The Pharmaceutical Industry at a Glance Drug Lag: Launch of NMEs in Japan Comparison of launch timing with the U.S. and Europe

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Tomoyuki Shibuguchi, Senior Researcher, Pharmaceutical Industry Policy Institute

Introduction

As Yoshida introduced in this ^news1), there are two aspects of drug lag: one is the problem of "unapproved drugs" that have been launched in other countries but not in Japan, and the other is the "lag" (delay) in which a drug has been launched in Japan but took longer than in other countries to be launched. The latter drug lag is a problem of "unapproved drugs" that have not been launched in Japan despite being on the market in Japan. Regarding the latter drug lag, Awamura reported on the status of the top 300 products in terms of global sales in Japan, the U.S., and ^Europe2), and found that the drug lag has been improving in recent years. In this news item, we report on a survey of the launch of NMEs approved in Japan between 2010 and 2020, focusing on the difference in timing and order of launch in Japan, the U.S., and Europe, and on annual changes in the order of launch.

Research Methods

The items approved as NMEs in Japan were based on "New Drugs Approved in Japan and Their Review Periods," as reported by Yoshida in Policy Research Institute News No. 62. ³⁾ The items approved as NMEs in the U.S., Europe, and Japan are also included in the list of items approved as NMEs in the U.S., Europe, and Japan. The approval status of these items in the U.S. and Europe was updated based on the data of "Global Approved Items" reported in the previous ^News4). The launch date of each product is based on the "First Launch" date in Japan, the U.S., and Europe using Evaluate Pharma of Evaluate Inc. For some items for which no information was available, Cortellis Competitive Intelligence from Clarivate was used, and the "Development Status" of each item was updated in Japan, the U.S., and Europe (or "EU" in the case of Europe, or "UK, France, and Germany"). The earliest "Launched" date in Japan, the U.S., and Europe (or "EU" or "U.K., France, and Germany in the case of Europe) was used for the "Development Status" of each product. For the Japanese launch dates, the above database was used as the basis, and for items for which no launch date was provided, the "date of market launch" provided in the interview form was used.

Since the earliest NME market launch date was used, the indication may not necessarily be the same in each country. However, if the review report confirmed that the drug was approved in Japan for an indication that is significantly different from the indication at the time of initial launch overseas (drug repositioning), the date of initial launch in each country was matched to the indication at the time of domestic approval.

Differences in Launch Dates of Approved Drugs 2010-2020

There were 436 items approved as NMEs in Japan from 2010 to 2020. Of these, 345 were already on the market in both or either the U.S. and Europe as of the end of May 2021. Figure 1 shows the median difference between the earliest launch date in Japan, the U.S., and Europe and the launch date in Japan, divided by the year of approval in Japan. The median value of the difference is shown in the graph. The graph consists of two line graphs. One graph shows the difference in launch dates for all products in each year, and the other graph shows the difference in launch dates for products that were submitted based on the results of the "Review Committee on Unapproved and Off-label Drugs of High Medical Need" held by the MHLW, which were excluded from the calculation as "products for which applications were publicly solicited or requested for development". The figures are based on the calculation of the number of products approved in 2010-2012.

The median difference in the timing of product launches for products approved between 2010 and 2012 ranged from 3.9 to 6.5 years, but the difference has been shorter since 2013, ranging from 0.7 to less than 3 years. Excluding publicly solicited or requested products, the median period was 3.9 to 4.5 years from 2010 to 2012, and 0.7 to 2.5 years thereafter, which is similar to the difference in the time of market launch for all products.

The table on the right side of Fig. 1 summarizes the number of items, mean value, and standard deviation for each year by the presence or absence of publicly solicited or requested products for development. Similar to the median trend, the mean value ranged from 5.2 to 7.2 years for products approved between 2010 and 2012, but from 2013 onward, the mean value showed a trend toward shortening, ranging from 2.6 to 5.3 years. The average value was higher than the median value because some items, such as publicly solicited or requested products, include a certain number of items for which more than 10 years have passed since their launch dates in the U.S. and Europe. Excluding publicly solicited or requested products (right side of Table 1), the shortening trend is even clearer, ranging from 4.8 to 7.2 years for products approved between 2010 and 2012 to 2.6 to 3.5 years for products approved in 2013 and beyond.

Difference in launch dates between biopharmaceuticals and other products

The items shown in Figure 1 were classified into ^{biopharmaceuticals5) and} non-biopharmaceuticals such as small molecule drugs, and the differences in the time of market launch were compared (Figures 2 and 3). The median time gap for biopharmaceuticals in 2010 was 3.7 years, but by 2020 it had shortened to about 1.3 years, and especially since 2015, it has been within 2 years for all years. Although there were some years with a large variation in the average value, many years in the early 2010s were more than 4 years, whereas from 2015 onward, the market launch of biopharmaceuticals was achieved in less than 4 years.

There were a small number of development solicitations and requests for biopharmaceuticals, but all of them took more than nine years from Europe or the U.S. to market in Japan, and the median and average values declined when the subject items were excluded.

The median difference in launch dates for small molecule drugs and other non-biopharmaceuticals also tended to shorten after 2013 (Fig. 3). In 2013 (excluding publicly solicited and requested products for development) and 2020, the median is about 0.7 years, and there are some cases where the median is less than one year.

Order of launch in Japan, US, and Europe

The previous section has examined annual trends in the difference in launch timing between Japan and the U.S. and Europe, and while the gap has been shortening since FY2013, we investigated whether there has been a change in the order in which products are launched in the three regions. As shown in Figure 4, in 2010, nearly 60% of the products approved in Japan were first launched in the U.S., followed by Europe, and Japan often came in third. This trend remained unchanged through 2015, but in 2020, although the largest number of products were first launched in the U.S., more products were first launched in Japan than in Europe, and the total number of first- and second-launched products in Japan increased to nearly 50%.

Consideration

So far, we have looked at the lag in the launch of NMEs approved in Japan from 2010 to 2020 by the year of approval. In all years, the launch lag has tended to shorten after 2013, especially for biopharmaceuticals. In addition, 7 of the 28 products approved in 2020 will be launched in Japan for the first time, exceeding the number of products approved in Europe in some years. This is due to (1) the shortening of the development lag resulting from an increase in international clinical trials, including in Japan, (2) the shortening and stabilization of the review period in Japan, and (3) the improvement of the environment of the pharmaceutical affairs and drug pricing systems, including the additional system for promotion of new drug creation and resolution of off-label drug indications.

Regarding the shortening of the development lag due to an increase in international clinical trials including Japan, the review reports confirm that applications for approval were filed for 9 of the 14 products with a shorter time-to-market gap than the median of 0.73 years by 2020, based on the results of international clinical trials including Japan, and that many of these international clinical trials were approved in the US and the EU as key trial results. Many of those international clinical trials were submitted for approval in the U.S. and the EU as the main study results. On the other hand, only 3 of the 14 products were launched in more than 0.73 years, suggesting that the increase in the number of global clinical trials contributed to the shortening of the development lag.

Therefore, we compared the number of items and the difference in launch timing between items for which the review reports confirmed that an application was filed based on the results of international clinical trials including Japan and other items, limited to biopharmaceuticals for which the trend of shortening the time lag between launch and approval was relatively easy to understand. Figure 5 shows that the number of applications filed based on the results of global clinical trials has been increasing since 2012, and that the median difference in time to market for these products is 0.8 years, which is shorter than the median of 3.5 years for the other products. The median time for the median of the difference in launch dates for these items is 0.8 years, which is shorter than the median of 3.5 years for other items. The median time is 3.2 years even when excluding items that were publicly solicited or requested for development.

In addition, as Awamura ^reported6), the number of international clinical trials conducted in Japan is increasing, with 362 (53.7%) of the 674 clinical trial plan notifications in FY2019 pertaining to international clinical trials, accounting for the majority (Figure 6). If this trend continues, the gap in launch timing between Japan and the U.S. and Europe is unlikely to widen.

As reported by Yoshida et al. in News No. ⁶¹⁷⁾, the median review period in Japan and the U.S. has been similar (approximately 10 months) since 2011 (Fig. 7), and the variation in the review period in Japan is relatively small and stable compared to the U.S. and Europe. The difference in the examination period has become smaller, and the examination period has become more stable in recent years. The fact that the difference in examination periods has become smaller and in recent years there has been almost no difference between the two countries may have contributed to the shortening of the difference in the timing of market launch.

Although it is not possible to quantitatively measure the effects of the last mentioned improvement of the pharmaceutical affairs and drug pricing systems, an additional system for promoting the creation of new drugs and the elimination of drug lag was introduced in FY2010 as an incentive for the development of innovative new drugs and the elimination of drug lag. For eligible drugs, NHI prices are maintained throughout the patent term, making it more predictable that drug development costs will be recovered. In addition, in FY2015, the Pioneer Drug Designation System (Pioneer Drug Designation System from 2020) and other systems were implemented with the aim of providing the world's most advanced therapeutic drugs to the market as soon as possible.

Summary

In this survey, we investigated the difference in launch timing between the U.S. and Europe for NMEs approved in Japan from 2010 to 2020. The survey showed that, while the trend of the U.S. and Europe being ahead of the U.S. and Europe, the difference in launch dates has been shortening since 2013, with the median difference being less than one year in some years, compared to a median of more than four years before that time. The reasons for this trend include an increase in the number of international clinical trials, including those conducted in Japan, the shortening and stabilization of the review period in Japan, and the improvement of the regulatory and NHI drug price system environment.

On the other hand, the environment surrounding NHI drug prices has been getting tougher year by year, as evidenced by the revision of the additional payment system for promotion of new drug creation and resolution of off-label drug use under the NHI price system overhaul in FY2018 and the implementation of the mid-year revision this fiscal year. Although no impact on the difference in timing of drug launches has been observed at this point, if the development lag is affected by a reduction in incentives to launch drugs in Japan, such as making it more difficult for Japan to be included in future international joint clinical trials, this could directly lead to an increase in the gap in timing of drug launches. Considering that drug development takes time, the impact is likely to be relatively long-lasting.

In addition, as Yoshida ^reported1) in this news item, new issues such as the increasing number of unapproved drugs, mainly items from emerging biopharmaceutical companies that do not have development sites in Japan, have also been brought to light. In order to bring innovative new drugs to Japanese patients as quickly as possible, it seems necessary to improve the development environment as well as the attractiveness of the Japanese pharmaceutical market environment.

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