Pharmaceutical Industry at a Glance Survey of International Clinical Trials in Recent Years -Trends in International Clinical Trials in Recent Years -Trends to 2023 and the Asian Region

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The Office of Pharmaceutical Industry Research Hiroshi Azuma, Senior Researcher
The Office of Pharmaceutical Industry Research Takahiro Shiraishi, Senior Researcher

Summary

1. Introduction

In recent years, pharmaceutical development has increasingly been conducted on a global scale, and clinical trials aimed at drug approval have emerged not within a single country, but as international joint trials that straddle national boundaries. A global clinical trial is a clinical trial designed for the development and approval of a new drug on a global scale, in which medical institutions in multiple countries participate in a single clinical trial and the trial proceeds simultaneously based on a common ^protocol1). 1) and play an important role in bringing new drugs to patients who want new treatment options faster.

So far, OPIR Views and Actionshas reported on the status of global clinical trials and analysis of participating ^{countries3, 4, 5, 6)} using the Clinical Trials Registry System (ClinicalTrials.gov) ²⁾ operated by the U.S. National Institutes of Health (NIH) and others. This is because each country in the world has its own clinical trial registration site, and while there are differences in registration status, ClinicalTrials.gov is considered appropriate as one representative database to focus on for a comprehensive survey of the global drug development status. We judged that ClinicalTrials.gov was suitable for the survey of the global situation because the U.S. is currently the most active site for drug development in the world, and even though ClinicalTrials.gov is a U.S. site, it includes information on clinical trials in which the U.S. does not participate due to corporate strategies such as the purpose of each company's information dissemination. The U.S. site is also a U.S.-based site.

On the other hand, OPIR Views and Actionsreported that the inclusion of participating countries in international clinical trials has a significant impact on the increase of unapproved drugs in ^Japan7) (Analysis of the inclusion of Japan in pivotal trials for anti-cancer drugs). Therefore, it is very important to investigate trends in international clinical trials in order to improve access to new drugs in Japan. OPIR Views and ActionsIn the latter half of the report, we will also analyze the trends of international clinical trials in which Asia participates and the involvement of emerging biopharmaceutical companies (EBPs) in these trials.

Survey Methodology

The survey method was the same as that used in OPIR Views and ActionsNo.66. The survey was conducted using the ClinicalTrials. ^gov2) clinical trial registration system operated by the National Institutes of Health (NIH) in the U.S. and other organizations, and the survey was conducted on Interventional Studies (Clinical Trials) registered in the system, including Phase 2 (ClinicalTrials.gov)2), we surveyed the number of trials and participation rates of Interventional Studies (Clinical Trials) registered in the system (as of July 1, 2024), which were Phase 2 (including Phase 1/2) or Phase 3 (including Phase 2/3) and whose Funder Type included Industry. Trials registered in only one country were defined as single-country trials, while those registered in two or more countries were defined as international collaborative trials. In this report, the major Asian regions are defined as Japan, South Korea, China, Taiwan, Singapore, and Thailand, based on the countries that frequently appear in the ordinal ranking of international clinical trials, and the regional classification is as per the Location section of ClinicalTrials.gov.

3. Trends in ClinicalTrials.gov registrations

Figure 1 shows the clinical trials registered on ClinicalTrials.gov from 2000 to 2023 by year of study start. It should be noted here that the figures for each category indicate that there are cases in which a single-country study is conducted at the start of each trial, but the number of trials enrolling in other countries expands over time. Therefore, the enrollment of each clinical trial changes depending on the time of year, and the closer to the data acquisition date, the more likely it is that the enrollment changes ^.) The total number of clinical trials also varied slightly depending on the time of confirmation (the previous total in 2021 was 3,364, data not disclosed).

4. Number of international clinical trials/single country trials by country

Table 1 shows the top 30 countries in terms of the cumulative number of trials from 2000 to 2023, categorized by country and trial type (global, single-country, and total number of trials). The overall trend for each country was the same as in the previous report.

Compared to the previous ranking, there was little change in the top ranking of international clinical trials, while Japan rose from 23rd to a tie for 19th place, the largest increase among the countries in the ranking. Considering that this index is based on the cumulative number of trials over 20 years and that fluctuations in ranking are unlikely to occur, a rise of 4 ranks in the two years since the last survey can be considered a significant event. Looking at other regions in Asia, the third position is occupied by South Korea and Taiwan, which will be analyzed in detail in the next section. On the other hand, the top countries that fell in the rankings were Belgium, Russia, Austria, Sweden, and Ukraine, etc. The impact of the situation in Russia and Ukraine since February 2022 cannot be simply linked, but it is assumed to have had a certain impact. In the ranking of total number of tests, Japan moved up one place to 13th place. The largest change in ranking was seen in China (from 16th to 11th), which we attribute to significant progress in single-country trials.

Figure 2 shows the number of global clinical trials for each of the major countries (the U.S., Japan, China, Germany, France, and the U.K.), and Figure 3 shows the ratio of participation to all global clinical trials conducted in the year.

The number of international clinical trials in each country is similar, but the ratio of participation to all international clinical trials in the U.S. remains high, and while there is little change in the European group, the Asian group is rising steadily. The gap between Japan and Europe is gradually narrowing. This suggests that the presence of the Asian region in global clinical trials is increasing.

5. Number of International Clinical Trials in Major Asian Regions

In general, the Asian region is geographically, culturally, and linguistically distant from Europe and the United States, and the ethnic groups within nations are said to be less diverse than those in Europe and the United States. There are also differences in the clinical trial environment and approval application systems. With the U.S. as the main venue for drug development in the world, it is necessary for Japan to overcome these challenges and participate in more international clinical trials to secure access to new drugs.

In this section, we analyze the involvement of Asian regions, including Japan, in global clinical trials in the U.S. clinical trial registration system. Figure 4 shows the number of trials involving the six major Asian regions (Japan, South Korea, China, Taiwan, Singapore, and Thailand) and their percentages of the total number of global clinical trials. Note that until the 2000s, the overall number of registered trials was also low, and the number and percentage of registrations in the Asian region were also confirmed to be low. Since the sample size was deemed too small for a proper comparative analysis with the most recent situation, data for the most recent 10 years from 2014 to 2023 are presented in the subsequent analysis. In the last 10 years, the percentage of trials involving any of the major Asian regions in the total number of global trials registered can be seen to be on a gradual upward trend: 289 trials in 2014 and 546 trials in 2021, the highest number in the analyzed period; in 2023, almost half of the trials (49.2%) involved one of the major Asian regions. In 2023, 49.2%, or almost half of the trials included major Asian regions, indicating a growing presence in the region, similar to the results in Figure 3 in the previous section.

Next, the number of international clinical trials by region (Figure 5) and the ratio of participation to all international clinical trials conducted in the relevant year (Figure 6) are shown. In Table 1 in Section 4, the number of international joint clinical trials conducted in the Asian region since 2000 was the highest in South Korea (3,669), followed by Taiwan (2,811) and Japan (2,698). Looking at the participation rate in international clinical trials by region over time, South Korea has been the country with the highest participation in international clinical trials in the Asian region over the last 10 years, participating in 30.7% of all trials in 2023. Taiwan has seen a gradual rise, with participation at 21.5% of the total in 2023. Japan replaced Taiwan in 2016 to become the second largest country in the Asian region, with 26.9% of the total in 2023. Furthermore, in recent years, China's participation rate has also been rising, and by 2023 it will be close to Taiwan's at 20.9% of the total.

Next, we examined Japan's participation among the major Asian regions. In other words, we analyzed the participation rate of Japan in international joint clinical trials with an eye on the Asian region (Figure 7). (Figure 7) The results show that Japan's participation rate has been on a gradual upward trend over the past 10 years, reaching 50.5% (150 out of 291 cases) in 2016, more than half of all cases, and 54.7% (225 out of 411 cases) in 2023. Thus, in recent years, Japan has participated in more than half of the global clinical trials registered on ClinicalTrials.gov that also include major Asian regions.

6. Number of EBP's International Clinical Trials in Major Asian Regions

In recent years, the remarkable rise of emerging biopharma (hereinafter referred to as "EBP") in drug development around the world has been reported in various ^{fields8, 9)}. In this paper, EBPs are defined as companies established after 1990 and with sales of less than $500 million in the year prior to the start of the trial, and the characteristics of EBP-led global clinical trials are investigated by using pharmaceutical companies, including large pharmaceutical companies, as the main comparative group. As mentioned earlier, it is important for EBPs to reduce the barriers to drug development in Japan in order to overcome the drug lag/loss issue. As an example, we believe that Japan's proactive participation in EBP-led international clinical trials is an effective measure to avoid the situation where additional trials are conducted for the sake of Japanese development. EBPs in this survey are companies from all over the world, including the U.S., Europe, and Asia, regardless of nationality.

In Table 2 and Figure 8, we categorized Japan's participation in international clinical trials involving the six major Asian regions by the number of trials for each organization listed as a Lead Sponsor on ClinicalTrials.gov. The results showed that the number of global clinical trials involving major Asian countries in the last 10 years was 3,898, of which 2,058 (52.8%) were conducted in Japan, as indicated by the orange color in Figures 4 and 7. In terms of the classification of sponsors, Japan participated in 1,830 (62.2%) of the 2,943 trials led by pharmaceutical companies (171 organizations). On the other hand, Japan participated in 214 of 871 trials (24.6%) led by EBPs (445 organizations), confirming a significant difference between the two.

Next, we also examined the participation of other regions within Asia. Figures 9a and 9b show the number of Asian studies in which Asia participated in each of the six major regions of Asia, broken down by the lead company. In the past 10 years, South Korea has participated in the largest number of pharmaceutical-led global clinical trials in Asia, with 1,859 (63.2%) of the 2,943 trials, followed by Japan, with 1,830 (62.2%) of the 2,943 trials. Taiwan followed with 1,385 trials (47.1%) and China with 1,007 trials (34.2%). On the other hand, among EBP-led international trials with Asian participation, South Korea remained the country with the largest number of participants, with 514 (59.0%) of the 871 trials. This was followed by Taiwan with 360 trials (41.3%), China with 253 trials (29.0%), and Japan in fourth place with 214 trials (24.6%). As a result, South Korea participated in the largest number of international trials involving Asian countries. Japan, on the other hand, participated in almost the same number of pharmaceutical-led trials as South Korea, but was far behind, with a 2.4-fold difference in the number of EBP-led trials.

To further investigate changes over time, Figure 10 shows the number of participating trials and participation rates as an annual trend. As a result, the number of trials has gradually increased from 3 in 2014 to a maximum of 37 in 2022. However, in terms of the percentage of all studies in which any of the other Asian regions participate, the percentage has remained in the 20% to 30% range since 2017, when it was 33.8% (25 out of 74 studies).

7. Discussion

This section focuses on Japan's participation in EBP-led global clinical trials in the major Asian regions mentioned in Section 6. The results obtained indicate that the number and participation rate of Japanese participants differ greatly depending on the lead organization, and that Japan's participation rate in EBP-led international clinical trials with an Asian perspective is unfortunately ahead of that of other regions. We believe that there are various factors behind this situation. For example, South Korea has been working on the development of a clinical trial environment as a national policy, and has invested 4.6 billion yen over five years since 2004 to establish 15 Clinical Trial ^Centers10). It is also inferred that the speed from the notification of a clinical trial to the start of the trial has also led to a shortening of the time period by conducting various procedures concurrently. The relatively low participation rate in Japan cannot be simply explained by the above-mentioned differences in geography, culture, language, and ethnic composition from Europe and the U.S. Due to its corporate characteristics, EBP is small in size and its sales are still small, and it is expected to appeal for prompt trial results through compact trials and to emphasize speed and cost in conducting trials. It is assumed that EBPs will focus on speed and cost. The debate is raging on various aspects and criteria, such as the clinical trial environment in Japan, the frequency of interviews with clinical development monitors (CRAs), the concentration of target patients, the frequency and centralization of clinical trial review committee meetings, and the manpower of physicians conducting clinical ^{trials11, 12)}. In addition, in the area of pharmaceutical affairs, the Director of the Division has issued a ^notice13) on the basic approach to conducting Phase I trials in Japanese patients before the start of international joint clinical trials for advanced drugs from overseas, and the entire country is currently seeking the best form for Japan.

8. Conclusion

This paper reports on the trends of global and single-country clinical trials based on the registration status of ClinicalTrials.gov. In recent years, Japan's participation in international clinical trials has increased as a percentage of the total number of registered trials. On the other hand, Japan is one of the top countries in Asia in terms of the participation rate in pharmaceutical company-led global clinical trials, but the participation rate in EBP company-led global clinical trials is less than half that of the top countries. I hope that industry, government, and academia will work together to find effective solutions, and that new drugs and new treatment options will reach the patients who need them as quickly as possible.

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