The Pharmaceutical Industry at a Glance Survey of International Clinical Trials in Recent Years

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Hiroshi Azuma, Senior Researcher, Pharmaceutical Industry Policy Institute

SUMMARY

1. Introduction

International joint clinical trials are an important initiative in bringing the latest pharmaceuticals to Japanese patients as quickly as possible. In the past, we have reported on the status of international joint clinical trials and analysis of participating countries in the Policy Research Institute ^News1)-3). In addition, international clinical trials are of great significance in eliminating the drug lag, which is represented by the issue of unapproved drugs in ^Japan4). This paper surveys trends in the most recent three years, focusing on comparisons with the previous report, Policy Research Institute News No. 58 (November 2019) ³⁾, and also analyzes trends in early clinical stages, which are becoming more important every year. Furthermore, it is undisputed that the impact of the new coronavirus disease (coronavirus disease 2019: COVID-19) has been felt in many areas of medicine in recent years. This paper will also briefly touch on the impact of the COVID-19 drug and vaccine trials on the overall level and composition of clinical trials.

2. research methods

The same methodology was first used for Policy Research Institute News No. 58 and for the survey. In the first section of this report, the same methodology was used as that used in the Policy Research Institute News No.58. In sections 4 and 5, we used the ClinicalTrials.gov, a clinical trial registration system operated by the National Institutes of Health (NIH) of the U.S., to identify Interventional Studies (Clinical Trials) that were registered in the system, Phase 2 (including Phase 1/2) or Phase 3 (including Phase 2/3) trials with a Funder Type of Industry were included in the study (as of April 8, 2022). In the following sections 6-7, the scope was further expanded to include Phase 1. In this report, we define a single-country study as one in which only one country is enrolled, and an international study as two or more in which more than one country is enrolled. In addition, classification by disease was made with reference to the International Classification of Diseases, 11th edition (ICD-11) of the World Health Organization (WHO) ⁵⁾.

3. international clinical trials conducted in Japan

First, the status of global clinical trials conducted in Japan is shown (Fig. 1).

The number of clinical trial plan notifications for global clinical trials has been increasing every year, reaching 450 in FY2020, a 3.6-fold increase from 124 in FY11, with an average annual growth rate of 15.4% over the past 10 ^years6). 6) The ratio to the total number of clinical trials also continued its upward trend, with 57.0%, more than half of which were international clinical trials. This is considered to be a confirmation of the increase in the number of international clinical trials for domestically approved drugs, thanks to various public and private initiatives and efforts. We believe that a comparison with international clinical trials conducted in other countries will provide an accurate picture of Japan's position in the global marketplace.

4. number of trials registered on ClinicalTrials.gov

Figure 2 shows the transition of trials registered on ClinicalTrials.gov by year of trial start from 2000 to 2021. The total number of trials registered with ClinicalTrials.gov increased rapidly from the early 2000s due to the worldwide trend to encourage the publication of clinical research ^results7) and the U.S. Food and Drug Administration's (FDA) revised ^law8) that mandated the pre-registration of clinical trials in the United States. Since then, the number of registered trials once leveled off, but again began a gradual upward trend from 2016. Focusing on the changes since the last report (2018), the number of trials increased markedly in 2021. Unpacking the breakdown, the number of single-country trials contributed more significantly to the increase. A detailed country-by-country and disease-by-disease analysis will be presented later in this report. The impact of COVID-19 cannot be ignored as a change in the last three years. This analysis will be presented later in this report.

5. number of global trials/single country trials by country

Table 1 shows the top 30 countries in terms of the cumulative number of clinical trials from 2000 to 2021, classified by country and trial type (international collaborative trials, single-country trials, and total number of trials). The overall trend for each country was the same as in the previous report. In this report, we would like to focus on comparisons with the previous report and changes in ranking. First, the U.S. remained prominent in both types of trials and total number of trials, with 11,708 global trials and 15,560 single-country trials, and its influence was still significant. On the other hand, Japan's ranking for global clinical trials rose from 28th to 23rd, and the number of trials increased by approximately 700 over the past three years. This can be understood as a sign that Japan's promotion of international joint clinical trials is making progress among the world's leading countries. On the other hand, the number of single-country trials increased by approximately 200, but the number of trials dropped from 2nd to 3rd place due to China's rapid progress. As for the total number of cases, it had risen slightly from 16th to 14th place.

Here, one country that has undergone a distinctive change is China. While China has traditionally been single-country oriented and ranked 35th this year (1,311 studies, not listed) in terms of international joint trials, it doubled the number of single-country trials from 1,094 to 2,087 in the previous survey and rose to second place in the ranking. Although we have not been able to investigate the nationalities of the companies conducting the trials, we will keep a close eye on the actual status of clinical trials in China in the future. We would also like to mention the trend of international clinical trials in Eastern European countries. We have already reported on the promotion of clinical trials in Eastern European countries by U.S. contract research organizations (CROs) in Policy Research Institute News No. 58. As is well known, the Russia-Ukraine conflict has been raging since the end of February this year. The number of international clinical trials conducted in both countries is not negligible compared to the total number of trials, with Russia in 11th place and Ukraine in 25th place. It can be assumed that the impact of the conflict on the statistics is not yet apparent at the time of compilation (April 8, 2022). Various economic activities in the region are currently stagnant, and it is assumed that the number of each examination will decrease significantly. The future fluctuations and their impact on other countries will be a point to watch closely.

Figure 3 shows the number of global clinical trials per year for each of the major countries (the U.S., Japan, China, Germany, France, and the U.K.), and Figure 4 shows the ratio of participation to all global clinical trials conducted in that year. The trend since 2010 has been flat until 2016 and has been increasing in all countries since then until 2018. Compared to other countries, the participation rate in Japan has been increasing steadily, with 217 trials as of 2018, accounting for 21.0% of the 1,035 trials worldwide (Figure 2). China also saw a rapid increase in the number of participating trials starting in 2016.

Focusing on the most recent three years, the number of trials decreased in all countries except Japan. However, it is too early to say that the number of trials is declining. In other words, the number of clinical trials in a single country at the start of each trial is expanding to other countries over time. In fact, depending on the timing of data collection from ClinicalTrials.gov, about 10% of trials tended to shift from single-country trials to international trials over a period of about three years, as shown in Figure 5. This is due to the fact that the registration of the country name of trials in which the country of implementation was unknown is progressing, and trials that were conducted in a single country are expanding their enrollment to international joint trials. It should be noted that the most recent data underestimates the actual situation.

6. clinical trial trends including Phase 1 trials 7.

So far, we have analyzed Phase 2 or Phase 3 trials. On the other hand, the significance of Phase 1 trials has changed in recent years and their presence is increasing. Especially in the field of oncology, platform-type trials such as basket trials and umbrella trials are being actively conducted. In addition, some of these trials are beginning to become pivotal trials for FDA ^approval4). Figure 6 shows an analysis that includes Phase 1 trials.

First, looking at international clinical trials (upper panel), the number and percentage of Phase 1 and 1/2 trials, which had almost zero enrollment in 2000, increased gradually until 2017, and in recent years they have grown to account for 20-30% of the total number of trials. In detail, the number of Phase 1/2 trials increased 1.7-fold from 180 trials in 2010 to 299 trials in 2017. Since 2010, the growth in the total number of all phases combined has moderated, while the proportion of Phase 1 and 1/2 trials has increased. In contrast, the number of Phase 3 trials has remained flat since 2006, and the relative decrease in the proportion of Phase 3 trials indicates that international clinical trials have moved to earlier stages.

On the other hand, single-country trials (bottom row) showed an increase in the number of trials in 2021, as mentioned above; the Phase breakdown did not change much from the previous year, indicating that the number of trials increased evenly at all stages. In addition, the Phase breakdown throughout all years differed significantly from that of international trials, with more than half of the single-country trials from 2011 onward maintaining Phase 1 and 1/2.

In order to explore the factors that may contribute to the increase in the number of clinical trials in 2021 as shown in Figures 2 and 6, the number of clinical trials conducted by country was divided into those for international joint trials and those for non-international joint trials, and Table 2 shows a selection of the top countries in each category. While many countries showed only moderate annual changes, the United States and China showed a remarkable increase in the number of single-country trials from 2020 to 2021, with an increase of 225 trials and 182 trials, respectively. The number of trials in the U.S. and China increased by 127 and 103 trials, respectively, mainly due to the expansion of oncology trials (Table 3). The number of trials related to COVID-19 also decreased by 67 in the U.S., while the number of trials in China remained almost unchanged with an increase of 4 trials.

Impact of COVID-19 on the number of clinical trials

Changing the topic slightly from international clinical trials, we touch on the impact of COVID-19-related trials on the overall number of trials: COVID-19 was first reported to WHO in December ²⁰¹⁹⁹⁾, and clinical trials, such as vaccine development, began in 2020 in various countries. In order to grasp how many trials are actually being conducted, Phase 1 to Phase 3 were targeted as in the previous section and classified by disease breakdown with reference to the Condition items listed on ClinicalTrials.gov. As shown in Figure 7, there were 504 trials in 2020 and 408 trials in 2021, accounting for 11.4% and 7.8% of the total, respectively, the second largest number after oncology. In 2020, the number of COVID-19-related trials did not directly contribute to the overall increase in the number of trials, which can be assumed to be due to delays in the start of trials in other areas. On the other hand, in 2021, the number of COVID-19-related trials decreased by 96 trials from 2020, but the total number of trials increased by 795 trials. This can be considered to be the result of progress in COVID-19 measures and the resumption of trials that were suspended or delayed in 2020.

In 2020, when COVID-19 suddenly took over, the number of studies in respiratory, infectious diseases (excluding COVID-19), and dermatology decreased by 29.7%, 28.8%, and 26.6%, respectively, while the number of studies in cancer remained almost the same and that in visual fields increased by 10.3%. In the visual field, there was an increase of 10.3%. The particularly large decreases in respiratory disease and infectious disease, including pneumonia and other complications, may be an indication of a slowdown due to concerns that the parallel conduct of clinical trials with the COVID-19 disaster would not provide accurate data. In terms of risk/benefit, clinical trials in the field of oncology, where many diseases are life-threatening, may have been less affected. On the other hand, a certain amount of delay may have been tolerated in the field of dermatological diseases, possibly resulting in a decrease in clinical trials.

In 2021, the number of clinical trials increased by double digits in each field except COVID-19-related and visual diseases, probably due to the fact that the medical field has established some measures to deal with COVID-19 and the infrastructure for conducting clinical trials has recovered. The V-shaped recovery in two years, as indicated by the increase and decrease in the total number of trials excluding COVID-19-related trials, suggests that the pharmaceutical industry has responded flexibly.

Table 5 shows the top 30 countries in terms of the total number of COVID-19-related trials in the two-year period, classified according to whether or not they were international joint trials and the year in which they were initiated. The U.S. ranked first in the total number of international trials, with 114 trials and a participation rate of 64%. This was followed by Brazil (72 studies, 40% participation), Mexico (55 studies, 31% participation), Spain (51 studies, 29% participation), and South Africa and Argentina (43 studies, 24% participation). Japan ranked 23rd with 14 trials and a participation rate of 7.9%. In the single-country studies, the United States ranked first with 241 studies, followed by China (49 studies), Brazil (30 studies), South Korea (29 studies), and the United Kingdom (24 studies), and Japan ranked 8th with 19 studies. The ranking trend of COVID-19 is different from that of other disease trials shown in Table 1 due to differences in infection status and the number of patients in each country, as well as the infection control policies of each government.

8. summary

Trends in international and single-country trials in recent years were reported based on trials registered on ClinicalTrials.gov. In addition, the status of international clinical trials including Phase 1 trials was analyzed. In terms of the future of Japan, the increasing number of international clinical trials is a good sign for the improvement of the drug lag, but as shown in Figure 3, the ratio is still low when compared to other major countries. The impact of COVID-19 on the overall number of clinical trials is expected to continue for a certain period of time, so we will continue to monitor the trend closely.

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