The Pharmaceutical Industry at a Glance Comparison of nationalities of patent generating organizations for NMEs approved 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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Kiyoshi Morimoto, Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute

SUMMARY

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 of NMEs in the world after the U.S. in total. 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 2019-2021. A breakdown of modalities in Japan shows that the number of small molecule drugs (small molecule drugs) created was less than 1/3 of the total after 2016. The number of non-small molecule modalities increased; the percentage of first-in-class NMEs did not decrease. The decline in the number of NMEs created in Japan was due to the decline in small molecule drugs and the fact that the increase in other new modalities did not compensate for this decline.

1. Introduction

The National Institute of Biomedical Innovation Policy (NIBIO) has been continuously surveying and reporting on the top 100 pharmaceutical products in terms of global sales by examining the basic ^{patents1) of} each product and the companies that were creating drugs at the time of ^filing2). In addition, Shibukuchi conducted a nationality survey of companies that created drugs approved as New Molecular Entity (NME) in Japan, the U.S., and Europe in order to understand the results of new drug creation and overall trends, and compared not only those with the largest sales but also those that created new drugs approved globally as a whole3). The results ^of the survey showed that the nationalities of the companies that created the drugs approved in two or more regions were compared.) The results showed that Japan was the second largest creator country for products approved in two or more regions, indicating that Japan has a certain position in the world. On the other hand, the number of drugs of Japanese origin and their share in the total number of drugs have been decreasing in recent years.

There are various stages before a drug is released to the market. 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. Based on an update of Shibukuchi's ^report3), which focused on the "ability to create new drugs" in the first stage of basic research, this report surveys the nationality of patent creation organizations for NME products approved in Japan, the U.S., and Europe, and extracts their characteristics and issues in Japan.

Survey Methodology

The survey covered NMEs approved in Japan, the U.S., and Europe during the nine-year period from 2013 to 2021, and those approved in two or more regions were defined as globally approved NMEs. After 2020, based on the latest new drug approval status, items identified as NMEs by each reviewing organization were selected, and the basic patents were identified for each item according to the method described below. The year at the first approval pole was used as the approval year of that NME. The number of NMEs is different from that in the previous ^survey3), since only a unipolar NME was approved in the previous survey, while a multipolar NME was added in the current survey. NME information extracted from Evaluate Pharma's ^database5) was collected and supplemented.

The basic patents for each product were obtained from Cortellis Competitive Intelligence of Clarivate Analytics, and the patents classified as "Product" were extracted from the patents in "Patent" of each product. The nationalities of the patent generating organizations were identified based on the patents classified as "Product" in the "Patent" category for each item. The nationality of the patent generating organization was the nationality of the applicant/assignee listed in the above patents, as in previous surveys ^{2) and 3)}. In cases where there were multiple applicants and their nationalities spanned two countries, 0.5 was assigned for each (there were no cases where there were more than three countries). Some products could not be identified due to lack of patents or other reasons.

Modalities were classified based on "Technology" in Cortellis Competitive Intelligence for each product. The classification of drug efficacy was based on The Anatomical TherapeuticChemical code (ATC code) of each product, referring to the WHO ATC/DDD Index 20236 ⁾.

Drug innovativeness was judged as first in class (FIC); the FDA annually announces drugs approved in the U.S. as first-in-class if they have a mode of action (MOA) that is different from existing drugs approved in the U.S. (7). For PMDA- and EMA-approved drugs, FICs are those that are the first MOA listed in the drug market in each country. Both were extracted from Evaluate Pharma's ^database5), and the items judged as FIC at either of the poles were designated as FIC items.

The founding years of the various institutions were extracted from Evaluate ^pharma5), and those missing were checked on the company's website. Japanese HQ companies were extracted from Pharma ^projects8).

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, those approved in two or more regions (globally approved products) were extracted, resulting in 341 products (Fig. 1). The U.S. was the largest source country, 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 below, with the United States leading in both number and percentage for each of the three years since 2013. Japan was second only 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 had decreased by half since the latter half of the 2010s. In terms of country ranking by year, Japan was in second place in 2013-2015 and 2016-2018, but in the three-year period 2019-2021, it was overtaken by Switzerland, which doubled both the number of items and percentage of total items during this period, to take third place, confirming the decline in new drug creation capacity originating from Japan.

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 2013-2021 triennial count, 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%. The number of antibody-drug conjugates (ADCs), nucleic acids, chimeric antigen receptor-T cells (CAR-T), gene therapy, and other modalities that have attracted attention in recent years (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 has been increasing, it was found that small molecules accounted for more than half of the globally approved products.

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

For the top five countries in global approved product creation (the U.S., Japan, Switzerland, the U.K., and Germany), the number of items and their percentages for each modality in each country were compiled as annual trends. Figure 3 shows the number of items originating from Japan. 17 out of 18 items in 2013-2015 were small molecule drugs, but in the following three years, 2016-2018, the number of small molecule drugs decreased to 5, less than 1/3 of the previous three years. 4.5 items in 2019-2021 did not increase either. In modalities other than small molecules, the number of drugs increased from one in 2013-2015 to three in 2016-2018 and three in 2019-2021. The share of small molecule drugs went from 94% to 63% to 60%. In Japan, the number of small molecule modalities decreased after 2016 and the number of non-small molecule modalities increased, but this was not enough to compensate for the decrease in small molecule drugs in terms of numbers, resulting in the number of items decreasing by less than half after 2016. 14 items of Japanese origin drugs in the three-year period 2010-2012 (small molecule rate 92 %, data omitted), indicating that 2013-2015 was not a one-time increase, but a decrease in Japan since 2016, with the decrease in low-molecular-weight drugs being the main reason for this.

Next, we tabulated 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 acid and CAR-T. 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% → 51%): 52%→47%→51%).

European countries with a similar number of products to Japan showed distinctive characteristics in the positioning of small molecule drugs. In Switzerland, the number of low-molecular-weight drugs in 2013-2015, 2016-2018, and 2019-2021 ranged from 7 to 3.5 to 7. In 2016-2018, when the number of low-molecular-weight drugs was low, the total number of drugs was also low. The percentage of low-molecular-weight drugs in the total number of items has remained above 70% in both periods, ranging from 78% to 78% to 70%. In the United Kingdom, the number of small molecule drugs decreased over time 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 ratio of low-molecular-weight drugs ranged from 40% to 67% to 60%.

The trends in Japan, the U.S., and Europe indicate that small molecule drugs support the total number of products in each country, and the total number of products tends to be determined by the extent to which other modalities can compensate for the decline in small molecule drugs.

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

In order to explore the characteristics of the disease areas, we examined the percentage of the total number of 341 drugs and the number of drugs approved in the top five countries by disease area for each of the three years (Figure 5). The top six disease drug classes (from top to bottom: ATC code L01, J, GI and metabolic agents, A, B, L04, and N) accounted for more than 70% of all diseases in each of the three-year periods. 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 and metabolic agents (A), and hematopoietic agents (B) decreased. The disease-drug classification of drugs of Japanese origin showed no tendency to specialize in any area, indicating that they target diseases similar to the disease-drug classification of the triad as a whole. The percentage of anti-cancer drugs (L01) remained unchanged, while 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 antineoplastics (L01), but other disease areas differed among countries, but none of them showed characteristic trends of diseases (data omitted in both cases).

Next, we looked at disease-specific characteristics of small molecule drug items (Figure 6). In Japan and overall, there was no bias in the approved small molecule items toward specific disease areas. Similarly, in Europe and the U.S., there was no particular disease area bias in small molecules (data omitted).

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, a comparison was made between Japan and the U.S. by categorizing institutions founded before and after 1990 (including 1990) (Table 2). In the U.S., 44 (46%) of the 95 small molecule drugs, excluding the four drugs that could not be identified, were founded in 1990 or later. In Japan, on the other hand, there were no small molecule products from institutions founded in 1990 or later.

Next, we looked at annual trends in the U.S. (Table 3): from 2013-2015, 2016-2018, and 2019-2021, the number of items for all institutions shifted from 29 to 36 to 30, while the number of items for institutions founded after 1990 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%). Separately, the number of items in institutions that had been in the market for 30 years or less from their establishment to the launch of their products shifted from 15 items (52%) to 21 items (58%) to 19 items (63%).

The results suggest that in the U.S., institutions established after 1990 or within 30 years of global approval of a product are the driving force behind the creation of new drugs, even for small molecules.

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). (Figure 7, but note that this R&D item also includes in-licensed products, etc.). Looking at the number of preclinical research items by modality for the Japanese 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 this period, but the increase was small compared to the decrease in the number of chemicals. This 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, the number of Phase II and Phase III drugs has remained flat or declined since around 2010, and this may also have influenced the decline in the number of drug approvals. 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 drug discovery has become more difficult. The number of preclinical stage small molecule drug studies has not declined in the U.S. HQ Company as in Japan (data omitted).

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

The definition of FIC is described in the section "Research Methods" in the main text. There were 188 FIC items in this study over the nine-year period 2013-2021. The U.S. was the leader overall with 118.5 items. Japan was second with 18.5 items. In the three-year trend, the number of approved products in the U.S. went from 33 to 42 to 43.5, and the percentage of approved products in the U.S. went from 53% to 71% to 65%. Japan went from 10 items to 5 items to 3.5 items, Switzerland from 3 items to 3 items to 6 items, the United Kingdom from 3 items to 2 items to 3 items, and Germany from 4 items to 2 items to 1 item.

By modality, 96 of 188 drugs, or more than half, were small molecule drugs (Fig. 9). This was followed by 44 monoclonal antibodies. The number of low-molecular-weight drugs approved every three years ranged from 38 to 25 to 33, and the percentage of low-molecular-weight drugs ranged from 61% to 42% to 49%.

Next, the percentage of FICs to approved products in each country was calculated (Table 4), and the overall percentage of FICs to approved products was 55% for the nine-year period 2013-2021. The United States exceeded the overall 55% with 60% for the full year. Japan's FIC ratio was 55%, the same as the overall ratio. 3-year trends were as follows: USA; 59% to 52% to 71%; Japan; 56% to 63% to 47%; Switzerland; 33% to 67% to 60%; UK; 43% to 33% to 75%; Germany; 50% to 67% to 40%, with FIC rates ranging from 33-75%. The FIC ratio in Japan remained unchanged, suggesting that it was not a qualitative decline. However, since the FIC ratio is increasing in the U.S., Switzerland, and the U.K., Japan will need to increase its FIC ratio in the future.

Conclusion and Discussion

We examined the country of affiliation of the basic patent application organization for global products that were approved in two or more of the poles of either Japan, the U.S., or Europe during 2013-2021. Japan was the second largest applicant country for the total number of years covered by the survey, but in the most recent period, 2019-2021, it was the third largest applicant country. The main reason for this decline was due to a decrease in the creation of small molecule drugs. The U.S. had also increased the number of non-small molecule modality products, but the percentage of small molecule drugs still exceeded 50% in the most recent period. In European countries, there was a correlation between the total number of products and the number of low-molecular-weight drugs, and the number of modality products other than low-molecular-weight drugs did not compensate for the decrease. The survey showed that although the percentage of low-molecular-weight drugs has been decreasing overall, they still accounted for 50% of the total number of drugs in the latest survey, suggesting that low-molecular-weight drugs are supporting the total number of drugs created in all three regions.

Looking back at trends in drug discovery modalities, the diversification of drug discovery modalities has sprouted from conventional small molecule drug discovery research, and drug discovery research in modalities other than small molecules has advanced dramatically. American bio-ventures played a central role in this drug discovery research. 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 has increased with each year of survey. In the U.S., we have ^reported9) that venture-originated small molecule drugs and large companies are coexisting and prospering together. In addition, the number of preclinicalstage small molecule drug studies has not declined in the U.S. HQ Company (data omitted). This suggests that small molecule drugs are supporting the maintenance of the total number of small molecule drugs in the U.S., and that startup companies are playing a major role in the creation of such small molecule drugs.

In Japan, on the other hand, the number of research 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). Since 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, there was a timing 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 for small molecule drug targets by domestic pharmaceutical companies peaked in 2003 and has been declining since ^then10). From various reports in the 2000s, it is clear that the superiority of novel modalities over small molecules and the number of Japanese companies in the field of novel modality research have been increasing. In the 2000s, various reports reported the superiority of novel modalities over small molecules and Japan's lagging behind in the field of novel modality ^{research11),12),13)}. These and the present survey suggest that the decline in small molecule drugs in Japan was due to the lower priority given to small molecule drug discovery research in the 2000s.

Few items of Chinese origin were included in the current 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 by 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. However, half of the modalities of both novel NMEs and FICs are small molecules. By increasing the specificity of target molecules and decreasing the affinity for other molecules that cause side effects through detailed molecular profiling, small molecules can now be used for control that was previously thought to be impossible. Furthermore, it is possible to combine small molecules with medium and large molecules to increase targeting to organs and enhance drug ^{efficacy14)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 ^expansion16). Therefore, not only support for drug discovery of new modalities, but also comprehensive policies to support small molecule drug discovery are needed.

Conclusion

In this study, it was suggested that the priority of small molecule drug discovery research in Japan is declining. In addition, it will be important to investigate the actual situation in the U.S., where there has been no decrease in small molecule drugs, 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 surveys of actual conditions of support from the government, in order to investigate the factors behind the decline in Japan's ability to create small molecule drugs. This will be an important research issue in the future in order to investigate the factors behind Japan's declining ability to create small molecule drugs.

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