The Pharmaceutical Industry at a Glance New Drugs Approved in Japan and Their Review Periods - Approval Results for 2021 and the Current Status of Globalization of the Japanese Market

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Masao Yoshida, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute (PIIPRI)

The Pharmaceuticals and Industrial Policy Research Institute (PIIPRI) continuously collects and analyzes information on drug approvals and review periods based on information published by regulatory ^{authorities1, 2, 3)}. In this news release, we surveyed the approval status and review periods of new drugs and new regenerative medicine products approved in Japan during the period from January to December 2021. In addition, we report on our survey and analysis of the current status of globalization of the Japanese market, as seen from our ongoing survey from 2010 to 2021, from the perspective of the number of approvals for drugs containing new active ingredients.

Survey Method

The survey covered drugs listed in the "List of Approved New Drugs " ⁴⁾ on the website of the Pharmaceuticals and Medical Devices Agency (PMDA). Items were counted by review report, and those for which multiple companies simultaneously submitted public knowledge applications for the same ingredient at the request of academic societies, etc., and those for which multiple ingredients were approved for concomitant drug therapy, etc., were counted as one item. Approval information for each item was extracted from review reports, lists of approved items for new drugs, package inserts, and pharmaceutical bulletins. Standard statistical analysis software Stata/IC 14.0 for Windows (Stata Corp LP, College Station, TX, USA) was used for analysis, and the review period was calculated as the period from the application date to the approval date. Since some items have significantly longer periods or shorter periods due to special exceptions, the main basic statistic is the median, and the number of samples, mean, and standard deviation are also shown.

Number and Breakdown of New Drugs Approved

Figure 1 shows the annual trend in the number of new drugs approved in Japan between 2010 and 2021. The number of new drugs approved in Japan in 2021 was 135, an increase of 10 over 2020 and higher than the average number of new drugs approved in 2010-2021 (118). Of these, 52 new molecular entities (NMEs) were approved, 14 more than in 2020. This was the second highest number of new drugs and NMEs approved since 2000, following 2014.

Table 1 shows a breakdown of the approved items. The breakdown by application category shows that in 2021, in addition to the aforementioned NMEs, there were 21 new-dose drugs and 4 biosimilars (biosimilars), and these numbers increased from 2020. On the other hand, the number of new-dose drugs approved in 2020 decreased by 7 to 51, compared to 59 in 2020.

By review category, 82 items were under normal review and 44 items were under priority review. Priority review items accounted for 33% of all approved items, and had remained at a high level (around 30%) since 2014. Of the priority review items, 40 were orphan drugs, an increase of 17 from 2020. The number of orphan drugs had been increasing since 2014, hovering around 20-30 items, but in 2021, the number was the highest to date at 40 items (Figure 2 ⁾. In addition, nine products received special exception approval for the indication of "prevention of infection or infectious disease caused by new coronavirus (SARS-CoV-2)," which is still spreading worldwide.

Review period for new drugs

Table 2 and Figure 3 show the review period for new drugs approved between 2010 and 2021. the median review period for all 135 drugs approved in 2021 was 9.9 months, 0.8 months shorter than in 2020 and similar to 2019, and has remained around 10 months since 2011, when the review period was significantly reduced It had remained at around 10 months since 2011, when the examination period was significantly shortened. The variation (standard deviation: SD) in the examination period was the smallest since 2010.

Next, by examination category, the median examination period was 11.2 months for regular examination items excluding expedited processing items and 8.3 months for priority examination items, which was also the same as the examination period since 2011. The 80th percentiles of the review periods for the regular review items (excluding expedited processing) and priority review items were 11.9 months and 9.1 months, respectively, indicating that the approval periods were close to the target values6) of 12 months and 9 months or less.

The median review period for the 52 NMEs approved in 2021 was 9.9 months, 0.7 months shorter than in 2020 and second only to 2015. The median review period for non-NMEs was 9.9 months, 0.9 months shorter than in 2020.

Approval of items subject to special approval and their review period

Table 4 shows the items approved for special approval in 2021. In 2021, nine products were approved for the prevention of infections caused by the novel coronavirus (SARS-CoV-2), which is still spreading worldwide, and for the suppression of infectious diseases and their onset. Of these, six were NMEs. By modality, five were vaccines (including three NMEs), three were antibody drugs (including two NMEs), and one was a small molecule drug (including one NME).

Next, Table 5 shows the review periods by modality for items that received special approval as measures against novel coronavirus infection (COVID-19). Since the review process for special approval differs from the normal review process, these figures are for reference only. 10 items have received special approval to combat COVID-19, including one in 2020, and the median review time was 30.5 days and the average was 40.2 days. Comparing with Tables 2 and 3, it can be seen that the special exception approval items were reviewed in a shorter period of time compared to the normal review process. Comparing the median and mean review times by modality, the median review time tended to be shorter for vaccines, antibody drugs, and small molecule drugs, in that order.

Analysis of New Medicinal Elements (NME)

A breakdown of the 52 NMEs approved in 2021 (Fig. 5) shows that 25 (48%) of the NMEs are under normal review, 18 (38%) are orphan drugs (including priority review items), and 2 (3%) are designated for pioneering review (including priority review items and orphan drugs), One item (2%) was designated for priority review other than rare disease drugs, and six items (11%) were designated for special approval. The number of NMEs approved as orphan drugs in 2021 was the second highest after ²⁰¹⁴²⁾. The number of NMEs that received special exception approval in 2021 was the highest ever.

The number of NMEs approved in 2021 was the second highest in history, following 2014. ²⁾ Looking at NME applicants by domestic and foreign-funded companies ^,7) domestic-funded companies accounted for 23 (44%) and foreign-funded companies for 29 (56%) of NMEs.

The NMEs were then classified into ^{biopharmaceuticals8) and} small molecule ^drugs9). 24 biopharmaceutical NMEs were approved in 2021, accounting for 46% of all NMEs. The number of biopharmaceutical NMEs approved in 2021 was 24, accounting for 46% of all NMEs, the largest number and highest percentage of all NMEs since ²⁰¹⁰²⁾. On the other hand, 28 small molecule and other drug NMEs were approved, maintaining the same number of approvals as in 2019 and ²⁰²⁰²⁾.

By drug ^class10), oncology drugs were the most common, accounting for 14 products or 27% of the total. This was followed by 12 other metabolic drugs, 6 biologics, 5 hormones, 4 CNS drugs, and 3 chemotherapy drugs, in that order. The six biological products included three COVID-19 vaccines, and the three chemotherapeutic agents were viral agents for COVID-19. In addition, regarding antibacterial agents (antimicrobial agents) reported by YUASA et al. in this policy research ^news11), the number of NMEs approved in 2021 was one.

Globalization of New Medicinal Products Containing New Active Ingredients (NMEs)

The current status of globalization of the Japanese market, as seen from the continuous survey from 2010 to 2021, was investigated and analyzed from the perspective of the number of new active ingredient-containing drugs (NMEs) approved. Globalization is defined in this paper as the percentage of globally approved items (items approved in one of the two regions, the U.S. and Europe, in addition to Japan).

This survey covers 488 NMEs approved in Japan from 2010 to 2021 (Table 1), and updates the status of approval in Europe and the U.S. based on the data reported in the previous News ³⁾ on "New Drug Approval Status in Japan, the U.S. and Europe. As of the time of each survey, we defined a globally approved drug as one that was approved by one of the two poles, the FDA in the US and the EMA in Europe, in addition to the PMDA in Japan, and a local drug as one that was not approved by the FDA and the EMA but only by the ^PMDA12).

As of the end of 2021, 362 (74%) of the 488 NMEs were globally approved and 126 (26%) were local drugs. It should be noted that these results represent data as of one point in time, the end of 2021, and local drugs may include items that will be approved in the U.S. and Europe in 2022 or later.

Next, to confirm the progress of globalization in the Japanese market, NMEs approved in Japan in the most recent five years as of the end of each year survey from 2014 to 2021 were included, and the globally approved items and local drugs at the time of each survey were extracted. Since the number of NMEs approved in a single year is affected by the small lag in approval between Japan and the U.S. and Europe, the number of NMEs approved in the most recent five years at the time of each annual survey is calculated as the total number of NMEs approved (Fig. 6).

Figure 6 shows that the number of globally approved drugs has remained between 141 and 156 since the 2014 survey, with a maximum increase of only about 10% over 2014. On the other hand, the number of local drugs decreased by 22 (33% compared to 2014) when compared between 2014 and 2021. The percentage of the number of globally approved drugs as a percentage of the total number of NMEs in Japan increased over time from 68% in 2014 to 76% in 2021.

The above shows that, although the number of globally approved NMEs in Japan has not increased significantly, the number of local drugs has decreased, and the overall ratio of globally approved NMEs has increased over time (≒ globalization is progressing). This is the structure of the globalization of the market.

In order to investigate the factors behind the above changes, a similar analysis was conducted for NMEs of ^{biopharmaceuticals8)} approved in Japan (Figure 7). The number of biopharmaceuticals approved globally increased from 42 in the 2014 survey to 61 in 2021, an increase of 19 (45% compared to 2014). On the other hand, the number of local drugs for biopharmaceuticals decreased by 10 (vs. 2014: 71%) when comparing 2014 and 2021. The number of globally approved biopharmaceuticals as a percentage of the total number of domestic bio-NMEs has increased over time from 75% in 2014 to 94% in 2021.

In addition, we examined the number of items by drug ^{category10) for} the 141 globally approved items and 67 local drugs as of the 2014 survey shown in Figure 6 and for the 145 globally approved items and 45 local drugs as of the 2021 survey ⁽ Table 6).

There were 8 drug classes with an increase in the number of globally approved drugs in 2021 compared to 2014, with oncology drugs accounting for the largest increase of 14 drugs, followed by biologics with an increase of 5 drugs. The number of drugs with decreasing indications was 9, with the largest decrease of 7 in other metabolic diseases, and zero drugs for blood and body fluids (a decrease of 5 drugs) were globally approved in the 2021 survey.

In addition, a comparison of local drugs between 2014 and 2021 shows that the number of local drugs increased in only four drug classes, while the number of local drugs decreased across the board in all other classes. In particular, the number of biologics decreased by the largest number (11), and the number of local drugs in the 2021 survey was zero. A detailed survey of the 11 biological products that were local drugs in the 2014 survey revealed that 9 of them were vaccines.

Finally, we compared changes in the percentage of globally approved drugs by drug class: of the drug classes with 10 or more NME-approved drugs in each of the 2014 and 2021 surveys, the largest increase in the percentage of globally approved drugs was for biologicals (from 58% to 100%), followed by central nervous system drugs (76% to 89%), chemotherapeutics (64% to 71%), and oncology drugs (82% to 84%), followed by a decrease only in other metabolic drugs (59% to 57%).

Taken together, the above studies indicate that the increase in the number of globally approved oncology drugs and biologics and the significant decrease in the number of biologics (primarily vaccines) for the domestic market have contributed to the increase in the percentage of globally approved biopharmaceutical NMEs, while many of the drug classes that account for the majority of NME approvals have also experienced an increase in the percentage of globally approved products. The increase in the proportion of globally approved items in the NME approved category of biopharmaceuticals has also led to an increase in the proportion of globally approved items in the domestic NME approved category (i.e., globalization has progressed).

Approval of new regenerative medicine products and their review period

The following section presents the approved new NMEs and their review periods (Table 7). 5 new NMEs were approved in 2021, the highest number ever approved in a single year. Note that Delitact Injection, Japan's first tumor-solving virus preparation, was approved with a seven-year time limit and conditions. In addition, all products were approved as regenerative medicine products for rare diseases, and one of them was a regenerative medicine product designated for pioneering review.

The median review period for new regenerative medical products approved in 2021 was 8.9 months (mean 8.1 months, standard deviation 1.7), compared to the median review period of 11.7 months (mean 15.6 months, standard deviation 10.4) ² for all 11 new regenerative medical products approved by 2020. shows a shortening of the review period compared to the median of 11.7 months (mean value 15.6 months, standard deviation 10.4)2) . In addition, as a target ^value6) of the review period for regenerative medical products, 50% of all priority items are to be processed within 9 months, and it was confirmed that the approval period was close to the target.

Discussion and Summary

This paper investigates the approval status of new drugs and new regenerative medicine products approved in Japan in 2021 and their review periods. We also summarized the same information on the items related to the special approval for therapeutic drugs for the new coronavirus, which is still raging in Japan. In addition, the report analyzes the number of new medicines containing active ingredients (NME) approved in 2021 by category, and the globalization of the Japanese market in terms of the number of NME approved between 2010 and 2021.

The number of new drugs approved in Japan in 2021 was 135, which is higher than the average number of new drugs approved in the past 11 years. A breakdown of the number of new drugs approved in Japan in 2021 shows that the number of NMEs increased by 14 compared to 2020. In addition, 40 orphan drugs were approved in 2021, the highest number to date, indicating that pharmaceutical companies and others are actively working to create drugs for patients suffering from rare diseases.

The median review period for new drugs approved in 2021 was 9.9 months, which has remained around 10 months since 2011, when the review period was significantly shortened, and the variation in review period (standard deviation) was the smallest since 2010. The variation in review times (standard deviation) was the smallest since 2010. Despite the various restrictions in the COVID-19 epidemic, the review authorities and the pharmaceutical industry cooperated appropriately in order to contribute to patient health and public health issues.

A survey of approved items for special approval and their review periods confirmed that a record number of nine items received special approval in 2021, and showed the review periods for 10 items that received special approval as a countermeasure to COVID-19, including Beckley in 2020. The results show that the special exception approval items were reviewed in an overwhelmingly short period of time compared to the normal review process, reaffirming the role of special exception approval as an emergency response. In addition, a comparison by modality showed that the review period tended to be shorter for vaccines, antibody drugs, and small molecule drugs, in that order. As discussed in detail in the previous News ³⁾, for NMEs (special exception approval) for vaccines, it may have taken time to confirm efficacy and safety in Japanese patients based on domestic Phase I/II studies and bridging with overseas clinical studies. On the other hand, in the case of NMEs (special exception approval) for low-molecular-weight drugs, it was confirmed from the Deliberation Result Report that Japan was also involved in the international Phase III study, which was treated as the main clinical trial and other study results at the time of approval review, which may have contributed to expediting the approval review.

Regarding the future of pharmaceutical approval in emergency situations, on December 27, 2021, the Pharmaceuticals and Medical Devices System Committee of the Health Sciences Council published the "Summary on the Approval of Pharmaceuticals and Medical Devices in Emergency Situations, " ¹⁴⁾ and plans to institutionalize an "emergency approval system. For reference, a comparison of the new system to be institutionalized (emergency approval system) and the current system is shown below (Table 8) ¹⁵⁾. The requirements for triggering the system are said to broadly include not only outbreaks of infectious diseases, but also nuclear accidents, radioactive contamination, and bioterrorism, and will cover not only vaccines and therapeutic drugs, but also pharmaceuticals in general, medical devices, and regenerative medical products. Unlike special approval, approval will be granted for a period of about two years, and the need to confirm efficacy within this period will be clearly stated. The issues that have been faced with the emergency approval system up to now have been discussed in detail in previous news items ^{2 and 3)}. However, the establishment of a system that meets the needs of the times is essential to prepare for possible future pandemics, and we hope that the system will overcome the various issues that remain.

An analysis of the number of NMEs approved in 2021 by category shows that the percentage of NMEs for rare disease drugs and NMEs with special approval was higher than in previous years in the survey by review category. As mentioned earlier, these figures may be the result of the pharmaceutical industry's efforts to address rare diseases and COVID-19. In addition, the number of NMEs for biopharmaceuticals approved in 2021 was the highest ever. As for biopharmaceuticals, the increase in the number of new indications and follow-on biologics was more remarkable than the increase in the number of NMEs approved in the previous year's ^survey2), but as seen from the results of the survey on special approval, in 2021, vaccines and antibody drugs to combat COVID-19 were developed in a short time due to scientific progress and as many as five products were approved. In addition, three CGRP antibodies for migraine prophylaxis were approved in the same ^year16), which were the result of many years of research and development efforts in the normal review process.

An analysis of the globalization of the Japanese market, which was conducted from the perspective of the number of NMEs approved, showed that the percentage of globally approved products has increased over the years, and the reasons for this are the increase in the number of globally approved oncology drugs and biological products and the decrease in the number of biological products (mainly vaccines) for the Japanese market, as well as the increase in the number of domestic NMEs The increase in the number of globally approved oncology drugs and biologics and the decrease in the number of biologics (mainly vaccines) for the domestic market have contributed to the increase in the ratio of globally approved products to the number of approved products in Japan. The increase in the number of globally approved oncology drugs can be attributed to the fact that many of these drugs are developed globally because many of them originated overseas or are derived from foreign companies, and also because disease segments have been subdivided in recent years and the domestic market for each segment is not so large, so the proportion of globally approved drugs that are being developed globally Therefore, the proportion of globally approved products that are being developed globally is considered to be increasing. Regarding the increase in the number of globally approved items of biological products, many items are developed globally because many of them originate from overseas or foreign companies, and vaccines in particular have been dependent on items from overseas in recent years, as was made clear in the response to COVID-19. The status of vaccines in Japan is reported in detail by Takasago in this Policy Research Institute ^News17). In terms of patients' access to medicines, local drugs developed only in Japan have contributed specifically to the needs of the domestic market. However, as globalization progresses from the perspective of approved products due to the expansion of foreign companies and the market characteristics of diseases, domestic pharmaceutical companies must not only continue to meet the needs specific to the domestic market, but also make a global contribution. In this context, Japanese pharmaceutical companies will not only have to continue to respond to the needs specific to the domestic market, but will also be asked more than ever how they can develop medicines that can contribute to the global market.

A survey of approved new regenerative medicine products and their review periods shows that the median review period for the five products approved in 2021 was 8.9 months, which is shorter than the review periods for the 11 new regenerative medicine products approved by 2020. In addition, all of the five approved products have been approved as regenerative medical products for rare diseases, and are establishing themselves as new treatment options for diseases that have been difficult to treat in the past.

In the above, we have discussed the current status of globalization of the Japanese market from the perspective of the number of NMEs approved, which can be seen from ongoing surveys, as well as a survey of approved products and their review periods in 2021. As pharmaceutical R&D becomes more diverse and sophisticated, we expect that new innovation and value will be created in response to changes in the environment and with a view to contributing to patients' health and public health issues.

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