Pharmaceutical Industry at a Glance Recent Trends of Unapproved Drugs in Japan -New Drug Approval Status in Japan and the U.S. in 2023

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The Office of Pharmaceutical Industry Research Chie Yoshiura, Senior Researcher
The Office of Pharmaceutical Industry Research Hiroshi Azuma, Senior Researcher
The Office of Pharmaceutical Industry Research Kiyoshi Morimoto, Senior Researcher

Summary

1. Introduction

The Office of Pharmaceutical Industry Research In OPIR Views and ActionsNo. 63 of July 2021, ¹⁾ we reported that there were signs of expansion of "domestically unapproved drugs" that are approved in other countries but not in Japan, and since then we have analyzed unapproved drugs and raised the issue of drug ^{lag/loss2, 3, 4, 5, 6, 7, 8, 9)}. In recent years, we have seen an increasing number of editorials on this issue in various fields, and in the last fiscal year, concrete efforts have been made to address this issue, including drug price ^{reform10) and} drug ^policy11). In this report, the number of unapproved drugs in Japan will be reviewed in light of the new drug approval status in 2023 in order to grasp the latest trend of unapproved drugs in Japan, and to report on the trends and characteristics of unapproved drugs in Japan.

Survey Methodology

The number of unapproved drugs in Japan was identified by comparing the number of NMEs approved in the U.S. from 2012 to 2023 with the number of unapproved drugs in Japan. Specifically, new molecular entities (NMEs) for each year listed in the "New Drug Therapy ^Approvals12) " report issued annually by the FDA were counted as U.S. NMEs, and the status of approval in Japan was surveyed by referring to the "List of New Drugs Approved13 ⁾ " issued annually by the PMDA. The domestic approval status was surveyed with reference to the List of New Drugs ^Approved13) issued by the PMDA every year. As mentioned earlier, the items in this report were compiled from the FDA's report "New DrugTherapy ^Approvals12)," and the items classified as vaccines and regenerative medicine products were not included in the survey.

Next, the number of unapproved drugs in Japan and the approval rate in Japan relative to the number of NMEs approved in the U.S. were tabulated for each survey point (as of the end of December of each year) in order to confirm annual changes in the number of unapproved drugs in Japan (Supplement 1). Since it was difficult to interpret the trend of changes in the number of unapproved drugs in Japan in each year (Supplement 1 and 2), the number of unapproved drugs in Japan was calculated for each survey point using this data set as in the analysis of OPIR Views and ActionsNo. ⁶³¹⁾ in July 2021, and the total for the five-year period from 2016 to 2023 was calculated as the total number of unapproved drugs in Japan for the five-year period The number of unapproved drugs was calculated as As a comparison, the five-year total of the number of NMEs approved in the U.S. was calculated in the same manner. In addition, the ratio of the number of unapproved drugs in Japan to the number of NMEs in the U.S. was calculated (Figure 1).

In the July 2021 OPIR Views and ActionsNo. ⁶³¹⁾, the number and ratio of NMEs not approved in Japan to those approved in either Europe or the U.S. were calculated for NMEs in Japan, the U.S., and Europe. In this report, however, the survey is limited to U.S. NMEs, and items not approved as NMEs in the U.S. are excluded. Since the NME status at the time of approval is not exactly the same in Japan, the U.S., and Europe, the same method used in the July 2021 OPIR Views and ActionsNo. ⁶³¹⁾ requires retroactive adjustment of the total number of NMEs in the year of initial approval when a product that was non-NME when initially approved is later approved as an NME in other regions, and in some cases the number of items changed compared to the past results. In this case, there were cases where the number of items changed compared to the past results. In this report, however, the survey was re-calculated by limiting the scope of the survey to NMEs in the U.S. in order to make the index plain and convincing, keeping in mind that this survey will be conducted continuously in the future. Due to this change, items approved only in Europe are no longer included in the survey. However, as reported in the July 2021 OPIR Views and ActionsNo. ⁶³¹⁾, only 8% of the NMEs approved in Europe and the U.S. between 2010 and 2020 were approved in Europe only (not approved in the U.S.), and many of the European-approved products will obtain U.S. approval, so the survey methodology changed in this report is consistent with the past The Office of Pharmaceutical Industry Research We believe that the results will be consistent with the survey.

For the domestic development status and disease classification of each of the surveyed items, we referred to the ATC classification listed in the information on each item in "Tomorrow's New Drugs (Technomic Production)". In addition, when classifying whether a company obtaining approval in the U.S. for each of the surveyed products was an emerging company (hereinafter referred to as EBP: EmergingBioPharma), we used information from Evaluate PharmaⓇ (as of March 2024), which was founded within 30 years as of the end of 2018 or 2023 and sold in 2018 or 2023, and with sales of less than US$500 million in 2018 or 2023 were classified as EBPs.

It should be noted that this survey is an analysis from the perspective of the number of approvals and development status, and does not take into account the medical needs in Japan.

Results

3-1. Number of Unapproved Drugs in Japan in relation to NMEs in the U.S.

As shown in Figure 1, the annual trend of the number of NMEs in the U.S. shows that the five-year total number of NMEs increased from 174 at the end of 2016 to 228 at the end of 2020 and 243 at the end of 2023. In contrast, the 5-year total number of unapproved drugs in Japan was 95 at the end of 2016, 159 at the end of 2020, and 164 at the end of 2023. The ratio of domestically unapproved drugs to the number of NMEs in the U.S. increased annually from 2016 to the end of the 2020 survey (from 54.6% to 69.7%), reaching a level where approximately 70% were unapproved in Japan, but then reached 66.4% at the end of the 2021 survey and has remained in the 60% range since then (66.4% to 64.4% to 67.5%).

This report presents an analysis of the characteristics of 164 unapproved drugs in Japan as of the end of 2023 for the most recent five-year period. The analysis results for 136 unapproved drugs as of the end of 2018, which was five years before 2023, are also included for comparison. Note that the 164 drugs at the end of 2023 were domestically unapproved drugs in NMEs that received U.S. approval from 2019 to 2023, whereas the 136 drugs at the end of 2018 were domestically unapproved drugs in NMEs that received U.S. approval from 2014 to 2018, so there is no overlap in items in each group.

3-2. development status of unapproved drugs in Japan

Figure 2 shows the breakdown of domestic development status of unapproved drugs in Japan at the end of 2023 and at the end of 2018. 77 of 164 (47.0%) of the unapproved drugs in Japan at the end of 2023 were in domestic development (including applications under review). 61 of 136 (44.9%) of the unapproved drugs at the end of 2018 were in domestic development. Compared to the number of unapproved drugs in development in Japan at the end of 2018, both the number of items and their percentage in the total number of unapproved drugs increased. Although there is a "lag" in the timing of approval, clinical development of these items is ongoing in Japan, so there is a possibility that they will be approved by the pharmaceutical affairs bodies in Japan in the future. Looking at items under development in Japan by stage of development, the number and percentage of items in early development before Phase 2 decreased for unapproved drugs as of the end of 2023, while the number and percentage of items in late development in Phase 3 increased compared to those in unapproved drugs as of the end of 2018.

The number of items with no domestic development information was 55 (40.4%) at the end of 2018, while it increased to 80 (48.8%) at the end of 2023. The The Office of Pharmaceutical Industry Researchdefines unapproved drugs that have not been developed in Japan as "drug-loss products. " ⁸⁾ These 80 products and 7 products for which "development has been discontinued, suspended, or there are no further reports" will remain as "unapproved drugs in Japan" unless new development is initiated in Japan.

3-3. characteristics of companies that obtained U.S. approval for unapproved drugs

The Office of Pharmaceutical Industry Research In past surveys conducted by the Japan Pharmaceutical Manufacturers Association (JMPMA), we have reported that the percentage of unapproved drugs in Japan is high for EBP-derived products that have no foothold in ^{Japan3, 4)}. In recent discussions, the increase in new drugs derived from EBPs is considered to be one of the reasons for the increase in the number of unapproved drugs in Japan, and ^measures14) are being taken to promote collaboration with EBPs. Figure 3 shows the number and percentage of items for which the company that obtained approval at the time of U.S. approval was an EBP for the unapproved drugs in Japan as of the end of 2023, which were the subject of analysis in this paper, and for items for which company information could be obtained from unapproved drugs in Japan as of the end of 2018.

The number of EBP-derived products was 71 at the end of 2023, up from 62 at the end of 2018, and the percentage of EBP-derived products was 46.4% at the end of 2023, the same level as 47.3% at the end of 2018.

3-4. development status of unapproved drugs in japan by companies that obtained approval in the u.s. (ebp-derived and pharma-derived)

The domestic development status of unapproved drugs indicated in 3-2 is shown in Figure 4 by the company that obtained approval at the time of U.S. approval for those items for which company information could be obtained.

Looking at the domestic development status of unapproved drugs by EBP and pharmaceutical origin, 45 (63.4%) of the 71 EBP-derived drugs at the end of 2023 had no development information, an increase in both number and percentage compared to 29 (46.8%) of the 62 EBP-derived drugs at the end of 2018. On the other hand, 22 (31.0%) of the 71 EBP-derived products at the end of 2023 were under development, a decrease in both number and percentage from 28 (45.2%) of the 62 EBP-derived products at the end of 2018.

3-5. Target Disease Classification of Unapproved Drugs in Japan

Figure 5 shows the number of unapproved drugs in Japan by disease category at the end of 2023 and 2018. 49 of the unapproved drugs at the end of 2023 were anti-cancer drugs, followed by neurological agents, gastrointestinal and metabolic agents, and systemic anti-infective agents. The percentages of unapproved drugs in Japan to the number of NMEs approved in the U.S. were as follows: antineoplastics (74.2%), neurological agents (75.0%), gastrointestinal and metabolic agents (68.0%), and systemic anti-infectives (66.7%) (not shown in the figures). decreased at the end of 2023.

Figure 6 shows the number of unapproved drugs in Japan by disease category and domestic development status as of the end of 2023. Among the unapproved drugs, those without domestic development information were, in descending order of number of items, drugs for the nervous system (15 items), anti-cancer drugs (13 items), systemic anti-infectives (7 items), and drugs for the gastrointestinal tract and metabolism (6 items).

Summary and Discussion

This paper investigates the status of unapproved drugs in Japan for NMEs approved by the U.S. FDA from 2012 to 2023. The five-year total number of unapproved drugs in Japan for U.S. NMEs increased from 95 at the end of 2016 to 159 at the end of 2020 and 164 at the end of 2023. The percentage of unapproved drugs in Japan increased annually from 2016 to the end of the 2020 survey, and remained high at 64.4% to 67.5% after the end of the 2021 survey (Figure 1).

Next, we surveyed the development status, companies that obtained U.S. and European approvals, and disease classifications for a total of 300 drugs: 164 drugs approved in the U.S. from 2019 to 2023 that were unapproved in Japan at the end of 2023, and 136 drugs approved in the U.S. from 2014 to 2018 that were unapproved at the end of 2018.2023 The following is a discussion of changes in the characteristics of each of the groups of products that were unapproved as of the end of 2023 and 2018, and the expected effects of the specific initiatives for unapproved drugs mentioned at the beginning of this report.

Of the 164 unapproved drugs in Japan at the end of 2023, 77 were under development in Japan. Compared to the 61 unapproved drugs that were under development in Japan at the end of 2018, the number of drugs in Phase 2 or earlier decreased and the number of drugs in Phase 3 increased (Figure 2). As a percentage of the number of NMEs approved in the U.S., 22.6% (55 of 243) were in Phase 3 as of the end of 2023, an increase compared to 12.2% (26 of 213) in Phase 3 as of the end of 2018 The decrease in the number of early development items before Phase 2 was EBP-derived items were larger (from 7 to 4 pharmaceutical-derived items and from 13 to 5 EBP-derived items), while the number of items in Phase 3 increased for both pharmaceutical- and EBP-derived items (from 18 to 38 pharmaceutical-derived items and from 8 to 14 EBP-derived items) (not shown). It is possible that the development in Japan, including some EBP-derived products, has been accelerated, for example, by obtaining the data necessary for domestic approval in parallel with the development in the U.S., or that the number of cases of Phase 1 alone leading to early approval as an additional study in Japan has increased. Such changes may be taken as an improving trend in terms of shortening the drug lag period. On the other hand, in OPIR Views and ActionsNo. 71 of March 2024, ⁹⁾ we discussed additional trials in Japan after approval in the U.S. and Europe as a factor affecting the occurrence of a long-term drug lag, and as of the end of 2023, there were still 77 unapproved drugs in development in Japan after U.S. approval (Figure 2). It is hoped that the number of unapproved drugs in development in Japan will decrease as Japanese participation in global clinical trials is promoted and unapproved drugs under development in Japan progress more quickly to be approved in Japan.

Regarding unapproved drugs without domestic development information, the number and percentage of unapproved drugs at the end of 2023 (80 items, 48.8%) increased compared to the number of unapproved drugs at the end of 2018 (55 items, 40.4%) (Figure 2). Furthermore, the number and percentage of unapproved drugs without domestic development information also increased when focusing on EBP-derived items (from 29 items, 46.8% to 45 items, 63.4%). Conversely, the number and percentage of unapproved drugs under development in Japan among EBP-derived products decreased (from 28 products, 45.2% to 22 products, 31.0%, Fig. 4). This is an increase from 13.6% (29 out of 213) at the end of 2018. It is possible that there are still hurdles to starting domestic development, such as for EBP-derived products that do not have a foothold in Japan.

In OPIR Views and ActionsNo. 66 of July ²⁰²²³⁾, we discussed the complexity of clinical trial procedures and other issues that contribute to the low number of EBP-derived products being included in pivotal trials in Japan, and noted the importance of measures to promote Japanese participation in international joint clinical trials for EBP products and to promote early partnerships with EBPs that intend to expand into the Japanese market. Recently, in addition to the reform of the pharmaceutical affairs system, new measures have been introduced to approach EBPs in the U.S., ^{such as the} PMDA's establishment of overseas ^offices14).

In addition to EBP-derived drugs, there were also unapproved drugs derived from pharmaceutical companies that have not yet been developed in Japan (Figure 4). In addition to the issues of the pharmaceutical affairs and clinical trial environment ⁽OPIR Views and Actions No. 66 of July ²⁰²²³⁾, expectations for development in Japan We discussed issues of business value and the importance of policies to ensure incentives and revenues for the introduction of EBP items. The 2024 reform of the NHI drug price ^system10) includes changes to appropriately evaluate innovations in innovative new drugs, such as the establishment of an additional fee for expedited introduction, and these changes are expected to promote the business development in Japan of unapproved drugs that are currently not developed domestically, whether derived from EBPs or pharmaceuticals. However, we also hope that ongoing discussions on measures to ensure economic rationality will continue.

In terms of disease categories of unapproved drugs as of the end of 2023, the largest number of products was anti-cancer drugs, which accounted for a large proportion of all new drugs, followed by neurological agents and gastrointestinal and metabolic agents. In the category of "No domestic development information," neurological agents accounted for the largest number of new drugs, followed by anti-cancer agents and systemic anti-infectives (Figure 6). One reason for the difference between the overall ratio and the ratio of "no information on domestic development" may reflect the positive aspects of progress in research and development, such as understanding the pathophysiology of anti-cancer agents. A ^survey15) conducted by The Office of Pharmaceutical Industry Researchon the actual status of pharmaceutical R&D reported that R&D in all areas is active, with the development pipeline for anti-cancer drugs accounting for about half of the total. On the other hand, the study reported that neurological drugs, for which there were many items with "no domestic development information," were one of the areas with the lowest probability of success in ^{the literature16) that} discusses the probability of success in drug development for global products. In addition, drug loss due to the difficulty of conducting clinical trials is also considered an issue for pediatric ^drugs17). In early 2024, the Japanese Ministry of Health, Labour and Welfare (JMHLW) issued a notice on the designation of drugs for rare ^diseases18) and a recommendation for the formulation of development plans for pediatric ^drugs19 ) .

5. conclusion

This paper reports on the latest status of unapproved drugs in Japan, taking into account information on new drug approvals in 2023. Although the increase in the number of unapproved drugs over the past two to three years has slowed, it is still at a high level and must continue to be monitored closely in order to maintain a high level of access to medicines in Japan comparable to that in Europe and the United States.

An analysis of the number of unapproved drugs as of the end of 2023 shows that there are still issues that are consistent with the direction of the drug lag/drug loss countermeasures, such as the large number of EBP-derived drugs for which development has not yet been started. The data sets used in the analysis are as follows

Supplement 1: Number of Unapproved Drugs in Japan and Percentage of U.S. NMEs Approved in Japan

The data set used for the analysis is as follows: Using NME approval information for the U.S. and Japan from 2012 to 2023, the number of unapproved drugs in Japan per year of initial approval in the U.S. and the approval rate of NMEs approved in the U.S. in Japan were tabulated for each survey point (at the end of December of each year).

The numbers circled by bold lines for each year represent the number of unapproved drugs in Japan and the approval rate in Japan relative to the number of NMEs in the U.S. in that year. The number of U.S. NMEs in each year increases or decreases, and the number of new unapproved drugs in Japan also varies from year to year. In this report, the number of NMEs in the U.S. and the number of unapproved drugs in Japan are calculated as a five-year total in order to follow the annual trends regardless of these year-to-year variations.

Supplement 2 Breakdown of 5-year total number of unapproved drugs in Japan

As mentioned above, the number of unapproved drugs in Japan is calculated as a five-year total in this report. The annual trends differ from the previous year due to the following factors: an increase in the number of new drugs not approved in Japan (corresponding to the figures in the bold line in Supplement 1), a decrease in the number of drugs not approved in the U.S. five years ago that remain unapproved in Japan, and a decrease in the number of drugs approved in Japan the previous year that are not included in the total. The figure below shows a breakdown of the difference between the five-year total number of unapproved drugs in Japan and the previous year, starting with the number of unapproved drugs at the end of 2016. Since all of the factors increased or decreased from one year to the next, it was difficult to determine year-to-year trends from year-to-year increases or decreases. For example, Figure 1 shows that the percentage of unapproved drugs remained high after the end of the 2021 survey, but at the end of 2021, the number of drugs approved in the previous year was relatively large (20), and at the end of the 2022 survey, there were only a few additional NMEs approved in the US that were unapproved in Japan. The magnitude of the impact differed from year to year.

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