in Japan from 2016 onward, with the decline in small molecule drugs being the primary reason for this.

Figure 3 Annual Trends in Modalities of Japanese Creation
Note: Items approved in Japan, the U.S., and Europe in two or more regions and first approved by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

Next, we compiled the three-year trend of the modality by country of creation for the top four countries other than Japan (the U.S., Switzerland, the U.K., and Germany) ( Figure 4 ). The U.S., which has the largest number of products created, had a large number of products in a variety of modalities, including high-profile modalities such as nucleic acids and CAR-T. However, there was no clear downward trend in the number of small molecule drugs or the ratio of small molecule drugs to products (number of products: 29 → 38.5 → 31.5; ratio: 52% → 47%; number of products: 38.5 → 31.5), Percentage: 52%→47%→51%).

European countries with a similar number of products to Japan showed characteristics in the positioning of small molecule drugs. In Switzerland, the change in the number of low-molecular-weight drugs from 2013 to 2015, 2016 to 2018, and 2019 to 2021 was 7 items → 3.5 items → 7 items, and the overall number of items was low in 2016 to 2018 when the number of low-molecular-weight drugs was low. The percentage of low-molecular-weight drugs in the total number of items remained above 70% in both periods, ranging from 78% to 78% to 70%. The United Kingdom showed a decrease over time in the number of small molecule drugs from 6 to 2 to 1 and the percentage from 86% to 33% to 25%. The number of non-low-molecular-weight drugs increased from 1 to 4 to 3, with new modalities compensating for the decrease in low-molecular-weight drugs to some extent, holding down the overall decrease in the number of drugs. In Germany, the number of low-molecular-weight drugs ranged from 2 to 2 to 3, and the percentage shifted from 40% to 67% to 60%.

From the trends in Japan, the U.S., and Europe, it appeared that low-molecular-weight drugs underpin the overall number of products in each country, and the total number of products is determined by the extent to which other modalities can compensate for the decline in the number of low-molecular-weight drugs.

Figure 4 Annual Trends in Modalities of Top Countries in Number of Creations
Note: Items approved in Japan, the U.S., and Europe in two or more regions and first approved by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

3-4. characteristics of each country in terms of disease drug classification

In order to explore the characteristics of disease areas, we examined the percentage of all 341 drugs and the top five countries in the number of drugs approved by disease area for each of the three years ( Figure 5 ). In all, the top six disease drug classes (from top to bottom: ATC code L01, J, J, A, B, L04, and N) accounted for more than 70% of all diseases in each of the three years. A closer look at these top disease drug categories by triennium shows that the percentages of malignant tumor agents (L01) and immunosuppressants (L04) increased with each passing year, while those of systemic anti-infectives (J), gastrointestinal tract and metabolic agents (A), and hematopoietic agents (B) decreased. The disease-drug classification of drugs of Japanese origin did not show any tendency to specialize in any one area, but rather covered diseases similar to the disease-drug classification of the triad as a whole. While the percentage of anti-cancer drugs (L01) remained unchanged, the percentage of systemic anti-infectives (J) was higher than the total. In the U.S., where L01s account for more than half of the total number of drugs, the growth rate of L01s was similar to that of the total. European countries also had the largest percentage of anti-cancer drugs (L01), while other disease areas differed among countries, but none of them showed characteristic disease trends (data omitted in both cases).

Figure 5 Annual Trends in Classification by Disease Drug (Percentage; Japan, Global)
Note: Items approved in Japan, the U.S., and Europe in two or more regions and first approved by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

Next, we looked at the characteristics of small molecule drug items by disease ( Figure 6 ). In Japan and overall, approved small molecules were not biased toward any particular disease area. Similarly, in Europe and the U.S., there was no particular disease area bias in small molecules (data omitted).

Figure 6 Annual Trends in Classification by Disease Drug (Number of Small Molecular Drug Items; Japan, Global)
Note: Items approved in Japan, the U.S., and Europe in two or more regions and first approved by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

3-5. Comparison of Patent Generating Organizations in Japan and the U.S.

In order to see the characteristics of institutions in patent applications for small molecule drugs, we categorized institutions into those established before and after 1990 (including 1990) and compared them to those in Japan and the U.S. ( Table 2 ). In the U.S., 44 (46%) of the 95 small molecule drug applications, excluding four that could not be identified, were filed by institutions founded in 1990 or later. In Japan, on the other hand, there were no small molecule products from institutions founded in 1990 or later.

Table 2 Japan-US Comparison of Basic Patent Application Organizations

Next, we looked at annual trends in the U.S. ( Table 3 ): from 2013 to 2015, 2016 to 2018, and 2019 to 2021, the number of items for all institutions shifted from 29 to 36 to 30, while the number of items for institutions founded in 1990 or later shifted from 9 (31%) to 17 (47%) to 18 (60%). The percentage of the institutions established after 1990 was 9 (31%) to 17 (47%) to 18 (60%). In addition, when the number of items in institutions that had been in the market for 30 years or less since their establishment was counted, the percentage of items in the institutions that had been in the market for 30 years or less since their establishment was 15 (52%), 21 (58%), and 19 (63%), respectively. The results suggest that in the U.S., institutions established after 1990 or within 30 years of the global approval of a product are the driving force behind the creation of new drugs, even for small molecules.

Table 3 Annual Trends in the US

3-6. Number of R&D Products of Pharmaceutical Companies Headquartered in Japan (Japan HQ Companies)

Since pharmaceutical companies were responsible for all basic patent applications for globally approved products in Japan ( Table 2 ), we analyzed the pipeline transition by modality for pharmaceutical companies headquartered in Japan ( Figure 7, but note that the R&D items include in-licensed products, etc.). Looking at the number of preclinical research items by modality for Japan HQ companies, the number of Chemicals research items decreased from around 1998 to 2002, and did not increase until 2012. The number of biologicals research items increased during that period, but the increase was small compared to the decrease in the number of chemicals. The decrease in the chemical pipeline suggests that small molecule drug discovery research became less of a priority during this period.

Although not directly related to the "ability to create new drugs" as seeds in the early stages of research, Phase II and Phase III have remained flat or declined since around 2010, which may also have influenced the decline in the number of drug approvals. In addition, the number of small molecule drugs in Phase II and Phase III has also been decreasing. In addition, the Phase II and III levels of small molecule drugs are higher than those of biologicals, but they have not yet been approved, so it is possible that small molecule drug discovery as an extension of conventional approaches has become more difficult. The number of preclinical stage small molecule drug studies has not declined in the US HQ Company as it has in Japan (data omitted).

Figure 7 Number of R&D items in Japan HQ Company

3-7. comparison of characteristics of each country in terms of innovativeness

As an evaluation of the ability of each country to create innovative new drugs, we conducted a survey on drugs that have been launched as FICs ( Figure 8 ). The number of FIC products in this survey was 188 over the nine-year period 2013-2021. The U.S. was the top country with 118.5 FICs. In the three-year trend, the number of FICs approved in the U.S. went from 33 to 42 to 43.5, and the percentage of FICs approved in the U.S. went from 53% to 71% to 65%. Japan went from 10 products to 5 products to 3.5 products, Switzerland from 3 products to 3 products to 6 products, the UK from 3 products to 2 products to 3 products, and Germany from 4 products to 2 products to 2 products.

Fig. 8 Top countries for FIC creation and transition
Note 1: Number is the number of items. When more than one organization is listed as an applicant, the number is divided equally by nationality.　　
Note 2: Items approved in two or more regions (Japan, the U.S., and Europe) and approved for the first time by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, and EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

By modality, 96 of 188 drugs, or more than half, were small molecules ( Fig. 9 ). Monoclonal antibodies accounted for 44 items. The number of low-molecular-weight drugs approved every three years was 38, 25, and 33, and the percentage of low-molecular-weight drugs was 61%, 42%, and 49%.

Fig. 9 FIC modality and transition
Note 1: Number is the number of items. When more than one organization is listed as an applicant, the number is divided equally by nationality.　　
Note 2: Items approved in two or more regions (Japan, the U.S., and Europe) and approved for the first time by one of the reviewing authorities in 2013 or later.
Source: Created by the Pharmaceutical Industry Policy Institute based on publicly available information from PMDA, FDA, and EMA, and Clarivate Analytics Cortellis Competitive Intelligence,
Evaluate Pharma (R) (as of August 2023)

We then calculated the ratio of FICs to approved items in each country ( Table 4 ), and found that for the nine-year period 2013-2021, the overall ratio of FICs to approved items was 55%. The U.S. exceeded the overall 55% with 60% for the full year. Japan was 55%, the same as the total, and the three-year trend was as follows: the United States; 59% to 52% to 71%; Japan; 56% to 63% to 47%; Switzerland; 33% to 67% to 60%; the United Kingdom; 43% to 33% to 75%; and Germany; 50% to 67% to 40%, with FIC rates ranging from 33-75%. The FIC ratio in Japan remained unchanged, suggesting that this was not a qualitative decline. However, the FIC ratio has increased in the U.S., Switzerland, and the U.K., suggesting that Japan will need to increase its FIC ratio in the future.

Table 4 FIC percentage of approved items

Conclusion and Discussion

We examined the country of affiliation of the basic patent application organization for global products that were approved in at least two of the poles, either Japan, the U.S., or Europe, from 2013 to 2021. Japan was the second largest applicant country for the total number of years covered by the survey, but was the third largest in the most recent period, 2019-2021. The main reason for the decline was due to a decrease in the creation of small molecule drugs. The U.S. had an increase in the number of non-small molecule modality products, but the percentage of small molecule drugs was still above 50% in the most recent period. In European countries, there is a correlation between the total number of products and the number of low-molecular-weight drugs, and the number of non-low-molecular-weight modalities has not compensated for the decline in the number of low-molecular-weight drugs. The survey shows that although the percentage of small molecule drugs has been decreasing overall, they still account for 50% of the total number of drugs in the latest survey, suggesting that small molecule drugs are supporting the total number of drugs created in each of the three regions.

Looking back at trends in drug discovery modalities, the diversification of drug discovery modalities has sprouted from traditional small molecule drug discovery research, and drug discovery research in modalities other than small molecules has advanced dramatically. The center of this drug discovery research was carried out by U.S. bio-ventures. On the other hand, looking at small molecules, about half of all modalities in the U.S. are still small molecules, and these originate from institutions that have been in business since 1990 or have been in operation for less than 30 years since their approval. The survey showed that the percentage increased with each year of survey. We have reported*9 that venture-originated small molecule drugs and large companies coexist in the U.S., and the number of preclinical stage small molecule drug studies has not declined in U.S. HQ companies (data omitted). The number of preclinical stage small molecule drugs has not declined at HQ companies in the U.S. (data omitted).

In Japan, on the other hand, the number of products has decreased since the late 2010s, but this is due to a decline in the number of small molecule drugs created and sluggish growth in the number of biotech drugs created, and a comparison with other countries reveals both aspects. Looking at the number of research items in Japan HQ Company, the number of small molecule drug research has been rapidly declining since the 2000s ( Figure 7 ). The median time from the filing of a basic patent application to its approval is 10 years (for both Japan, the U.S., and Europe, data omitted), and most of the basic patents in this study were issued in the 2000s, indicating a time overlap between the decline in the number of small molecule drug research items and the timing of patent applications. We have reported that the number of published patents on small molecule drug targets by Japanese domestic pharmaceutical companies has been decreasing since its peak in 2003*10. Various reports in the 2000s actively called for the superiority of novel modalities over small molecules and Japan's lagging behind in the field of novel modality research .11*12*13 Based on the above and this survey, the decline of small molecule drugs in Japan can be explained by the fact that the number of small molecule drugs in Japan has been decreasing since the 2000s. These and the current survey suggest that the decline in small molecule drugs in Japan is due to the declining priority given to small molecule drug discovery research in the 2000s.

Few items of Chinese origin were included in the survey. In the 2000s, when most patent applications were filed, there was still not much drug discovery research in China. However, the increasing presence of China in drug discovery in recent years suggests that the number of items of Chinese origin is expected to increase in the near future.

Although the modality should be selected based on what is best suited for the treatment of the target disease, there are still many mechanisms that can be handled by small molecules. It has been said that the areas that can be targeted with small molecules have been almost completely explored, but on the other hand, half of the modalities of both novel NMEs and FICs are small molecules. By increasing the specificity of target molecules through detailed molecular profiling and reducing the affinity for other molecules that may cause side effects, small molecules can now be used to control the disease in ways that were previously thought to be impossible. Furthermore, it is possible to increase targeting to organs and enhance drug efficacy by combining small molecules with small molecules and macromolecules*14*15. Knowledge of small molecule drug discovery is also needed in the design of new modalities such as small molecules, targeted protein degradation (TPD), ADCs, and nucleic acid modifications. There is still much room to utilize Japan's expertise in small molecule drug discovery. The wider the scope of basic research, the greater the potential for expansion*16. Therefore, a comprehensive policy that supports not only drug discovery of new modalities but also small molecule drug discovery may be necessary.

Conclusion

In this study, it was suggested that the priority of small molecule drug discovery research in Japan is declining. In addition, it is important to investigate the actual situation in which small molecule drugs have not decreased in the U.S. as a contrast, in addition to the changes in the pipelines of Japanese companies, trends in research in disease areas in academia, collaborative research, and investigation of the actual status of support from the government. This will be an important research issue in the future to investigate the factors behind the decline in Japan's ability to create small molecule drugs.

( Kiyoshi Morimoto, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute)

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