Topics Drug Lag: Comparison of the status of unapproved drugs in Japan and Europe -Based on drugs approved in the U.S. from 2010 to 2021

Printable PDF

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

Executive Summary

The number of "unapproved drugs" that are already approved in Europe and the U.S. but not yet approved in Japan is increasing, and this increase in the late 2010s is a challenge for access to medicines in Japan, especially for drugs created by emerging companies in the U.S., where development activities are becoming more independent. Under these circumstances, a comparison of the unapproved drug situation with that in Europe was sought, based on the idea that the U.S. is unique in the pharmaceutical market. This paper compares the status of unapproved drugs in Japan and Europe, and finds that the speed of approval of new drugs approved in the U.S. is slower in Japan than in Europe, and the estimated final approval rate is also lower. In particular, the approval rate in Japan for items from emerging companies is notably lower than in Europe, raising concerns about the impact on access to medicines. Given this, the expansion of unapproved drugs in Japan should be viewed as a challenge unique to Japan, and policy responses to promote and ensure access to the latest medicines need to be considered.

1. Introduction

The environment surrounding NHI drug prices is becoming more challenging every year, with 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 pricing system in FY2018 and the implementation of mid-year revisions in FY2021, and there is growing concern that a "drug lag" may resurface as the attractiveness of the Japanese drug market ^declines1). The Pharmaceutical and Industrial Policy Research Institute (PIIPRI) reported on the drug lag situation in recent years in PIIPRI News No.63 and No.66, and found that (1) the gap between the timing of drug launches in Japan and that in Europe and the United States tends to be shorter for drugs that have been launched in ^Japan2) and (2) the number of "drugs not approved in Japan" that have been approved in other countries but not yet approved in Japan has been decreasing. 2) The number of "unapproved drugs in Japan" that have been approved in other countries but not in Japan showed signs of expansion in the latter half of the 2010s. One of the reasons for this is that the number of drugs discovered by emerging companies, which are becoming more independent in their development activities, is increasing in Europe and the United States, and these companies do not have development subsidiaries in Japan, so they are not developing drugs in ^Japan3). 4) The increase in the number of unapproved drugs in Japan is due to the low rate of inclusion of Japanese companies in international clinical trials, especially those conducted as pivotal trials for products of startup companies, and the Japanese clinical trial environment, pharmaceutical affairs system, and the low expected business value of Japanese development are assumed to be the main reasons for this increase5 ⁾. ⁵⁾.

Based on these results, there has been an increase in the number of editorials from various quarters calling the current situation where foreign companies, including rapidly emerging foreign start-ups, are passing through Japan without even starting drug development in Japan a new drug lag. As society's interest in this issue grows, there is a need for further clarification of facts and reality.

In order to gain a deeper understanding of the situation of unapproved drugs in Japan, this report expands the scope of the survey from the analysis of unapproved drugs and factors in Japan, which has been the subject of previous studies, to a comparative study of unapproved drugs in Japan and Europe, using new drugs in the United States as a benchmark. The U.S. is the largest market, accounting for approximately 40% of the global pharmaceutical market in terms of ^sales6), with many of the first products launched in Japan, the U.S., and ^Europe6), higher incentives for innovation through drug prices and other ^means1), the highest number of international clinical trials conducted by ^country7), and the remarkable rise of emerging ^companies8), 8) It is sometimes regarded as a special country that sets itself apart from other countries. Therefore, a comparison of the approval status of new drugs approved in the U.S. in Europe, where the market environment is closer to that of Japan, would be useful information for analyzing the issue of unapproved drugs in Japan. In this report, we review the disease classifications, domestic development status, and unapproved status of new drugs approved in the U.S. from 2010 to 2021, and analyze the unapproved status by comparing Japan and Europe, as well as pharmaceutical companies and startups.

2. research methods

The scope of this study included drugs containing New Molecular Entity (NME) approved by the Center for Drug Evaluation Research (CDER) of the U.S. Food and Drug Administration (FDA) from 2010 to 2021. NMEs were counted for drugs listed in the "New Molecular Entity (NME) Drug & Original Biologic Approvals Calendar Year " ⁹⁾. It should be noted that items approved by the FDA's Center for Biologics Evaluation and Research (CBER) ¹⁰⁾ were not included as a limitation of the survey. In Japan, the drugs were those listed in the "List of New Drugs Approved " ¹¹ on the website of the Pharmaceuticals and Medical Devices Agency (PMDA), while in Europe, the drugs were those approved by the European Medicines Agency (EMA) under the central review system and listed in the "European The European category was defined as medicinal products approved by the European Medicines Agency (EMA) through the central review process and listed in the "European Medicines Agency Annual Reports " ¹²⁾.

Disease classification was based on The Anatomical Therapeutic Chemical code (ATC code) of each item by referring to the WHO ^website13). For items for which no ATC code was assigned, those expected from analogous drugs were used.

Information on domestic development of the surveyed drugs was based on the description in "New Drugs for Tomorrow (Technomic Production). For items for which information on the development stage had been obtained approximately three years earlier, "No further information" was used for items for which information on the continuation of development could not be confirmed. In addition, items for which only preclinical development information was available were included in the "no development information" category.

The technical classification was divided into synthetic chemical drugs and biopharmaceuticals. Synthetic chemical drugs are drugs (small molecules, nucleic acids, peptides, etc.) produced by stepwise chemical synthesis. Biopharmaceuticals are defined as those with "Genetical Recombination" in the generic name, such as antibodies, and those with "Specified Biological Derivatives Product" or "Biological Derivatives Product" in the package insert. For products not approved in Japan, we individually investigated the FDA and EMA approval information and the websites of each company.

Companies were classified as Emerging Bio Pharma (EBP) if they had been approved within 30 years of their establishment and had sales of less than US$500 million in the year prior to approval, and as Pharma (EBP) if they were not approved. (EBPs) are defined as emerging bio-pharma (EBPs). Overseas affiliates of Japanese companies are not included in the EBP category. Companies not listed in EvaluatePharma were supplemented by web searches.

Standard statistical analysis software Stata/IC 14.0 for Window (s Stata Corp LP, College Station, TX, USA) was used for the analysis.

3-1. disease classification and domestic development status of FDA-approved NMEs

First, we review the disease classifications and domestic development status of the 481 NMEs approved by the FDA from 2010 to 2021 that were the subject of this study (Figure 1).

Looking at the disease areas of NMEs approved by the FDA during this period, antineoplastic agents were the most common, accounting for 123 products, or 26% of the total. This is more than double the number of systemic infectious disease agents, which came in second with 55 (11%), indicating that antineoplastic agents were actively approved in the United States. Other top approved drugs included 53 (11%) for gastrointestinal and metabolic, 49 (10%) for neurological, and 41 (9%) for immunomodulatory, showing the trend of NME approvals by disease area in the US from 2010 to 2021.

Next, looking at the 253 unapproved drugs in Japan as of the end of the 2021 survey, anti-cancer drugs were the most common, at 52 (21% of the total; the same applies to the 253 drugs in the population). The largest number of anti-tumor drugs was 52 (21%; population: 253). Although the number of drugs approved in Japan is the largest among all therapeutic areas, with 71, the percentage of anti-cancer drugs is higher than that of unapproved drugs as a whole due to the large number of FDA-approved drugs. Of the 52 unapproved drugs, 32 are still under development in Japan, confirming the efforts of pharmaceutical companies to obtain approval in Japan. The number of unapproved drugs in other therapeutic areas is 31 (12%) for neurological agents, 29 (11%) for gastrointestinal and metabolic agents, and 27 (11%) for systemic infectious disease agents.

Finally, we will look at the 137 unapproved drugs for which no development information is currently available. In terms of disease areas, 20 (15%) are systemic infectious disease agents, 19 (19%) are gastrointestinal and metabolic agents, and 19 (11%) are systemic infectious disease agents. The following therapeutic areas were followed by gastrointestinal and metabolic agents (19 items, 14%), neurological agents (17 items, 12%), diagnostics and others (15 items, 11%), and anti-cancer agents (14 items, 10%). Although the contents of each of these areas are not discussed here, please refer to the previous issue of NME News for an analysis of anti-cancer drugs, systemic infectious disease drugs, and nervous system drugs, which are slightly different from those surveyed in this ^report4).

3-2. technology classification of FDA-approved NMEs and unapproved drugs in Japan

Next, an overview of the 481 NMEs surveyed is provided by dividing them by the technical classification of the active ingredient (biopharmaceuticals and synthetic drugs) (Figure 2).

Looking at the technical classification of the 481 NMEs approved by the FDA during this period, biopharmaceuticals accounted for 122 (25%), or a quarter of the total, while synthetic drugs accounted for 359 (75%). Next, looking at the 253 unapproved drugs in Japan, the percentage of biopharmaceuticals dropped to 20% (51 items) and 80% (202 items) were synthetic chemical drugs compared to the total number of FDA-approved drugs. Furthermore, for the 137 drugs not approved in Japan for which no information on domestic development was available, the percentage of biopharmaceuticals declined further to 15% (20 drugs), 10 percentage points lower than the overall FDA-approved drugs, and 85% (117 drugs) were synthetic chemical drugs. In other words, the development of U.S.-approved NMEs (biopharmaceuticals) in Japan was not lagging behind that of synthetic drugs; rather, the percentage of unapproved drugs that existed as unapproved drugs was low and the percentage of those developed domestically was high.

3-3. status of unapproved drugs for fda-approved nme in japan

Next, we review the status of unapproved drugs in Japan for the 481 NMEs surveyed in this report (Figure 3).

As of the end of 2021, the domestic approval status of the 481 NMEs approved by the FDA over the 12-year period from 2010 to 2021 was 228 (47%) approved in Japan and 253 (53%) unapproved in Japan.

Looking at the domestic development status of the 253 unapproved drugs in Japan as of the end of 2021, 83 (33%) were under development in Japan, and for the remaining 170 (67%), no information on domestic development activity was available at present. These items are a group of products that have no plans to be introduced in Japan.

Information on special regulatory ^measures14) at the time of FDA approval was examined for the 137 items with no information on development in Japan, excluding those items for which development in Japan has been discontinued, suspended, or no further information was available. Priority ^Review15), which designates new drugs with clinical results that lead to a significant improvement in efficacy or safety, was confirmed for 78 (57%) of the 137 drugs with no domestic development information. In addition, 61 (45%) of the Orphan drugs, which are designated for new drugs developed for diseases that, in principle, affect fewer than 200,000 patients in the U.S., were designated. The Fast Track category, which designates new drugs that meet unmet needs for serious diseases, have no existing drugs, or have the potential to surpass existing treatments, was designated for 52 (38%) of the drugs, and the Breakthrough Therapy category, which designates new drugs that have the potential to be breakthroughs that will lead to more substantial innovations than the Fast Track drugs. Breakthrough Therapy, which designates drugs that have the potential to be breakthroughs that will lead to further substantive innovations beyond Fast Track, was confirmed for 28 items (20%). The percentage of each of the above special measures was within 0 to 3 percentage points above or below the percentage of all 481 FDA-approved NMEs surveyed. On the other hand, for Accelerated Approval, a fast-track approval for serious diseases that is expected to meet unmet needs based on surrogate/intermediate endpoint results and is intended to speed access to patients, 14 of the 137 NMEs with no domestic development information (10%) were approved, while the remaining 14 of the 137 NMEs with no domestic development information (10%) were approved for serious diseases. 10%), which is 5 percentage points lower than the overall percentage of FDA-approved NMEs (15%), indicating that the rate of domestic development is higher than other groups designated for special measures in the pharmaceutical affairs.

4-1. Comparison of FDA-approved NMEs in Japan and Europe

We will now compare the status of unapproved drugs in Japan and Europe, which is the main topic of this paper. First, we surveyed the approval status of 481 NMEs approved by the FDA from 2010 to 2021 in Japan and Europe as of the end of 2021 (Figure 4).

As mentioned above, 228 (47%) were approved and 253 (53%) were unapproved in Japan, while 326 (68%) were approved and 155 (32%) were unapproved in Europe. As a result, although this is a snapshot as of the end of 2021, Japan has 98 fewer approved products than Europe, with a 21-point lower approval rate (i.e., a higher percentage of unapproved drugs), indicating that many products have not entered Japan.

4-2. Comparison of Approval Rates of FDA-approved NMEs in Japan and Europe (Statistical Analysis)

To compare the number of unapproved drugs in Japan and Europe, the number of unapproved drugs and approval rates in Japan and Europe were tabulated for the 481 NMEs approved by the FDA at each survey point (end of December of each year) (Figure 5). The overall view shows that the approval rate is lower in Japan than in Europe at all time points, indicating that the number of unapproved drugs in Japan is higher than in Europe.

Next, using the above data set, panel data on trends in cumulative approval rates in Japan and Europe were created and divided into the entire study year (2010-2021) and the earlier (2010-2015) and later (2016-2021) periods to examine the relationship between the number of years since the year of initial approval and approval rates for US NMEs. Logistic regression analysis was performed to examine the relationship between the elapsed time since the first US NME approval year and the approval rate (Figure 6, Supplement 1).

The results of the analysis (Figure 6, left) showed that the percentage of items approved in the same year (x=0) in the U.S. and Japan was 19%, while the percentage of items approved in the same year as the U.S. in Europe was 35%, a difference of 16 percentage points. Comparing the levels at 5 years (x=5) and 10 years (x=10) after U.S. approval, the estimated approval rate in Japan increases over time to 59% at 5 years and 67% at 10 years, approaching the height where the curve asymptotes (68%). On the other hand, the estimated approval rates in Europe are 78% for 5 years and 78% for 10 years, indicating that the curve is already approaching the asymptote (79%) 5 years after approval in the US. This indicates that the height of the curve is higher in Europe than in Japan, both initially and eventually (i.e., higher approval rates). And it can be seen that Europe has a faster approval rate for U.S. NMEs than Japan, with an estimated approval rate that is 11 percentage points higher than that of Japan, both initially and finally. In other words, while Europe has about 80% approval as early as 1-3 years after U.S. approval, Japan's approval rate is estimated to be less than 70% even after 10 years, although the approval rate gradually increases over 10 years, indicating a greater risk of drug lag compared to Europe.

In addition, the results are shown in Figure 6 (right), where the survey years are analyzed separately for the first semester (2010-2015) and the second semester (2016-2021). In the earlier period, the percentage of products approved in the same year in the U.S. and Japan (x=0) was 21%, while in the later period it was 14%. Comparing the estimated level 5 years after approval in the U.S. (x=5), 59% of the products approved in the U.S. in the previous period were approved in Japan, while 44% were approved in the latter period, a decrease of 15 points from the previous period. In Europe, on the other hand, the percentage of products approved in the same year in both the U.S. and Europe (x=0) was 43% in the previous year, while it was 29% in the second year, a decrease of 14 percentage points from the previous year. Comparing the estimated levels five years after approval in the U.S. (x=5), 79% of the products approved in the U.S. in the previous period were approved in Europe, while the level dropped to 74% in the latter period. In other words, both the Japanese and European poles suggest that the curve is higher in the earlier period than in the later period, both in the early and in the final period. This lower approval rate in Japan and Europe in the late period compared to the early period was statistically significant (Supplement 1). Comparing Japan and Europe, there was a 22-point difference between the approval rates in Japan and Europe in the early period, but in the late period, the difference had narrowed to a 15-point difference, although the level had declined in both poles compared to the early period. However, in the second half of the period, the difference had widened to 30 points, compared to a 20-point difference in the first period. Thus, in Japan, in particular, approval was delayed and the approval rate declined in the second half of the period compared to the first half, indicating that the risk of a drug lag has increased compared to Europe.

4-3. Number and Percentage of Unapproved FDA-approved NMEs in Japan and Europe Over Time

Using the data set presented in the previous section (Figure 5), we compiled the total number of US-approved NMEs from the previous period (2010-2015) to the latter period (2016-2021) by 6-year period, as well as the number of unapproved drugs in Japan and Europe, respectively. In addition, the ratio of the number of unapproved drugs in Japan and Europe to the number of approved NMEs in the U.S. was calculated and changes over time were tracked (Figure 7).

The results show that the number of unapproved drugs in Japan was larger than that in Europe, and the ratio of unapproved drugs was more than 20 percentage points higher in all years covered by the survey. In detail, in both Japan and Europe, the percentage of unapproved drugs showed an increasing trend from the earlier period (2010-2015) to the later period (2016-2021) of the surveyed years, with 66% of the number of US NMEs in 2016-2021 being unapproved drugs in Japan and 42% unapproved drugs in Europe. Since the number of U.S. NMEs itself also increased during this period, the number of NMEs increased from 123 domestically unapproved drugs and 59 European unapproved drugs in the previous period (2010-2015) to 183 domestically unapproved drugs and 116 European unapproved drugs in the latter period (2016-2021).

4-4. change over time in the number and percentage of unapproved FDA-approved NMEs in Japan and Europe: eliminating the effect of delayed approvals

Although the annual trend in Fig. 7 shows the increasing trend of unapproved drugs in Japan and Europe, one issue with this visualization method is that it does not fully represent the actual status of unapproved drugs, since there is a high probability that a drug that was approved by the FDA in the last year of the target year and for which Japan was included in an international joint clinical trial, will be approved in Japan the year following the year of U.S. approval. This is a point that is not fully expressed in the actual status of unapproved drugs. For example, when looking at the status of unapproved drugs in Japan and Europe for NMEs approved in the U.S. in 2019, as shown in Figure 5, 43 unapproved drugs (5 approved in 2019) in Japan and 39 (9 approved in 2019) in Europe will be counted in the same year, 2019, while the same number will be counted in the next year, 2020, and the number of unapproved drugs will be 37 in Japan. In the following year, 2020, the number of unapproved drugs will be 37 in Japan (6 approved in 2020) and 24 in Europe (15 approved in 2020), indicating that a large number of drugs will be approved in both Japan and Europe in the year following the year of U.S. approval. In its latest drug lag ^{estimation16)}, the PMDA estimated the approval delays from the U.S. for drugs containing new active ingredients approved in Japan from FY 2008 to FY 2020 based on the FDA's New Molecular Entity (NME) Drug & Original Biologic Approvals, the same survey subject as this report. The data are for items listed in the FDA's New Molecular Entity (NME) Drug & Original Biologic Approvals, which is the same as the subject of this report. According to the estimation, the items approved in Japan are considered to have a six-month approval delay from the U.S., and the median approval delay is within 0.4 to 1.0 year for all of the years covered. Therefore, by setting the time point for the number of unapproved drugs in Figure 7 to one year later, at least half of the effects of approval delays within one year in Japan can be eliminated.

Figure 8, a graphical representation based on the above, is shown below. The number of unapproved drugs in Japan and Europe for the period 2016-2021 is the aggregate number as of the end of September 2022 and is shown for reference. As a result of following the trends, the number of unapproved drugs in Japan was higher than in Europe in all surveyed years, and the percentage of unapproved drugs was more than 20 percentage points higher in Japan than in Europe. In detail, in both Japan and Europe, the percentage of unapproved drugs showed an increasing trend from the surveyed years 2010-2015 to 2015-2020, with 57% of the number of US NMEs being unapproved in Japan and 31% being unapproved in Europe in 2015-2020, and the number of unapproved drugs increasing over time. Thus, even with the visualization method that excludes the effect of approval delays within one year of U.S. approval, the number of domestically unapproved drugs showed an increasing trend, and the percentage of unapproved drugs was more than 20 percentage points higher in all target years than in Europe.

5-1. comparison of EBP and Pharma items approved in Japan and Europe

We will now compare the status of unapproved drugs in Japan and Europe for the items of emerging companies (EBPs) and pharmaceutical companies (Pharma). First, for the 481 NMEs approved by the FDA from 2010 to 2021, we examined the classification of companies applying for approval and the approval status of EBP and Pharma items in Japan and Europe as of the end of 2021 (Figure 9).

The companies applying for approval of the 481 FDA-approved NMEs were classified into the three categories of EBP, Pharma, and Academia/NPO. 176 (37%) were EBP items, 300 (62%) were Pharma items, and 5 (1%) were Academia/NPO items.

Next, looking at the approval status of 176 EBP and 300 Pharma products in Japan and Europe, more than 60% of both EBP and Pharma products were approved in Europe, with 73% (220 products) of Pharma products in particular, and 60% (60%) of EBP products (105 products) in Pharma products. In Japan, on the other hand, more than 60% of the Pharma products were approved. On the other hand, in Japan, although more than half of the Pharma products were approved, the approval rate was 59% (178 products), 14 percentage points lower than in Europe, and for EBP products, 50 (28%) were approved and 126 (72%) were unapproved, approximately 2.5 times more than the number approved. This is 32 percentage points lower than the approval rate in Europe. Thus, the difference in approval rates between Japan and Europe is particularly large for EBP items, and there is also a difference for Pharma items.

5-2. comparison of unapproved status of EBP and Pharma products in Japan

Based on the approval status of EBP and Pharma items in Japan shown in the previous section, we investigated the domestic development status of unapproved drugs (Figure 10).

Of the 176 drugs for which EBPs have applied for approval in the U.S., 126 are unapproved in Japan. Looking at the domestic development status as of the end of 2021, 40 (32%) are under development in Japan, and for the remaining 86 (68%), no information on domestic development was available at present. Among them, 75 items (59%) accounted for those without development information. On the other hand, for the 122 Pharma products, 43 (35%) were under domestic development, a similar percentage to that of EBP, while the remaining 79 (65%) had no information on domestic development in progress, of which 57 (47%) had no domestic development information.

A comparison of the development status between EBP and Pharma shows a slight difference, with 22 (18%) Pharma items (9 points higher than EBP) having discontinued or suspended development and no further information, while more than half (53%) (65 items) showed evidence of clinical development. It is difficult to specify the reason for "discontinuation or suspension," but the reasons were diverse, including strategic reasons, changes in the business environment, failure of clinical trials in Japan, and reports of serious side effects in the U.S. and Europe, as reported in a previous issue of the NIHS ^News3).

Next, we examined the information on special regulatory ^measures14) at the time of FDA approval for items for which EBP and Pharma had obtained FDA approval and for which no information on domestic development was available (Figure 10, bottom row).

For Pharma items, the percentage of items with all special regulatory action designations decreased compared to the percentage of FDA-approved NME 481 items, indicating that a higher percentage of these special action items are developed in Japan. On the other hand, the percentage of EBPs was up 6 points (64%) for Priority Review, 3 points (48%) for Orphan, 8 points (44%) for Fast Track, 1 point (24%) for Breakthrough Therapy, and 1 point (24%) for Acceleration Therapy compared to the percentage for FDA-approved NME481. The percentage of all the items designated as special measures except Accelerated Approval was higher, up 6 points (64%), Orphan up 3 points (48%), Fast Track up 8 points (44%), Breakthrough Therapy up 1 point (24%), and Accelerated Approval down 3 points (12%), confirming that many of the EBP items that remain undeveloped in Japan are those with these special measures designations. This means that many of the EBPs that have not been developed in Japan are still in the market.

6. main points of this study

In this paper, we conducted a comparative study of the status of 481 NMEs approved by the U.S. FDA from 2010 to 2021, the status of unapproved drugs in Japan and Europe, and the status of EBPs and items submitted for Pharma approval. The main findings from this survey are presented below.

7. discussion and summary

From this point on, the survey results obtained will be discussed. First, the overview of disease areas and domestic development status of all FDA-approved NMEs (Figure 1) was designed to provide a bird's-eye view of all 481 products by disease area. Using this data, for example, the percentage of the number of NMEs without domestic development information and their rank (Rank) in the disease area can be calculated for each disease area in the US.

When aggregated as Figure 11 from the above perspective, differences in domestic development status can be seen even for the top five disease areas in the number of U.S. NMEs, indicating that the percentage of items without domestic development information is relatively low in the areas of anti-cancer drugs and immunomodulatory drugs. Including cardiovascular agents, which ranked first in Rank 1, with a low percentage of items with no domestic development information, these areas are considered to have entered Japan at a high rate due to the match between unmet medical needs, market needs taking into account the number of patients, and economic rationality on the part of companies. However, it should be noted that some of the unapproved drugs for which there is no information on development in Japan, for example, include drugs for which there is an unmet medical need but the market needs and economic rationale do not match because they are indicated for rare cancers or rare segments with small patient populations, and therefore they remain without development ⁴⁾ On the other hand, the drugs in the lower ranks of ^the Rank are not included in the list of drugs.

On the other hand, looking at the areas that are lower in Rank, in the area of anti-parasitic drugs, etc., it is thought that these drugs have not entered Japan because they are in disease areas such as tropical infectious diseases, where the number of patients occurring in Japan is extremely small. The U.S. has a policy of actively promoting research and development and approval of items that it considers important for security and public health, even if there is no market need for them, such as the recently discussed smallpox ^drug17) for monkeypox, and antibacterial agents for drug-resistant ^{bacteria4, 18)} in the area of systemic infectious disease drugs. These areas are considered to be critical access issues in emergency situations in Japan as well, where drugs are not approved domestically and therefore cannot be used promptly.

In addition, as shown in Figure 3, the 138 items for which no development information is available in Japan include many items that have been designated as special measures in the U.S. Therefore, it would be possible to conduct a deeper analysis of the factors that prevent these items from entering Japan by surveying the items for each disease area. This is an issue for future study.

In the overview of technology classification of FDA-approved NMEs, biopharmaceuticals and chemically synthesized drugs were compared, as shown in Figure 2. The percentage of biopharmaceuticals that are unapproved in Japan is lower than the percentage of biopharmaceuticals in the total FDA-approved NMEs, and furthermore, the percentage classified as biopharmaceuticals is even lower when narrowed down to unapproved drugs for which there is no domestic development information. In other words, biopharmaceuticals did not lag behind synthetic chemical drugs in development; rather, a higher percentage of biopharmaceuticals were developed. Although Japan's contribution to the creation of biopharmaceuticals is lower than that of chemically synthesized drugs in terms of the number of drugs by ^{nationality19)} of companies creating the top drugs in terms of global sales, the percentage of NMEs (biopharmaceuticals) approved in the US that are not approved in Japan is not high, and the product mix in the Japanese pharmaceutical market clearly shows that the top products are biotech. The composition of ^the Japanese drug market is clearly shifting toward biotech ^products20), indicating that the current drug lag does not reflect the problem of biotech competitiveness.

A comparison of the status of unapproved drugs in Japan and Europe shows that the approval rate in Japan is lower than in Europe and the percentage of unapproved drugs in Japan is 21 percentage points higher than in Europe, as shown in Figure 4. However, since the data in Figure 4 is a snapshot as of the end of 2021, statistical methods and changes in the number of unapproved drugs over time were also investigated and analyzed at the same time. Although the order is back and forth, Figures 7 and 8, which track the changes in the number of unapproved drugs in Japan and Europe, show that there is a trend of increasing unapproved drugs in both Japan and Europe, coupled with an increase in the number of US-approved NME, and that the difference in the ratio of unapproved drugs between Japan and Europe is always around 20 points. This result remained unchanged even after excluding the effect of approval delays of one year or less, which occur because a large number of products are approved in Japan and Europe in the year following the year of U.S. approval.

The logistic curve estimates indicate that Japan is approving US-approved NMEs at a slower rate than Europe, and the final approval rate estimates are also lower (Figure 6, Supplement 1). While Europe almost reaches the final approval rate level within 3-5 years after US approval, Japan's approval rate is expected to increase slowly with each passing year due to the larger approval delay with the US than with Europe. Regarding the approval lag, the latest drug lag ^estimate16) by PMDA introduced in the text stated that the median is within 1 year, but according to a paper by Nakamura et al. of Keio University published in 2022, for drugs containing new active ingredients approved in Japan from 2008 to 2018, ⁽²⁰²²⁾, the development lag in Japan relative to the U.S. has not decreased when looking at the overall distribution of development lag from the U.S. rather than the median, and they state that even in recent years, nearly 40% of all drugs have a development lag of 3 years or more compared to the U.S. ²¹⁾, suggesting that the late approval of drugs with such a large lag may be a factor in the 21) The late approval of drugs with such a large lag is thought to be a factor in the slow approval speed of US-approved NMEs in Japan.

The difference in the final approval rate level between Japan and Europe shown in Figure 6 also represents an estimate of the percentage of drugs that are considered clinically necessary and approved at least in the U.S. and Europe, but have not entered Japan despite waiting. According to the current estimates, the gap in the level of final approval rates between Japan and Europe is larger in the latter half of the survey period (2016-2021) than in the previous period (2010-2015), and should be monitored closely. As for the difference in the initial approval rate level between Japan and Europe, the gap narrowed in the latter half of the period compared to the previous period, but this was largely due to the impact of the large drop in the initial approval rate in Europe in the latter half of the period. In Europe, in the first half of the 2010s, there were many items that were approved in Europe first or in the same year as the US, but in recent years, the number of items approved in the US first has been increasing more than ^before22). Although the reasons for this are not clear, the scale of the U.S. market relative to Europe and the large incentives for innovation may have made the U.S. market more attractive, and the U.S. market may have become the primary focus of the European market.

The approval status in Japan and Europe for EBP and Pharma items submitted for approval shown in Figure 9 indicates that the approval rate was lower for EBP items than for Pharma items in both Europe and Japan. For Europe, the approval rate for both EBP and Pharma was over 60%, but for Japan, while Pharma items were approved at around 60%, the approval rate for EBP items was notably low at 28%. As analyzed by Iida et al. in a previous news ^article5), this may be due in part to the low rate of Japanese incorporation into international clinical trials conducted as pivotal studies for emerging company items. A look at the number of international clinical ^trials7 by country for the top five European ethical drug sales countries (Germany, France, Italy, the U.K., and Spain) ^{6) and} the status of pivotal ^trials5) for emerging companies' products in each country shows that the five European countries, like the U.S., are always in the top rank, with a large difference from Japan. The reasons for this are the clinical trial environment in Japan, the pharmaceutical affairs system, and the low expected business value of Japanese expansion ^.5) The Ministry of Health, Labor and Welfare's recent "Expert Committee on Comprehensive Measures to Achieve a Rapid and Stable Supply of Pharmaceuticals " ^{1) also} addressed this drug lag issue, and future policy responses are anticipated. We look forward to future policy responses to this issue.

A comparison of the status of unapproved drugs in Japan for EBP and Pharma items in Figure 10 shows that among EBP items, a higher percentage of unapproved drugs without domestic development information are those that have received special regulatory action designation in the US. This means that a number of clinically important drugs may be included, and the increase in the number of unapproved drugs once again confirms that access to new drugs in Japan will be a challenge.

Conclusion

In this study, we compared the status of unapproved drugs in Japan and Europe based on NMEs approved in the U.S. from 2010 to 2021. The results showed that the approval rate of new drugs approved in the U.S. is slower in Japan than in Europe, and the estimated final approval rate is also lower. This has been the case since the early years of the study, but has worsened in the later years (2016-2021). One reason for this is that the approval rate of EBP products in Japan is notably lower than in Europe, and with the increasing presence of EBPs in the US-approved NME, there are concerns about the future impact on access to newer drugs. For a comparison between Japan and Europe, Nagaoka et al. in their econometric analysis of the international diffusion of new drugs published in this newsletter analyzed the factors contributing to the difference in the status of unapproved drugs between Japan and Europe. The authors refer to their analysis for a better understanding of the current ^{situation22).}

IQVIA forecasts that Japan's pharmaceutical market will be the only one among the 10 leading countries in the world to experience negative growth and will be overtaken by Germany in 2026, falling back to fourth place in the ^world23). Foreign start-ups, who are thinking about how to get approval and access to patients as quickly as possible and how to monetize their products in the U.S., the largest market, are not interested in Japan, especially in the early stages of development, and are putting Japan on the back burner. Under such circumstances, what happens when they get information about the shrinking size of the Japanese market in the global pharmaceutical market? This could accelerate the decline in Japan's attractiveness as an investment destination, leading to an even greater number of unapproved drugs in Japan and an acceleration of the drug lag.

All pharmaceutical companies, including start-ups, conduct business activities based on the philosophy of contributing to patients and the world. However, it is obvious that they cannot invest in R&D for drugs that have low expected business value, cannot recoup their investment, and are unpredictable as to when they will be able to recoup their investment, unless there is some incentive to do so. In order for the world to recognize Japan as a good investment destination, what must Japan improve, and in what areas will Japan appeal to the world in the future? As people are becoming increasingly aware that the drug lag is a problem directly linked to the disadvantage of the Japanese people in terms of delayed access to medicines, serious consideration must now be given to this issue. The drug lag is a pitfall because it is difficult to see who should solve it, and we should increase the number of people working together with a strong desire to fill the hole" ⁽ words of Professor Emeritus Mizutani of Tokyo Medical and Dental ^{University24)}. We sincerely hope that the multiple ^{evidences2-5, 22, and 25)} presented by the National Institute of Biomedical Innovation Policy will help to solve this problem.

9. acknowledgements

We received the cooperation of Sadao Nagaoka, Director of the Pharmaceutical and Industrial Policy Research Institute (Professor, Tokyo Keizai University), in the statistical analysis used in this study. We would like to express our deep appreciation for his cooperation.

Appendix 1 Details of Statistical Analysis

The logistic curves used in the analysis are as follows. The explained variables (lcy _{, lag} ) are the approval rates in Japan per elapsed year (lag) for each year cy (cohort year) that NMEs were approved in Europe and the United States, and the following estimation models are used. The first estimation model is

Lcy _{, lag = b0 + b1/(1 + exp (b2lag))} (1)

and this is estimated for Japan and Europe for the full period (t = 2010-2021) and for the first period (t = 2010-2015, period = 0) and the second period (t = 2016-2021, period = 1), respectively. In model (1), the initial height of the curve (lag=0) is b0 + (b1)/2, and the height at which the curve asymptotes is b0 + b1. Since the number of drugs (COHORT_n) on which the approval rate is based differs for each cohort year in value, a weighted regression analysis is performed to reflect this. The average cohort_n for the entire period is 40, 34 for the first semester, and 46 for the second semester. Although all years in the first and second terms are used as elapsed years, they do not differ significantly when standardized to 5 years. In addition, items approved in Japan or Europe prior to the U.S. approval are treated as if they were approved in the same year as the U.S. and are assumed to have a lapse year of 0 year.

The estimation results are as follows. Figure 6 is depicted by the estimated logistic curves. It suggests that the height of the curve is higher in the previous period, both initially and eventually.

Due to the limited number of data, it is difficult to test the significance of the difference between the early and late periods for the logistic curves with the three parameters above respectively. In the following, we test the hypotheses that b0 is equal and b1 is equal between the earlier and later periods; the difference in b0 indicates whether there is an average level difference in approval rates, while the difference in b1 indicates whether there is a difference in slope as well as a difference in mean. The estimation uses data from the earlier and later periods combined and introduces a cross term between b0 or b1 and the later period dummy in the estimation equation (1) (whose coefficient is b0A or b1A, respectively, which indicates the amount of change in the coefficient in the later period). The elapsed time since U.S. approval is assumed to be up to 5 years.

The estimation results are as follows.

As shown in the results, the approval rate significantly decreases in the later period for both Japan and Europe, regardless of the assumptions used. For Japan, the first estimation result with the assumption that b0 is equal in the first and second periods shows that the approval rate significantly decreased by 7% in the second period as the average for the entire period. The second set of estimates, with the hypothesis that b1 is equal in the first and second periods, shows a 10% decline in the final approval rate in the second period and a 5% decline in the first period. For Europe, the first set of estimation results show a significant 12% drop in the approval rate in the late period as the average for the entire period. The second set of estimates shows a 13% drop in the final approval rate in the late period and a 6% drop in the early period.

Finally, to check the robustness of the results, we test the significance of the differences below simply assuming that only the level can differ between the earlier and later periods. The estimates are restricted to elapsed years up to 5 years.

Lcy _{, lag} = ( _{βlate period*period} ) + _{∑lagβlag*lag} + constant (2)

The model assumes that the height of the curve differs between the early and late periods only in the late beta period.

The estimation results for each coefficient in model (2) are as follows. The estimation results show that the approval rate is significantly 7% lower in the later period for Japan and significantly 11% lower in the later period for Europe, both of which are almost identical to the first estimation results in Table 2 in the Appendix.

Return to News List

TOP