Topics Drug Lag: Can Unapproved Drugs Meet Japan's Unmet Medical Needs?

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Masao Yoshida, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Tomoyuki Shibuguchi, Former Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute (PIIPRI)
Shinichiro Iida, Senior Researcher, Pharmaceuticals and Industrial Policy Research Institute

Executive Summary

The number of "unapproved drugs in Japan" that have already been approved in Europe and the U.S. but not yet approved by the pharmaceutical affairs bodies in Japan is increasing. in the late 2010s, the ratio of unapproved drugs in Japan to drugs containing new active ingredients approved in Europe and the U.S. increased over time, and the approval rate in Japan of drugs approved in Europe and the U.S. declined. However, although the increase in the number of unapproved drugs was demonstrated, there was no investigation into whether these drugs could meet unmet medical needs. In this paper, we show that unapproved drugs in Japan include a number of clinically important drugs that could address many unmet medical needs. In particular, the number of unapproved drugs for orphan drugs, antineoplastics, systemic infectious diseases, and neurological agents is increasing, and the proportion of clinically important drugs in these target areas is high. In addition, a high percentage of unapproved drugs without domestic development information remain clinically important, suggesting that access to new drugs in Japan may be a challenge. This suggests that the expansion of unapproved drugs in Japan needs to be viewed as a phenomenon of an ongoing drug lag, and policy responses to promote and ensure access to the latest drugs need to be considered.

1. Introduction

The environment surrounding NHI drug prices is becoming more severe every year, as evidenced by the revision of the additional system for promoting the creation of new drugs and elimination of off-label drug use in the overhaul of the NHI drug price system in FY 2018 and the implementation of mid-year revisions in FY 2021, and many people are concerned about a resurgence of "drug lag" due to the declining attractiveness of the Japanese pharmaceutical market. The Pharmaceutical and Industrial Policy Research Institute (PIIPRI) reported on the recent situation of the drug lag in its Policy Research Institute News No. 63 of July 2021, ^1,2) and concluded that (1) the gap between the timing of drug launches in Japan and that in Europe and the US tends to be shortening for drugs that have been launched in Japan, (2) the number of "drugs approved in other countries but not approved in Japan" has been increasing, and (3) the number of "drugs not approved in Japan" has been decreasing. (2) There are signs of expansion in the number of "unapproved drugs in Japan" that have been approved in other countries but not in Japan. Since this report, we have seen an increase in the number of editorials on drug lag in various fields, indicating the high level of interest in this issue in Japanese society.

Drug lag refers to the problem of drugs that have already been approved in other countries taking a long time to receive regulatory approval in Japan, and has two ^{aspects1, 2)}. The other is the issue of "unapproved drugs" in Japan that have been approved in other countries but not in Japan. Regarding the former issue, Shibukuchi and Awamura reported that the number of international joint clinical trials including ^Japan3), the shortening and stabilization of the review period in ^Japan4), and the improvement of the pharmaceutical affairs and drug pricing systems have contributed to the shortening of the review period, and the situation has been improving in recent ^{years2, 5)}.

The latter issue of "unapproved drugs in Japan" was addressed by calculating the ratio of the number of unapproved drugs in Japan to the number of NMEs in the US and Europe for drugs approved as New Molecular Entity (NME) in Japan, the US, and Europe from 2010 to 2020, As a result, the number of unapproved drugs and their ratio increased in the late 2010s (Figure 1) ^.1) At the ^same time, the number of drugs approved in the U.S. and Europe increased. At the same time, panel data on the cumulative approval rate of NMEs approved in the U.S. and Europe in Japan were also prepared, and the relationship between the number of years since the year of initial approval and the domestic approval rate of U.S. and European NMEs was analyzed to show that the approval rate of U.S. and European NMEs declined in Japan in the late 2010s compared to the early 2010s1). ¹⁾. 1) One of the reasons for the growth of unapproved drugs in Japan is that an increasing number of drugs created by emerging biopharmaceutical companies, which are becoming more independent in their development activities, are being approved in the U.S. and Europe, and these companies do not have development subsidiaries in Japan. The report also noted that the challenge is how to attract these emerging biopharmaceutical companies that do not have a development base in Japan to ^Japan1).

In the previous report, we presented a limitation of the survey. The previous report analyzed the number of NMEs approved in Japan, the U.S., and Europe from the viewpoint of their approval numbers and development status, and did not take into account whether these NMEs are clinically important drugs that can meet unmet medical needs. In order to view the problem of the expansion of unapproved drugs in Japan as a problem of access to new drugs for the ^public6), it is necessary to consider how many clinically important drugs are included among the unapproved drugs. In order to examine whether the expansion of unapproved drugs in Japan is a problem of access to new drugs for the public, we conducted a survey to determine whether the growing number of unapproved drugs is a group of drugs that can meet unmet medical needs in Japan from the viewpoint of their clinical importance.

2. research methods

The survey covered 117 unapproved drugs as of the 2016 survey, which was the bottom of the unapproved drug ratio in the previous News ¹⁾, and 176 unapproved drugs as of the most recent 2020 survey (Fig. 1). 117 drugs in 2016 are those approved in the US and Europe in the five years from 2012 to 2016. The 176 NMEs in 2020 refer to NMEs approved in Europe and the U.S. during the five-year period from 2016 to 2020 that have not been approved in Japan as of the end of 2020 (i.e., unapproved drugs in Japan). The following terms used in this paper are defined as follows.

The following terms used in this paper are defined. Unmet medical needs refers to "unmet medical needs, i.e., medical needs for diseases for which there is still no effective treatment. " ⁷⁾ It does not take into account factors such as the projected number of patients, market size, manufacturers' business priorities, or economic rationale.

A clinically important drug that can meet an unmet medical need is defined as "a drug that clearly outperforms existing therapies in terms of efficacy or effectiveness for patients for whom no treatment options are available," and is defined by the U.S. Food and Drug Administration (FDA) as a Fast Track drug, which is a drug that has been approved for use in the treatment of a disease for which no treatment options are available, According to the FDA's public ^{information4, 8)}, FDA Fast Track (FT) is defined as a new drug that meets an unmet medical need for a serious disease or has the potential to outperform existing drugs and existing treatments. Breakthrough Therapy (BT) is defined as a potential breakthrough that may lead to a more substantial innovation than FT, which is consistent with this definition. For each unapproved drug that has not yet been approved in Japan, there were limitations in conducting desk research to clarify the degree of clinical importance of the drug using information from Japan. Therefore, it was decided to extrapolate information on special regulatory action designations (FT and BT designations) at the time of approval of new drugs in the U.S. ⁹⁾, where more than 80% of new drugs sold worldwide are approved and marketed, to ^Japan9), where approximately 40% of new drugs are approved and marketed. It is also considered that PRIME-designated ^{products4, 10)} by the European Medicines Agency (EMA) should ^also be included because they meet the definition of a clinically important drug here. However, since PRIME-designated products were first approved by the EMA in 2018, and similar designations did not exist until then, they were excluded from the tabulation to ensure fairness in comparing the early and late 2010s.

Clinical Importance of Unapproved Drugs in Japan

To determine how many of the unapproved drugs in Japan contain clinically important drugs that could address unmet medical needs, the number of unapproved drugs as of the 2016 survey and the number of unapproved drugs as of the 2020 survey, 117 of which were unapproved as of the 2016 survey and 176 of which were unapproved as of the 2020 survey, was calculated using the number of special regulatory action designations (FDA's FT and BT designations) and their percentages (Figure 2, left). Drugs that received both FT and BT designations were not included in the number of FT-designated products, but were counted as BT-designated products.

Of the 176 unapproved drugs at the time of the 2020 survey, 51 NMEs received BT designation from the FDA and 42 received FT designation, making the total number of clinically important drugs with BT and FT designations 93, or 53% of all unapproved drugs. (= BT-designated + FT-designated) were 42, or 36% of all unapproved drugs, indicating that the number and percentage had expanded by the time of the 2020 survey.

For comparison, the percentages of BT and FT in FDA-approved NMEs were analyzed for NMEs approved by the FDA from 2012-2016 and NMEs approved by the FDA from 2016-2020 in order to align the time periods covered with unapproved drugs as of the 2016 survey and the 2020 survey, respectively. were analyzed. The results showed that 44% of NMEs approved by the FDA in 2012-2016 and 55% in 2016-2020 received BT or FT. This indicates that the percentage of clinically important drugs increased in unapproved drugs during this time period as much as or more than the overall trend in FDA-approved NMEs.

4-1. unapproved drugs in Japan: orphan drugs

In considering unmet medical needs, rare diseases are a prime example of diseases for which there is still no effective treatment. Here, we conducted a survey to determine the number of unapproved drugs in Japan that have received orphan designation from the FDA and EMA (Fig. 2, right). For the differences in the criteria for orphan designation between Japan, the U.S., and Europe, please refer to the past Policy Research Institute ^{News4, 11).}

Of the 176 unapproved drugs in the 2020 survey, 90 NMEs had received orphan designation by the FDA or EMA, accounting for 51% of all unapproved drugs. showed that the number and their percentage had expanded as of the time of the survey.

As a comparison, the percentage of FDA-approved NMEs with orphan designation was examined: the percentage of approved NMEs with orphan designation among FDA-approved NMEs from 2012-2016 was 40%, and 50% from 2016-2020; the percentage of orphan drugs among unapproved drugs was The increase in the percentage of orphan drug designations in the total number of approved NMEs was found to be roughly equivalent to the increase in the percentage of orphan drug designations in the total number of FDA-approved NMEs.

4-2. unapproved drugs in japan: analysis of clinical importance of orphan drugs and domestic development information

The status of FDA FT and BT designations and information on domestic development of unapproved NMEs that had received orphan designation in the U.S. and Europe were surveyed. The survey covered 90 drugs for which domestic development information was available at the time of the 2020 survey (Figure 3).

Of the 90 domestic unapproved drugs with orphan designation, 39 NMEs received BT designation from the FDA and 29 received FT designation. The total number of clinically important drugs with BT and FT designations was 68, accounting for 75% of all unapproved drugs covered (Figure 3, left). This percentage was more than 20 percentage points higher than the 53% share of clinically important drugs (= BT-designated + FT-designated drugs) among the 176 unapproved drugs as of the 2020 survey, as shown in Chapter 3.

Next, for the 90 unapproved drugs in Japan that received orphan designation in the U.S. and Europe, 40 drugs for which development information was available in Japan as of the end of 2020 and 50 drugs for which development information was not available were classified by the year of approval in the U.S. and Europe, and the tentative status of delayed approval in Japan between the year of U.S. and European approval and the 2020 survey is shown (Figure 3, center). Of the 90 unapproved orphan-designated drugs, 43 (48%), nearly half, had an approval delay of two years or more (= lag) as of the 2020 survey. In addition, more than half (50) of the unapproved drugs were not developed in Japan, 24 of which were approved in the U.S. or Europe before 2018. Of the 40 drugs for which development information was available, 19, accounting for about half, had a lag of more than two years, indicating that even among the unapproved drugs for which development information was available, many had already experienced approval delays.

Finally, looking at the status of special regulatory action designations (FT and BT designations) for the 50 NMEs that received orphan designation in the U.S. and Europe but for which no development information was available in Japan, there are 18 NMEs each with BT and FT designations from the FDA, and the total number of clinically important drugs with BT designation and FT designation totaled 36 products, accounting for 72% of the total number of unapproved drugs covered (Figure 3, right).

5-1. unapproved drugs in japan by drug class

To understand the increase in the number of unapproved drugs in Japan in the late 2010s, we conducted a comparative survey of 117 unapproved drugs in Japan as of 2016 and 176 unapproved drugs in Japan as of 2020, by drug ^category12) (Figure 4).

Looking at the number of unapproved drugs in Japan as of the 2020 survey by efficacy category, the largest number of 44 drugs, or 25% of the total, were anti-cancer agents (L01). The classification of drugs with 10 or more unapproved drugs in Japan is as follows: systemic anti-infectives (J) 22 (12.5%), neurological agents (N) 22 (12.5%), gastrointestinal and metabolic agents (A) 19 (11%), others (V, diagnostic agents, etc.) 12 (7%), blood and blood-forming organs agents (B) 11 (6%), and others (V, diagnostic agents, etc.) 12 (7%), and others (B, blood and blood-forming organs) 11 (6%). The number of products in this category was 19 (11%). The top three areas of antineoplastic agents (L01), systemic anti-infectives (J), and drugs for the nervous system (N) accounted for 88 half of the total number of unapproved drugs.

The next section compares data as of the 2020 survey with data as of the 2016 survey. One major difference is that the number of unapproved drugs for anti-cancer agents increased from 21 in 2016 to 44 in 2020, more than doubling the number of unapproved drugs. There was also a doubling of the number of neurological agents, from 11 in 2016 to 22 in 2020.

Next, we look at the 90 unapproved drugs with orphan designation in the U.S. and Europe discussed in Chapter 4 by drug class: of the 90 unapproved drugs with orphan designation at the end of the 2020 survey, 32 were anti-cancer drugs (L01), the largest number, 10 were gastrointestinal and metabolic drugs (A), 9 were blood and blood-forming organ drugs (B), 9 were systemic anti-infective drugs (C), 10 were systemic anti-infective drugs (C), 9 were systemic anti-infective drugs (D), and 10 were systemic anti-infective drugs (E). This was followed by 10 drugs for the gastrointestinal tract and metabolism (A), 9 drugs for blood and blood-forming organs (B), 8 systemic anti-infectives (J), 6 drugs for the nervous system (N), and 6 anti-parasitic drugs, insecticides, and insect repellents (P). In particular, for antineoplastics and drugs for blood and blood-forming organs, more than 70% of the unapproved drugs in the target areas were orphan-designated products. On the other hand, in the areas of systemic anti-infectives and drugs for the nervous system, orphan drugs accounted for less than 40% of unapproved drugs.

Finally, we compare data for unapproved European and U.S. orphan-designated products by therapeutic area as of the 2020 survey and as of 2016. In the case of anti-cancer drugs, the number of orphan drugs was 15 in 2016, and the percentage of orphan drugs within the same therapeutic area was 71%. This means that a high percentage of NMEs for rare cancers and rare segments remained unapproved in both years. In addition, 8 (36%) systemic anti-infectives and 6 (27%) neurological agents, which accounted for less than 40% of the total number of unapproved drugs in 2020, were still unapproved in 2016, with 4 (24%) systemic anti-infectives and 2 (18%) neurological agents, respectively. Both the number and percentage of unapproved drugs increased significantly in both drug classes.

5-2. unapproved drugs in japan: analysis of anti-cancer drugs

In order to conduct a more detailed analysis by therapeutic category, a survey was conducted incorporating disease classification, clinical importance, and development information for the top three areas of unapproved drugs in 2020 for which domestic development information was available at the time of the survey, namely, anti-cancer agents (L01), systemic anti-infectives (J), and neurological agents (N), which accounted for half of all unapproved drugs. The survey incorporated disease classification, clinical importance, and development information for the top three therapeutic areas of L01, J, and N.

For the 44 anti-cancer drugs that account for the largest number of unapproved drugs in Japan, we used the "List of drugs and indications that are unapproved or off-label under the Pharmaceutical Affairs Law in Japan (revised October 31, 2021, February 28, 2021, and April 30, 2020 editions) ¹³⁾ published by the National Cancer Center, a national research institute. The analysis was conducted based on the drug's cancer type information and the evidence information from the NCCN (National Comprehensive Cancer Network: a guideline development organization formed by leading cancer centers in the United States) ^{13, 14)}. The NCCN Evidence 2A or higher used in the analysis indicates that there is a unified NCCN consensus that an evidence-based intervention is appropriate and recommended (Figure 5).

First, we examined the breakdown of unapproved drugs by cancer type. The largest number of NMEs, 18 or 41%, were approved for the indication of "hematologic cancers," which are known as rare cancers, followed by 8 (18%) for breast, 4 (9%) for urology, 3 (7%) for lung, and 2 (5%) for GIST (gastrointestinal stromal tumor) (Figure 5, upper left) As shown in Chapter 5-1, the number of drugs approved for rare cancers such as hematologic cancers and GIST and Orphan-designated NMEs for rare segments accounted for 32 products (73%).

Next, to determine whether the 44 unapproved drugs were drugs that could meet unmet medical needs, we analyzed their clinical importance based on the FDA's FT and BT designation information. The results showed that 25 NMEs received BT designation from the FDA and 7 received FT designation, for a total of 32 drugs or 73% of the total. In addition, 11 NMEs with NCCN guideline evidence level 2A or higher were included for other unapproved drugs (Figure 5, upper right).

The 44 unapproved anti-cancer drugs were divided into 31 drugs for which development information was available in Japan as of the end of 2020 and 13 drugs for which development information was not available, and the tentative status of delayed approval in Japan between the year of approval in Europe and the United States and the time of the 2020 survey is shown (Figure 5, lower left). Of the 44 unapproved drugs, 20 (45%) had an approval delay of two years or more (= lag) as of the 2020 survey. For this therapeutic area, 31 (70%) unapproved drugs were in development in Japan, 14 of which were approved in the U.S. or Europe before 2018. Of the 13 drugs for which there was no domestic development information, 6 also had a lag of more than 2 years.

Finally, looking at the status of special regulatory action designations (FT and BT designations) for the 13 drugs for which there was no domestic development information, there were 10 NMEs that received BT or FT designation from the FDA as clinically important drugs, accounting for 77% of the unapproved drugs covered (Figure 5, bottom right).

5-3. unapproved drugs in japan: systemic anti-infectives

Twenty-two systemic anti-infective drugs in the top three unapproved drug classes in Japan as of the 2020 survey were surveyed, incorporating disease classification, clinical importance, and development information (Figure 6). For details of antibacterial agents including AMR (Antimicrobial Resistance) agents in this area, please refer to the analysis by YUASA et al. in "Policy Research Institute News No. 65" (March 2022) ¹⁵⁾.

The disease classification of systemic anti-infectives is shown in Figure 6 (upper left). 10 NMEs, accounting for 45% of the total, were the most common antimicrobial agents indicated for the treatment of AMR, and including one other antimicrobial agent, they accounted for half of the total. This was followed by a total of seven antiviral drugs (32%), four HIV, two HCV, and one HDV, and four drugs (18%) considered approved in relation to security and public health crisis management, including Ebola, smallpox, and anthrax. Regarding this drug category, it can be seen that a large number of unapproved drugs include AMR ^{drugs15, 16)} for which it is becoming increasingly difficult to respond with existing drugs in Japan and abroad and new drugs are desired, and NMEs related to security and public health crisis ^{management17)}.

Next, looking at the clinical importance of the 22 unapproved drugs based on the FDA's FT and BT designation information, there were 7 NMEs with BT designation from the FDA and 10 with FT designation, accounting for a total of 17 drugs or 77% (Figure 6, top right).

Next, the 22 unapproved drugs for systemic anti-infectives were classified into two categories: 4 drugs for which development information was available in Japan as of the end of 2020, and 18 drugs for which no development information was available, and the tentative status of delayed approval in Japan between the year of approval in Europe and the United States and the time of the 2020 survey is shown (Figure 6, lower left). Of the 22 unapproved drugs, 13 (59%), more than half, had an approval delay of two years or more (= lag) as of the 2020 survey. In addition, only 18% (4 drugs) of the unapproved drugs in this therapeutic area are under development in Japan, again confirming that the situation is different from that in the area of anti-cancer agents, where 70% of unapproved drugs were under development, as mentioned in the previous News ¹⁾. The four NMEs for which development information was available were NMEs approved in the US and Europe after 2018, and included AMR and HIV drugs.

Finally, looking at the status of special regulatory action designations (FT and BT designations) for the 18 drugs for which no domestic development information was available, there were 14 NMEs that received BT or FT designation from the FDA as clinically important drugs, accounting for 77% of the unapproved drugs covered (Figure 6, right).

5-4. unapproved drugs in japan: drugs for the nervous system

As a final part of the survey, 22 nervous system drugs in the top three unapproved drug classes in Japan as of the 2020 survey were surveyed, incorporating disease classification, clinical importance, and development information (Figure 7).

In terms of disease classifications for nervous system drugs, analgesics (N02) were the most common, accounting for 8 products or 36% of the total (Figure 7, top left). This included seven anti-migraine products, many of which were approved in Europe and the United States between 2018 and 2020. They were followed by five other neurological drugs (N07) (23%), four antiepileptic drugs (18%), three schizophrenia drugs (14%), and two psychostimulants (N06).

Next, looking at the clinical importance of the 22 unapproved drugs based on the FDA's FT and BT designation information, three NMEs received BT designation from the FDA and seven received FT designation, for a total of 10 drugs or 45% of the total (Figure 7, top right).

Next, the 22 unapproved drugs for the nervous system were classified into two groups: 10 for which development information was available in Japan as of the end of 2020 and 12 for which no development information was available, and the tentative status of delayed approval in Japan between the year of approval in Europe and the United States and the time of the 2020 survey is shown (Figure 7, lower left). Of the 22 unapproved drugs, 11 (50%), or half of the 22 drugs, had an approval delay of two years or more (= lag) as of the 2020 survey. In addition, 45% (10 drugs) of the unapproved drugs in this therapeutic area had been developed in Japan. However, of the six unapproved neurological agents shown in Figure 4 that had received orphan designation in the U.S. and Europe, development information was not available for five of them. Of the 10 drugs for which development information was obtained, six were antimigraine agents and three were antiepileptic drugs, although these are not shown in the figure, indicating a bias in the disease categories of the drugs developed in Japan. In addition, five NMEs, half of which were approved in the U.S. and Europe before 2018, when there is a lag of more than two years from their approval in the U.S. and Europe.

Finally, looking at the status of special regulatory action designations (FT and BT designations) for the 12 NMEs for which there was no domestic development information, 8 NMEs received BT or FT designation from the FDA, accounting for 67%, indicating that many NMEs that are deemed to be drugs of high clinical importance that can meet unmet medical needs remained in high numbers. (Figure 7, bottom right).

Summary and Discussion

In this paper, in order to examine closely whether the expansion of unapproved drugs in Japan (Figure 1), as described in Policy Research Institute News No. 631 ^), is a problem of access to new drugs for the ^public6), we examine whether the increasing number of unapproved drugs are clinically important drugs that can meet unmet medical needs by examining the number and percentage of NMEs designated as BTs and FTs by the FDA. The following section will discuss the content of the survey and analysis. From this point forward, based on our survey analysis, we will consider whether the expansion of unapproved drugs in Japan will be a problem for public access to new drugs.

In Chapter 3 of this report, we showed that the number and percentage of clinically important drugs in the NMEs as of the 2020 survey have expanded since 2016 (Figure 2, left). 176 NMEs as of the 2020 survey include drugs with FT or BT designations in the U.S., more than half (53%) of the 176 drugs in the NMEs as of the 2020 survey. 53%, an increase of 17 percentage points from 36% in 2016, which was similar to the trend in FT and BT designations for all FDA-approved NMEs. In other words, there was no significant difference in the percentage of FDA-designated clinically important NMEs and other NMEs that were unapproved in Japan as of the 2016 and 2020 surveys, indicating that clinical importance, by itself, is not a significant incentive to initiate development in Japan. This indicates that clinical importance by itself is not a major incentive to initiate development in Japan. And the fact that these clinically important NMEs remain as unapproved drugs is considered to be a problem for the public in terms of access to new drugs.

In Chapter 4 of this report, we surveyed unapproved drugs in Japan that have received orphan designation in Europe and the United States for rare diseases, which are important in considering unmet medical needs and represent diseases for which there is still no effective treatment, and showed that the number of unapproved drugs and their ratio are expanding (Figure 2, right). Of the 90 domestic unapproved drugs with orphan designation as of 2020, clinically important drugs with FT or BT designation in the U.S. accounted for 75%. More than half of the unapproved drugs with orphan designation were not developed in Japan, and 72% of the 50 unapproved drugs with no development information were clinically important drugs (Figure 3).

However, more than 70% of the drugs were judged to be clinically important in the United ^{States9) ,} where more than 80% of new drugs marketed worldwide are approved, and therefore, it is likely that there are many drugs that could be clinically important if developed in Japan. (9), where more than 80% of new drugs marketed worldwide are approved, it is likely that there are many drugs that could become clinically important if developed in Japan as well. In addition, 40 drugs under development are considered to be NMEs that have been judged by pharmaceutical companies and others to be worth bringing to the domestic market, but 48% of the drugs had a lag of more than two years after approval in Europe and the U.S. (Figure 3). As an addition, a survey of domestic approval status as of the end of 2021 revealed that 14 of the 90 unapproved drugs that received orphan designation in the U.S. and Europe had received domestic approval in 2021. On the other hand, for the 76 drugs that were not approved in 2021, there was an additional lag of one year from the provisional approval delay figures in Figure 3.

Thus, a detailed look at the clinical importance and domestic development information of unapproved drugs for rare diseases shows that there are many unapproved drugs that could meet unmet medical needs in Japan, and that either they have not been developed or, even if they have been developed, the lag of several years would still make them ineffective. The lack of development of these drugs, or the lag of several years when they are developed, is thought to cause delays in access to needed new drugs for patients who still lack effective therapies.

In Chapter 5 of this report, we conducted a survey of unapproved drugs in Japan by drug class, and found that unapproved drugs in the top three therapeutic areas of anti-cancer agents, systemic anti-infectives, and neurological agents accounted for half of all unapproved drugs in Japan as of 2020, with the number of unapproved drugs in anti-cancer agents and neurological agents in particular doubling compared to 2016. This was thought to have influenced the expansion of unapproved drugs during this period (Figure 4).

Next, we discuss the differences in the status of unapproved drugs by disease area by comparing the top three areas that account for half of all unapproved drugs. Among the 44 unapproved drugs in the area of anti-cancer agents, 73% have orphan designations for rare cancers and rare segments such as hematologic cancers and GIST, and 73% are clinically important drugs with FT or BT designations in the United States, This indicates that there are many drugs that could meet unmet medical needs that are not yet approved in Japan. The survey also found that although the number of unapproved drugs in the area of anti-cancer agents in Japan was higher than in other therapeutic areas, 70% (31 drugs) of the unapproved drugs were in development in Japan. However, the 13 unapproved drugs for which development information was not available also include 9 (69%) drugs for rare cancer indications and 10 (77%) drugs of clinical importance, and the fact that these NMEs will remain unapproved will be a problem in terms of new drug access for patients who still lack effective treatment options.

On the other hand, among the 22 unapproved drugs for systemic infectious diseases, 77% were clinically important drugs with FT or BT designation in the U.S., while only less than 20% were in development in Japan (Figure 6). Looking at the disease classifications of the 22 unapproved drugs, 68% of the drugs included novel antimicrobials and drugs related to security and public health risk management, indicating that these drug groups are not being actively developed in Japan. For example, the Japan Agency for Medical Research and Development (AMED) has published the "List of Pathogens to be Targeted in AMR Drug Discovery Research (2021 Edition) ¹⁶⁾ and has called for the strengthening of measures against new antimicrobial agents, but the difficulty of including AMR infection cases in clinical trials, low profitability of antimicrobial agents, and other reasons have made development difficult. The difficulty of development due to the difficulty of incorporating AMR infection cases into clinical trials, low profitability of antimicrobial agents, and other reasons have been discussed extensively and have become a major ^problem15). In other words, although there are many clinically important drugs that can meet unmet medical needs in this therapeutic area, they remain unapproved because of difficulties in development due to difficulties in establishing clinical trials, small market size, low profitability, and the small number of patients at present. The number of patients is small at this point. The need for clinically important unapproved drugs will be recognized by society in general when the number of patients increases explosively, as in the case of new coronary infections, but at that time, the drugs will not be available promptly because they are not approved in Japan, which could be a serious new drug access problem in emergency situations.

In the area of drugs for the nervous system, although slightly less than half of the unapproved drugs were in development in Japan, the target diseases for which items were in development were unevenly distributed. In addition, 67% of the drugs with no development information were designated as BT or FT by the FDA, indicating that many drugs that are deemed clinically important in the U.S. and can address unmet medical needs are not approved in Japan (Figure 7). In this drug area, it is assumed that even clinically important drugs are hesitant to be developed due to the extremely difficult verification of efficacy through clinical development and the low probability of success in clinical trials. Therefore, although development of drugs with a large market is prioritized, clinical importance alone may not be enough of an incentive for development.

Conclusion

In this study, we have investigated and analyzed whether the expansion of domestically unapproved drugs is a ^problem6) of access to new drugs for the public. In conclusion, we suggest that the current unapproved drugs in Japan include drugs that could address many unmet medical needs and pose a challenge to access to new drugs in Japan. Although some areas, such as infectious diseases, may not appear to be a problem for access to new drugs at first glance, there is a need to consider policy responses as a risk management issue for the entire nation.

The biggest problem with a drug lag is that clinically important drugs that clearly outperform existing therapies or are effective for patients who have no treatment options do not enter the domestic market, creating an access problem for patients. While it is desirable that the "lag" in approval and launch of domestically developed drugs be as short as possible, it is possible that patients will be able to access these drugs in Japan in the future. However, it is important to understand that drugs that have not yet been developed in Japan may be available overseas, but not in Japan, even if they wait.

Recently, an increasing number of experts have begun to refer to the current situation as a "drug lag," in which drugs are being passed over by foreign companies, including emerging foreign biopharmaceutical companies, without even being developed in Japan, as a new drug loss. The expansion of unapproved drugs in Japan is considered to be a phenomenon of drug loss, and we will combine the results of the detailed analysis of factors contributing to the increase in unapproved ^drugs18) reported by Iida et al. in this news item, as well as the results of drug lag situations and factor analysis published by other organizations, to establish a national policy to provide the public with appropriate new drugs without delay, as in the US and Europe. We hope that the government as a whole will take policy measures to establish a situation where appropriate new drugs are provided to the public without lagging behind Europe and the U.S. 3.

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