Policy Research Institute page Analysis of Countries Participating in International Clinical Trials in Recent Years Based on ClinicalTrials.gov, a clinical trial registration system

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The National Institute of Biomedical Innovation (NIBIO) has previously reported the results of several surveys on the status of global clinical trials, but has not conducted a similar survey since 2012, when the number of clinical trial protocol submissions for global clinical trials in Japan increased rapidly. In this issue, we report the results of a survey on Japan's participation in global clinical trials in recent years, comparing Japan's participation with that of major countries around the world, and present the results.

In Policy Research Institute News No.57, we reported that the drug lag has been improving in recent years*1 based on the status of the world's top 300 products in terms of sales launched in Japan, the U.S., and Europe. The report also noted that the review period by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has been shortened to the same level as that of the U.S. Food and Drug Administration (FDA), and that international joint clinical trials are now being conducted in Japan. In FY2018, 389 (50.9%) of 764 notifications of clinical trial plans were related to international clinical trials, accounting for the majority ( Figure 1 )*2.

Figure 1: Number of Notifications of Clinical Trial Plans for Global Clinical Trials
Source: Prepared based on the annual business report of the Pharmaceuticals and Medical Devices Agency (PMDA)

In the past, the National Institute for Health Policy Research (NIPS) has conducted an analysis of the status of global clinical trials and the number of cases in Japan based on a questionnaire survey of pharmaceutical companies*3 and a comparison of the number of global clinical trials between Japan and other countries*4 based on trials registered on ClinicalTrials.gov. However, we have not compared the number of global clinical trials between Japan and other countries since 2012, when the number of clinical trial plans submitted for global clinical trials increased rapidly.

In order to analyze the participation of Japan and other countries in global clinical trials since 2012, we conducted a survey on the number of studies conducted in each country. The survey was conducted using the ClinicalTrials.gov, a clinical trial registration system operated by the National Institutes of Health (NIH) in the United States and other countries. or Phase 3, and the Funder Type was registered as Industry (as of September 5, 2019). For the purposes of this study, we defined trials with two or more registered sites in two or more countries as global trials and trials with one site in one country as single-country trials.

Number of trials registered on ClinicalTrials.gov by year

Figure 2 shows the number of trials registered on ClinicalTrials.gov (Phase 2 or Phase 3, Funder Type: Industry) by the year when each trial started (2000-2018).

Fig. 2 Annual changes in the number of trials registered on ClinicalTrials.gov (international clinical trials / single country trials)
Source: Created based on ClinicalTrials.gov

The number of trials for both international and single-country trials increased rapidly from 2000 to 2006, and then remained flat until 2018, with no major fluctuations in either case: 800 to 900 trials for international trials and 1,400 to 1,600 trials for single-country trials.

In addition to the revision of the Declaration of Helsinki in 2000 (making publication of clinical research results mandatory) and the 2004 International Council of Medical Journal Editors (ICMJE) statement*5 (studies not registered in a public clinical trial publication database before the start of subject entry are not allowed to be published in medical journals that are members of the ICMJE, such as the Lancet In addition, the FDA amended the law in 1997 and 2007*6 to require that trials conducted by submitting an Investigational New Drug application (IND) to the FDA be pre-registered on ClinicalTrials.gov, which has led to an increase in trial registrations from the U.S. and around the world. On the other hand, the overall number of trials has not changed since 2006, when trial registration became established, so the number of Phase 2 or Phase 3 trials itself has not changed significantly since 2006.

Number of trials by country for international trials/single country trials

The number of international joint trials/single country trials (cumulative number of trials from 2000 to 2018) was calculated for each country, and the top 30 countries by international joint trials, single country trials, and total number of trials are shown in Table 1.

Table 1 Top 30 Countries in Number of Multinational/Single-Country Trials
Source: Based on ClinicalTrials.gov

The United States, Germany, Canada, the United Kingdom, France, Spain, and Italy, in that order, had the highest number of trials conducted in international joint trials, with the exception of two North American countries (the United States and Canada) and Australia, which were dominated by European countries (in addition to the five major countries, Eastern European countries such as Poland, Russia, the Czech Republic, and Hungary also ranked high). In contrast, the highest ranking Asian country was South Korea (15th), followed by Taiwan (21st), Japan (28th) with 1,396 examinations, and China (40th) with 867 examinations, which did not rank in the top 30.

On the other hand, the U.S. had by far the largest number of single-country examinations with 13,153, about 10 times the number of the second-ranked Japan. In addition to the U.S., Japan, Germany, China, and Canada ranked first, followed by South Korea in sixth place, indicating a trend toward a relatively high number of Asian countries other than the U.S. In terms of the total number of trials (international joint trials + single-country trials), the United States had the largest number of both international joint trials and single-country trials, followed by European countries (Germany, the United Kingdom, France, Spain, and Italy) and Canada, which had the largest number of international joint trials, with Japan and China ranking 16th and 23rd, respectively.

The number of single-country trials in the U.S. is extremely large compared to the number of international trials, which is unique compared to the top-ranking European countries for international trials outside the U.S. The number of single-country trials in the U.S. is extremely large compared to the number of international trials. Although it is possible that single-country trials in European countries are not intended for submission to the U.S. (FDA) and are not registered on ClinicalTrials.gov, the clinical trial registration system in the U.S., Europe is a close area and in the same economic zone (European Union), and the European Medicines Agency (EMA) is responsible for the central review process. However, the close proximity of European countries to each other, their location in the same economic zone (European Union), and the adoption of a central review system by the European Medicines Agency (EMA) led us to consider the possibility that many so-called "European collaborative trials" were being conducted in two or more European countries. In addition, since the early 2000s, when many international clinical trials were conducted worldwide, major contract research organizations (CROs) in the U.S. have been taking the initiative in conducting trials (obtaining cases) in Eastern European countries such as Poland and the Czech Republic*7, 7 Although Japan also often conducts joint trials in Asia with other Asian countries such as South Korea, Taiwan, and Singapore, the number of such trials itself is considered to be smaller than in Europe.

Number of Trials of International Clinical Trials in Major Countries Yearly

Figure 3 shows the annual number of studies of international clinical trials by major country, and Figure 4 shows the ratio to the total number of studies. The U.S. saw a sharp increase from 2000 to 2006, in line with the increase in registrations to ClinicalTrials.gov, with 549 trials in 2006, and a gradual rise since then, to 684 trials in 2018. This represented 77.5% of all international trials registered on ClinicalTrials.gov. For Germany and France, the trend of increase had ceased since 2006, with Germany averaging 400 trials per year (about 45% of the total) and France averaging 320 trials per year (35-40% of the total). However, both Germany and France saw an annual increase in the number of trials participating in international clinical trials with the U.S., while the number of trials in international clinical trials conducted solely in European countries was on a downward trend. In the U.K., the number of trials remained at around 300 trials (about 30% of the total) from 2006 to 2011, but after 2012, the number slightly increased to around 350 trials (40-45% of the total). Japan, on the other hand, had 19 examinations in 2006, but had continued to increase since then, reaching 174 examinations per year (19.7% of the total) in 2018, an increase of about 10 times. China had increased from 57 trials in 2006 to 83 trials (9.4% of the total) in 2018, but participation in international joint trials had not increased as much as in Japan. However, China's "Opinions on Deepening Reform of the Review and Approval System and Recommendations for Pharmaceutical and Medical Device Innovation" (Agency letter [2017] No. 42), including optimization of the clinical trial review procedure (if the IND is not rejected by the Chinese authorities within a certain period after IND submission, it is considered IND approval), priority review, acceptance of overseas data, etc. The Opinions on Pharmaceutical Regulatory Reform were issued jointly by the Chinese Central Regulatory Commission and the State Council Regulatory Commission in October 2017, and we believe that China's participation in international joint clinical trials may increase in the future.

Figure 3: Annual number of international clinical trials in major countries (year of study start: 2000-2018)
Source: Created based on ClinicalTrials.gov

Figure 4 Percentage of major countries participating in international clinical trials
Source: Created based on ClinicalTrials.gov

Analysis of Nationality of Companies Conducting Multinational Clinical Trials in Japan

The 1396 international clinical trials conducted in Japan (trial start years 2000-2018) selected in the previous section were surveyed based on the "Sponsors/Collaborators"" information registered in ClinicalTrials.gov regarding which nationalities were conducting these trials (Fig. 5). ( Figure 5 ). As a result, the percentage of trials in which Japanese companies were sponsors/collaborators of global clinical trials, including those conducted in collaboration with overseas companies, was only 13.8% of the total. In addition, looking at annual trends, although the number of international joint clinical trials conducted in Japan is increasing, the percentage of trials in which Japanese companies are involved has not changed significantly, at 10-20%, indicating that Japanese participation in international joint clinical trials conducted by overseas companies, mainly global megapharmaceutical companies, is increasing, The main reason for the increase in the number of international clinical trials conducted in Japan has been Japan's increasing participation in international clinical trials conducted by overseas companies, mainly global megapharmaceutical companies.

Fig. 5 Nationality of Sponsors/Collaborators of International Clinical Trials in Japan
Source: Created based on ClinicalTrials.gov

Summary

We have reported that the number of international clinical trials conducted in Japan has been increasing in recent years, and now a new survey based on clinical trials registered on ClinicalTrials.gov shows that the number of international clinical trials conducted in Japan has continued to increase since 2014, and that the increase is more pronounced than in other major countries. The study found that the number of global clinical trials conducted in Japan has continued to increase since 2014, and that Japan now participates in approximately 20% of all global clinical trials conducted worldwide.

The increase in the number of global clinical trials being conducted in Japan is a desirable trend, as more innovative drugs are submitted simultaneously in Japan, the U.S., and Europe, and these drugs are delivered to patients in Japan as soon as possible. On the other hand, these international joint clinical trials are currently being conducted mainly by global megapharmaceutical companies in Europe and the U.S. For Japanese companies to achieve further growth in the future, it is important to actively promote international joint clinical trials with a view to simultaneous development in the U.S., Europe, and Japan.

( Shinichiro Awamura, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute)

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