Policy Research Institute page Drug Lag: Status and Characteristics of Unapproved Drugs in Japan

1-2. addressing the issue of unapproved and off-label drugs

In April 2010, the "Additional Drug Price for Promotion of New Drug Creation and Resolution of Off-label Drugs" was introduced on a trial basis as part of the NHI drug price system, and the MHLW established the "Study Council for Unapproved Drugs and Indications of High Medical Need" ("Study Council") to promote development of unapproved drugs and off-label drugs by pharmaceutical companies.*6*7 Here In order to understand the status of promotion of development of unapproved drugs and off-label indications in Japan, the following table shows the status of approved drugs for which companies were solicited or requested to develop based on the results of the study by the Study Council ( Table 1 and Fig. 1 ).

Table 1: Approval status of drugs for which development companies were solicited or development requests were made (by timing of development requests)
Note 1: Some co-development projects and multiple development requests were approved by the pharmaceutical affairs bodies in a single regulatory approval, and thus duplicate totals are shown.
Note 2: The timing of development requests for each round is as follows (Round I: June 18 to August 17, 2009; Round II: August 17, 2011; Round III: June 18 to August 17, 2010; Round IV: June 18 to August 17, 2011). II: August 2, 2011 to September 30, 2011. Session III: August 1, 2013 - June 30, 2015. IVth: July 1, 2015 - present. (Currently, requests are solicited on an as-needed basis.)
Source: Compiled by MHLW Policy Research Institute based on the Ministry of Health, Labour and Welfare's "Study Group on Unapproved and Off-label Drugs of High Medical Need: List of drugs for which development companies were solicited or development requests were made" (updated on February 15, 2021).

Figure 1: Approval status of drugs for which development companies were solicited or development requests were made (by year of approval)
Note: Some joint development projects and multiple development requests were approved by the pharmaceutical affairs bodies under a single regulatory approval, so the data are duplicated.
Source: MHLW, "Study Group on Unapproved and Off-label Drugs of High Medical Need: List of drugs for which development companies were solicited or development requests were made" (updated on February 15, 2021).

So far, the Ministry of Health, Labour and Welfare (MHLW) has issued a total of four development requests for the I-IV series, and the total number of requested drugs is 393. Looking at the approval status of the requested drugs, 294 (75%) of the 393 requests were approved, of which 70 (63) were for New Molecular Entity (NME) drugs. Looking at the approval status of development-requested drugs by year of approval, a large number of target drugs were approved in the early 2010s, when the drug lag was an issue*8. 8 This has led to the development and regulatory approval of many unapproved and off-label drugs, and has improved this problem.

Survey Methodology

The survey covered items approved as NMEs in Japan, the U.S., and Europe from 2010 to 2020, and unapproved drugs in Japan were identified by comparing the approval dates in the U.S. and Europe with the approval status in Japan. Specifically, based on the items listed in PMDA's "Database of Unapproved Drugs (updated on March 1, 2021), "*9 we checked and supplemented the information on NME approvals in Japan, the U.S., and Europe*10*11*12 by using a database*13 constructed by the Policy Research Institute.

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

3) Number of Unapproved Drugs and Percentage of Unapproved Drugs in Japan Over Time

In order to confirm changes in the number of unapproved drugs in Japan, information on NME approvals in Japan, the U.S., and Europe from 2010 to 2020 was used to compile the number of unapproved drugs in Japan and the approval rate in Japan for NMEs approved in the U.S. and Europe at each survey point (the end of December in each year)*14. The number of unapproved drugs in Japan and the approval rate in Japan for NMEs approved in Europe and the U.S. were calculated for each survey point from 2014 to 2020, and the five-year total was then calculated. For comparison, the total number of NMEs in the U.S. and Europe was calculated in the same way, and the ratio of the number of unapproved drugs in Japan to the number of NMEs in the U.S. and Europe was also calculated to track changes over time ( Figure 2 ).

Figure 2: Annual changes in the number of NMEs not approved in Japan and their percentages (sum of the most recent 5 years)
Note: NMEs approved in Japan, the U.S., and Europe between 2010 and 2020 were targeted, and the number of unapproved drugs in Japan and the number of NMEs in the U.S. and Europe were surveyed for the most recent five years at each survey point (end of December in each year), and the five-year total was calculated. In the case of NMEs approved in both the U.S. and Europe, only the year of the first approval was counted.
Source: Prepared by the Policy Research Institute based on publicly available information from PMDA, FDA, and EMA.

As a result, the percentage of unapproved drugs in Japan decreased (from 65% to 56%) from 2014 to 2016, but the percentage of unapproved drugs in Japan increased from the bottom at the time of the 2016 survey, and by the end of 2020, 72% of NMEs in the US and Europe were unapproved drugs in Japan. Since the number of NMEs in Europe and the U.S. itself also increased during this period, the total number of unapproved drugs in Japan (total for the most recent five years) was 117 at the end of 2016, but had increased 1.5-fold to 176 at the end of 2020.

Here, we attempted a statistical analysis to verify the above result that the number of unapproved drugs in Japan tends to increase in the latter half of the 2010s. Using the dataset used to create Figure 2, we generated panel data on the cumulative approval rate of NMEs approved in the US and Europe in Japan from 2010 to 2020. Then, a logistic regression analysis was conducted to examine the relationship between the number of years elapsed since the year of initial approval and the approval rate for NMEs in Europe and the U.S. separately for the early 2010s (2010-2014) and the late 2010s (2015-2020) ( Figure 3 )*14.

Figure 3 Comparison of domestic approval rates of US and European NMEs in the early and late 2010s (results of statistical analysis)
Note: Logistic regression analysis was conducted on the panel data regarding the trend of cumulative approval rates in Japan for NMEs approved in the U.S. and Europe from 2010 to 2020. The graphs are plotted from the following estimation result equation.
Early period: y = -0.274 + 0.895 / (1 + exp (-0.574 x x), R2 = 0.644)
Latter period: y = -0.303 + 0.849/(1 + exp (-0.622 x x), R2 = 0.882)
Source: Prepared by NIHS based on publicly available information from PMDA, FDA, and EMA.

The analysis showed that in the early 2010s, 17% of items were approved in the same year in Europe and the U.S. and in Japan, compared to 12% in the late 2010s. Comparing the level 10 years after approval in Europe and the U.S., 62% of items approved in Europe and the U.S. were approved in Japan in the early 2010s, while the level dropped to 54% in the late 2010s. This suggests that the curve was higher in the early period than in the late period, both initially and eventually. This decrease in the approval rate in Japan in the late 2010s compared to the early 2010s was statistically significant*14.

4-1. status of unapproved drugs in the u.s. and europe

We will now examine in detail the 265 NMEs that were first approved in the U.S. and Europe between 2010 and 2020 that were not approved in Japan as of the end of December 2020.

First, Figure 4 shows a breakdown of the number of NMEs unapproved in Japan as of the end of December 2020 and their approval status in Europe and the U.S. Of the 265 NMEs unapproved in Japan as of the end of December 2020, 125 were globally approved in both the U.S. and Europe, accounting for 47% of the total. Of the 265 drugs approved in Japan as of the end of December 2020, 119 (45%) were approved only in the U.S., almost the same number as globally approved drugs, while only 21 (8%) were approved only in Europe.

Figure 4: Approval status of unapproved drugs in Japan in the U.S. and Europe (as of the end of December 2020)
Note: Figures in the bar chart indicate the number of items that are unapproved in Japan. For NMEs approved in both the U.S. and Europe, only the year of first approval was counted as 1.
Source: Prepared by the National Institute for Policy Studies based on publicly available information from PMDA, FDA, and EMA.

Next, looking at each year of first approval in Europe and the U.S., the percentage of domestically unapproved drugs approved in both the U.S. and Europe exceeded 50% in each year, with the exception of the most recent years, 2020, 2019, and 2012. As we approached 2020, the percentage of domestically unapproved drugs approved only in the U.S. was higher, and there were only a few items approved only in Europe in each year. However, based on the results of recent surveys, the most common order in which NMEs are launched in Japan, the U.S., Europe, and Japan, in that order*4, it can be assumed that even for NMEs approved only in the U.S. at the time of this survey, there will be several products approved in Europe and Japan from 2021 onward. The number of unapproved drugs in Japan as of the end of December 2020 is expected to be approximately 1,000.

4-2. Development Status of Unapproved Drugs in Japan

Figure 5 shows a breakdown of the development status of unapproved drugs in Japan as of the end of December 2020. Although there is a "lag" between the approval dates of these drugs and those in Europe and the U.S., clinical development trials are ongoing in Japan, and there is a possibility that these drugs will be approved by the regulatory authorities in Japan in the near future.

Figure 5: Development status of unapproved drugs in Japan (as of the end of December 2020)
Note 1: Development information follows the description in "Tomorrow's New Drugs" (Technomic Co., Ltd.), a database of drug development information. No further information" is given for items for which three years have passed since the development stage information was obtained, but for which no information on the continuation of development could be confirmed.
Note 2: The numbers in the bar graph indicate the number of items that are not approved in Japan. In the case of NMEs approved in both the U.S. and Europe, only the year of first approval is counted as one.
Source: Prepared by NIHS based on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs.

On the other hand, 33 items (13%) were judged to have had their development suspended or discontinued in Japan (including items for which there has been no further development information for three years). Although it is difficult to specify the reason for "discontinuation or suspension," there were a wide range of reasons, 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. In addition, 149 items (56%) had no information on development in Japan. These 182 unapproved drugs (69%) that are not currently under development in Japan will remain unapproved in Japan unless new domestic development is initiated in 2021 or later.

Next, we reviewed the development information for the items remaining as unapproved drugs in Japan by the year of their initial approval in Europe and the United States. Sixty-six of the 83 items in development, accounting for 80%, were approved between 2017 and 2020, and 76 items, accounting for more than 90%, were approved between 2015 and 2020 in the U.S. and Europe, and less than 10% (7 items) of all items in development had development information for items that were approved before 2014, which is even earlier. However, there were 28 unapproved drugs that were under development in Japan before 2014 (7 items) and 21 items whose development was discontinued or suspended (21 items), which totaled 28 items. Looking at the total number of unapproved drugs in Japan from this perspective, there were 116 drugs for which efforts were being made by pharmaceutical companies to obtain regulatory approval in Japan, accounting for 44% of all unapproved drugs in Japan.

4-3 Characteristics of Unapproved Drugs without Information on Development in Japan

Here, we investigated the characteristics of the 149 items that were classified as "no information on domestic development" with no evidence of domestic development by the end of the December 2020 survey ( Fig. 6 ).

Figure 6: Characteristics of unapproved drugs with no domestic development information (as of the end of December 2020)
Note 1: Development information is based on "Tomorrow's New Drugs".
Note 2: Authors' classification of the presence or absence of Japanese subsidiaries is based on each company's public information.
Source: Prepared by NIHS based on public information by PMDA, FDA, and EMA, public information by each company, and "Tomorrow's New Drugs.

First, we checked for orphan designation in the U.S. and Europe. The 149 items were classified by orphan designation, and those with orphan designation accounted for 57 items (38%). According to the NIHS News No. 61, the percentage of NMEs approved in the U.S. and Europe with orphan designation over the past five years (2015-2019) has remained at around 40%*11. In other words, the percentage of orphan designations in the U.S. and Europe for NMEs approved in the U.S. and Europe for NMEs without domestic development information was not significantly different from the percentage for NMEs approved in the U.S. and Europe.

Next, we checked the approval status in the U.S. and Europe. Of the 149 NMEs not approved in Japan with no development information in Japan, 56 (38%) were globally approved in both the U.S. and Europe. Compared to the overall case of domestically unapproved drugs in Figure 4, 9% fewer items without domestic development information were approved in both the US and Europe, and 8% more items were approved only in the US.

Finally, we investigated the development companies in Europe and the U.S. for the products without domestic development information. 147 out of 149 products were developed by overseas companies*15 To further examine the details of the development companies, we checked whether the target overseas companies had Japanese subsidiaries or not. The results showed that 99 items (66%) were developed by overseas companies without Japanese subsidiaries.

4-4. classification and development status of unapproved drugs in Japan

To conclude the survey, Figure 7 shows the classification*16 and domestic development status of 265 unapproved drugs in Japan as of the end of December 2020.

Figure 7: Classification and Development Status of Unapproved Drugs in Japan (as of December 31, 2020)
Note: Development status follows that of "Tomorrow's New Drugs". For items for which information on the development stage has been available for about three years, "No further information" is given for items for which information on the continuation of development could not be confirmed.
Source: Compiled by NIHS based on publicly available information from PMDA, FDA, and EMA, WHO ATC index, and "Tomorrow's New Drugs.

Looking at the domestic unapproved drugs by efficacy category, anti-cancer agents (L01) accounted for the largest number of 52 (20%). Looking at the 83 drugs in development in Japan shown in Figure 5 by drug class, anti-cancer agents (L01) accounted for 33 drugs, or 40% of the total number of drugs in development in Japan. This number accounted for 63% of the 52 unapproved anti-cancer drugs in Japan. Thus, for unapproved anti-cancer drugs, not only the number of items under development in Japan was higher than for other drug classes, but also the percentage was larger, indicating that many items had already been initiated for development in Japan.

On the other hand, looking at the 149 items for which no domestic development information was available by drug class, 22 were systemic anti-infectives (J), 22 were gastrointestinal and metabolic agents (A), 15 were nervous system agents (N), 15 were others (V, diagnostic agents, etc.), and 14 were anti-cancer agents (L01), more than anti-cancer agents Four drug classes were identified. Of these, systemic anti-infectives (J) and gastrointestinal and metabolic agents (A), which had the largest number of unapproved drugs in Japan, accounted for only 5-6% of the total number of drugs in development in Japan (83 drugs), with 6 and 5 drugs in development in Japan respectively, indicating that many unapproved drugs remain undeveloped.

5. Discussion

The following section discusses the results obtained from the survey of the status of unapproved drugs in Japan and their characteristics.

First, changes over time in the number and percentage of domestically unapproved drugs show an increasing trend in the number of unapproved drugs in Japan in the late 2010s. We mentioned that domestically unapproved drugs are one aspect of drug lag, but the results of the survey in terms of the number of approved items and the percentage of approved items show signs of expansion in this aspect. In order to find out the reason for this, we conducted a detailed survey of unapproved drugs in Japan as of the end of December 2020.

From the survey of the approval status in Europe and the United States, we found that approximately half (47%) of the unapproved drugs in Japan include globally approved items that have been approved in both the United States and Europe. We had thought that the domestically unapproved items might include most of the local drugs in each region that are not globally deployed, but this idea was rejected.

The survey of domestic development status showed that 44% of all unapproved drugs in Japan were being developed domestically by various pharmaceutical companies, while the remaining 56% were items for which no development information was available. While it is desirable to keep the lag time as short as possible for "items in development in Japan," there is a possibility that patients will be able to access these drugs in Japan in the future. However, "items with no development information" will remain as unapproved drugs unless domestic development begins after the time of the survey.

A further analysis of the "items with no development information" showed that 38% were orphan drugs in the U.S. and Europe, but a comparison of that percentage with the percentage of orphan drugs in the U.S. and European NMEs as a whole showed that there was not a significant difference between the two. However, since orphan drugs are rare and thus raise issues of market size and clinical trial feasibility, the percentage of orphan drugs that begin clinical development in Japan alone in the future is expected to be low, and many may remain as unapproved drugs in Japan. Orphan drugs that are unapproved in Japan include drugs for genetic diseases and rare cancers for which clinical trials cannot be conducted due to the extremely small number of patients in Japan.17 If overseas development and approval takes precedence, it will be difficult to conduct validation trials in Japan, and scientific evidence in Japan will be weak, resulting in a drug lag. This results in a drug lag. In order to provide the public with the most advanced medical care, it is important for pharmaceutical companies to participate in international joint trials on a scale that enables them to examine the efficacy and safety of their products, including those for Japanese patients, and to start from the beginning with the possibility of simultaneous approval both in Japan and overseas.

For items for which there is no information on development in Japan, the percentage of items approved only in the U.S. was larger than that for unapproved drugs in Japan as a whole. In addition, 66% of the NMEs with no domestic development information were NMEs developed in the US or Europe by foreign companies without Japanese subsidiaries. According to a recent IQVIA report, "Global Trends in R&D: Overview through 2020," more than 40% of NMEs approved in the past three years were developed by Emerging According to the "Global Trends in R&D: Overview through 2020" report, more than 40% of NMEs approved in the past three years have been developed and launched by emerging biopharma*18, and many of these emerging biopharma companies do not have Japanese subsidiaries. In addition, many of the emerging biopharma companies originated in the U.S., and a high percentage of them are thought to develop and market their products only in the U.S. Therefore, a high percentage of unapproved drugs in Japan that do not have domestic development information were thought to be approved in the U.S. only. This highlighted how to attract emerging biopharmaceutical companies to domestic development as one issue to solve the problem of unapproved drugs in Japan. It is also important to attract emerging biopharmaceutical companies themselves to Japan by creating an environment that facilitates international joint clinical trials, by providing incentives for companies and an environment that encourages them to conduct clinical development in Japan, by creating an attractive domestic market, etc., and by ensuring access to new drugs for the Japanese public by specializing in the products of emerging biopharmaceutical companies and introducing them in Japan. It is also important to attract emerging biopharmaceutical companies to Japan by creating an attractive domestic market.

The survey of unapproved drugs in Japan by therapeutic category showed that the number of unapproved drugs in Japan for anti-cancer agents is the largest compared to other therapeutic categories, but the percentage of drugs in clinical development in Japan is also the largest, indicating that development efforts by pharmaceutical companies are continuing for many unapproved drugs. In the future, we hope that the "lag" in approval timing will become shorter, and that the percentage of unapproved drugs in Japan that have not yet been developed, such as drugs for rare cancers, will decrease further.

In the survey of items without development information by drug category, the percentage of unapproved drugs classified as anti-infective agents was high, but we assume that this may be due to the fact that there have been few incentives for companies in Japan to promote research and development of drugs for treating drug-resistant (AMR) bacteria and other infectious diseases. We recognize that certain measures have been taken with the establishment of the "designated drug for specific use" designation system by the Ministry of Health, Labour and Welfare in the fall of 2020, but we also feel that more effective anti-infective measures are needed in light of the recent COVID-19 pandemic in Japan. For example, it may be time to seriously discuss new types of incentives such as the subscription-based reimbursement model implemented in the UK in 2020*19.

6. summary

In this issue, we have taken up the status of unapproved drugs in Japan and their characteristics. One aspect of the drug lag, domestically unapproved drugs, showed signs of expansion in the late 2010s, and in particular, how to attract emerging biopharmaceutical companies to domestic development emerged as one issue to solve the problem of unapproved drugs in Japan. We also found that it is necessary to take measures not only for anti-cancer drugs, which have a large number of unapproved drugs in Japan, but also for anti-infective drugs, for which there are many items for which there is no domestic development information. The following four points were identified as important in resolving these issues: (1) creating an environment that facilitates international joint clinical trials, (2) creating an environment that encourages companies to conduct clinical development in Japan, (3) providing new types of incentives to companies in the area of infectious diseases, etc., and (4) creating an attractive domestic market.

As mentioned in the introduction, many are concerned about the reoccurrence of a drug lag resulting from reduced incentives to launch drugs in the Japanese pharmaceutical market. If the approval rate of European and US NMEs in Japan continues to decline and the number of unapproved drugs in Japan increases, the public may not have rapid access to innovative new drugs in the future. I would like to close this paper with the hope that national discussion will proceed so that an appropriate system that understands the value of innovation and pharmaceuticals will be put into operation.

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

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