The Pharmaceutical Industry at a Glance New Drugs Approved in Japan and Their Review Periods -New Drugs Approved in Japan and Their Review Periods in 2022 and Survey of Secular Trends

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Hiroshi Azuma, Senior Researcher, Pharmaceutical Industry Policy Institute

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 newsletter, we examine the approval status and review periods of new drugs and new regenerative medicine products approved in Japan from January to December 2022. In addition, we also report on topics for 2022 as seen from the survey of trends over time.

Survey Method

The survey covered drugs listed in the "List of New Drugs Approved " ⁴⁾ on the website of the Pharmaceuticals and Medical Devices Agency (PMDA). Items were counted for each review report, and those for which multiple companies simultaneously submitted public knowledge applications for the same drug ingredient in response to requests from academic societies, etc., and those for which multiple ingredients were approved for concomitant drug therapy, etc., were counted as a single 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 (StataCorp LP, College Station, TX, USA) was used for analysis, and the review period was calculated as the period from the date of application for approval 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 shown together.

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 2022. The number of new drugs approved in Japan in 2022 was 174, an increase of 39 over 2021. This is more than the average number of new drugs approved between 2010 and 2021 (119), and the highest number since 2010. Of these, 52 new molecular entities (NMEs) were approved, the same number as in 2021, making this the second highest number of NMEs approved since 2000, after 2014.

The breakdown of approved items is then shown in Table 1. The breakdown by application category shows that 86 new indication drugs were approved, an increase of 35 over 2021, and 10 other new route-of-dosage drugs, an increase of 5 over 2021. On the other hand, 17 new-dose drugs decreased by 4 items compared to 2021.

By review category, 129 items were under normal review and 37 items were under priority review. Priority review items accounted for 21% of all approved items, the lowest level since 2014. Of the priority review items, 31 were orphan drugs, a decrease of 9 from 2021. The number of orphan drugs has increased since 2014, reaching a maximum of 40 in 2021, but in 2022 it was at the same level as before 2020 (Figure 2). The number of items approved in 2022 for items subject to the pioneering review and designation system (currently the pioneering drug designation system) was one item, down one item from ²⁰²¹⁵⁾. In addition, seven products received special approval for the indication of "prevention of infection or infectious disease caused by new-type coronavirus (SARS-CoV-2)," and another product was approved under the newly established emergency approval category in 2022. In addition, the number of expedited processing items increased by 35 from 2021 to 46 in 2022, mainly due to the increase in the number of publicly available applications for infertility drugs, which will be covered by insurance from April 2022. Details will be discussed in the discussion section.

Review period for new drugs

Table 2 and Figure 3 show the review period for new drugs approved between 2010 and 2022. 174 drugs were approved in 2022, and the median review period was 9.4 months, 0.5 months shorter than in 2021, the shortest median since 2011, when the review period was significantly reduced to around 10 months. The median was 9.4 months, 0.5 months shorter than in 2021.

By examination category, the median duration was 10.8 months for normal examination items (excluding expedited processing items) and 8.4 months for priority examination items, which was the same level as that in 2021. The 80th percentile of the review period for NMEs (excluding expedited processing) and priority review items were 11.9 months and 9.2 months, respectively, which were close to the target ^values6) of 12 months and 9 months, respectively.

Next, Table 3 and Figure 4 show the changes in the review period when classified into NME and non-NME. 52 NME items were approved in 2022, and the median review period was 10.8 months, 0.9 months longer than in 2021. On the other hand, the median review period for non-NMEs was 8.4 months, 1.5 months shorter than in 2021 and the shortest since 2010.

Approval and Review Period for Special Approval and Emergency Approval

Table 4 shows the items approved in 2022 for special and emergency approvals, which are drugs for the prevention of infections caused by novel coronavirus (SARS-CoV-2), infections and Seven new products were approved in 2022 with the indication of "prevention of infectious diseases caused by new-type coronavirus (SARS-CoV-2) and suppression of their onset". Of these, two were NMEs. By modality, five were vaccines, and one each was a small molecule drug and an antibody drug. The median review period for all seven products was 69.0 days (2.3 months), the mean was 57.3 days (1.9 months), and the standard deviation (SD) was 24.6 days (0.8 months). Seventeen COVID-19 compliant products have received special approval so far, including 10 products that will be approved until 2021.

In 2022, the "Act on Quality, Efficacy and Safety Assurance of Drugs and Medical Devices" (so-called Pharmaceutical Affairs Law) was partially amended to establish an emergency approval system. One new low-molecular-weight drug received emergency approval (one-year term) under this category, with a review period of 9.0 months, or 270 days.

Analysis of New Medicinal Elements (NME)

First, NMEs for new drugs approved between 2010 and 2022 were analyzed by modality, biopharmaceuticals (Fig. 5) and small molecule drugs (Fig. 6). The number of approved biopharmaceuticals was 67, the highest number since 2010. Of these, 23 were NMEs, 2 were follow-on biologics, and 42 were others (e.g., new indications). The ratio of the number of approved biopharmaceuticals to the total number of approved products was examined over the years, and found that the ratio had remained flat at 37-39% since 2018. On the other hand, the number of approved small molecule drugs in 2022 was 107, showing an upward trend since 2017 and the highest number since 2015. Of these, 29 were NMEs and 78 were non-NMEs.

Next, we examined the breakdown of NMEs approved in 2022 (Figure 7). 28 (54%) NMEs are under normal review, 17 (32%) are for orphan drugs (including priority review items), 1 (2%) is designated for pioneering review (including priority review items and orphan drugs), and 3 (3%) are for priority review other than orphan drugs. The number of items for priority review other than drugs for rare diseases was 3 (6%), for special approval 2 (4%), and for emergency approval 1 (2%). In terms of efficacy ^category7), oncology drugs and other metabolic drugs were the most common, accounting for 8 items or 15% each. Biologics followed with 6, chemotherapeutics and CNS drugs with 5, and allergy drugs and cardiovascular drugs with 3, in that order. The number of NMEs approved in 2022 was 23, accounting for 44% of all NMEs, one less than in 2021, but the number of NMEs and their share of all NMEs were the second highest since 2010, after 2021. The number of NMEs decreased by one compared to 2021. In terms of NME applications by domestic and foreign-funded companies, ¹⁰⁾ 18 (35%) were from domestic-funded companies and 34 (65%) were from foreign-funded companies. The percentage of NMEs by domestic-funded firms has been low since ^{20172, 11)}.

Approval of new regenerative medicine products and their review period

The following is a list of approved new regenerative medicine products and their review periods (Table 5). 6 new regenerative medicine products were approved in 2022, the highest number ever approved in a single year, and all of them were approved as regenerative medicine products for rare diseases. The median review period for new regenerative medical products approved in 2022 was 9.3 months (mean: 9.1 months, standard deviation: 0.8 months).

The target for the review period for regenerative medical ^products6) was set at 50% of all priority items to be processed within 9 months, and it was confirmed that approval was granted in a period close to the target.

Discussion and Summary

This report examines the approval status and review period for new drugs and new regenerative medicine products approved in Japan in 2022.

The number of approved drugs in 2022 is 174, which is the largest number since 2000, the period of our ^survey1,2). Especially noteworthy are the 85 items reported by the Subcommittee, 46 items for expedited processing in the review category, and 86 items for new indications in the application category. This is an increase of 47, 35, and 35 items, respectively, over the previous year, and can be regarded as a characteristic item in 2022. One of the major differences from previous years is that infertility drugs will be covered by insurance from April 2022. The Ministry of Health, Labour and Welfare ⁽ MHLW, see MHLW ^webpage13), the Cabinet decision in May 2020 on the National Outline of Measures for Society with Declining Birthrate led to the approval of many items as publicly available applications, thanks to the prompt response of the Medical Insurance Committee of the Social Security Council, related disease societies, and pharmaceutical companies. In fact, 32 items had been approved by August 2022, which indicates that the approval was granted promptly and without waiting for a long period of time after the enforcement of the law, and that this has enabled a timely approach to those suffering from infertility. We hope that this will help to halt the aging of Japan's population and declining birthrate, which is an important issue for the country.

In terms of new indications (Figure 8), the number of approved drugs has generally increased since 2017. By efficacy category, oncology drugs are the most common, accounting for 30% (197 drugs) of all approved drugs since 2010. This is followed by other metabolic drugs and drugs for the central nervous system during the entire period, with hormonal drugs standing out in 2022, coupled with the above-mentioned insurance coverage for infertility treatment. The largest number of oncology drugs can be attributed to the accelerated identification of causative genes using next-generation sequencers in oncology, basket-type clinical trials to verify the effects of single drugs on multiple diseases, and umbrella-type clinical trials to verify the effects of multiple drugs on single diseases, resulting in attempts to expand the range of indications for various drugs to various types of cancer. As a result, various drugs have been attempted to expand their indications to various types of cancers. In particular, the recent progress of various clinical trials including combination therapy for immune checkpoint inhibitors such as PD-1/PD-L1 antibodies has also had a significant impact. ¹⁴⁾

The median review period for new drugs approved in 2022 was 9.4 months, a significant reduction. This was largely due to the large number of items other than NMEs (median 8.4 months), especially those that were expedited by public knowledge applications.

With regard to the approval of items for special approval and their review period, the median review period for items approved in 2022 was 2.3 months, which is an extremely short period of time, and is a very significant item in response to COVID-19. In light of the rate of appearance of mutant strains of the virus, it is very important to maintain the current rapid response in the future. In addition, in 2022, the Pharmaceutical Affairs Law was partially amended and an emergency approval system came into effect. We shall touch on this again below.

The purpose of the amendment is to provide an expedited approval system that grants approval with conditions and a time limit when the efficacy of a drug is presumed, subject to safety confirmation, in an emergency situation. It is also important to note that approval is granted regardless of the approval status of foreign countries. 2022 saw the first application of this system for Zocova Tablets, a drug for the treatment of novel coronavirus infection, which is significant in the sense that it was the first case to be approved. At the same time, discussions have begun on operational improvements and the suitability of application requirements for a better system, and we hope that the system will be flexible and appropriate as a safety net for the public's health.

Regarding the analysis of new active ingredient (NME) drugs, we analyzed the data by modality and confirmed the transition of biopharmaceuticals and small molecule drugs. The number of NMEs increased in both categories, but the percentage remained at the same level as in previous years. Among biopharmaceuticals, the number of non-NME and non-bio follow-on products increased by 15 items compared to the previous year, and although hormones for fertility treatment made a certain contribution with 6 items out of a total of 39 items, new indications and new dosages for oncology drugs accounted for almost half with 19 items. Therefore, the position of biopharmaceuticals in the oncology field is considered to be significant.

Regarding the number of approved new regenerative medicine products and their review periods, a record number of six products were approved. The number of approved products in 2022 are human cell-processed products, such as chimeric antigen receptor T-cell therapy (CAR-T cell therapy), and the increase in advanced technology in pharmaceuticals over the years is very significant.

We have reported on a survey of items approved in 2022 and their review periods, as well as characteristic events in 2022 based on trends over time since 2010, and we believe that the impact of pharmaceuticals on society will increase in the future as we coexist with COVID-19 and live through the "With Corona Era. We hope that all stakeholders in industry, government, and academia will generate innovation through the advancement of science and technology, and contribute to the health and peace of mind of patients and their families.

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