Points of View Survey on Countries Conducting Clinical Trials ～Comparison among Drug Discovery Modalities

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Yosuke Takahashi, Senior Researcher, National Institute of Biomedical Innovation Policy

SUMMARY

1. Introduction

In the "Policy Research Institute News No. 65," "Current Status and Future Prospects of Gene Therapy in Practical Use," we reviewed the development trends of gene therapy and gene-cell therapy, summarized development issues in Japan, and introduced efforts to solve these ^issues1). 1) In the article, the author also mentioned that "if these issues are not resolved, they could lead to drug losses more serious than drug lag," and expressed hope that gene therapy research and development would be revitalized in Japan. At the same time, there has been growing concern in recent years about a resurgence of "drug lag" in the Japanese pharmaceutical ^market2),3) and "drug loss" has become a social problem, and the Ministry of Health, Labor, and Welfare's "Expert Panel on Comprehensive Measures to Achieve a Rapid and Stable Supply of Pharmaceutical Products ⁴⁾ The Ministry of Health, Labour and Welfare's "Expert Panel on Comprehensive Measures to Achieve a Rapid and Stable Supply of Drugs" has just discussed solutions. In this paper, we attempt to investigate signs of a "drug lag" or "drug loss," with particular attention to gene therapy and gene-cell therapy in Japan. One leading indicator of future new drugs is the drug pipeline in the clinical trial stage. In Policy Research Institute News No. 68, we conducted a survey regarding originator companies of products in Phase 3 development, and examined the nationalities of companies active in pharmaceutical R&D and their changes over time, as well as analyzed international development lag ^trends5). However, in analyzing and discussing new drug trends in the Japanese market, not only the nationality of the developing company, but also the region where the clinical trials are being conducted will be an important indicator. Therefore, this report focuses on the countries where clinical trials are conducted (i.e., the nationality of the sites where clinical trials are conducted), and investigates from the perspective of differences among drug discovery modalities and changes over time.

Survey Methodology

In this series of research studies, we used the information contained in the drug database Evaluate Pharma (as of September 2023), which contains clinical trial information from ClinicalTrials. ^gov6), ^EudraCT7), and jRCT ⁸⁾ (formerly JapicCTI), and the analysis was performed for all phase clinical trials listed there. The modality of the test substance as a drug candidate was classified based on the Technology section in Evaluate Pharma. Specifically, small molecule chemistry, antibody therapeutics (monoclonal and recombinant antibody), recombinant protein therapeutics, protein peptide therapeutics, nucleic acid therapeutics, DNA RNA therapeutics, and cell therapy: DNA RNA therapeutics, Cell Therapy, Gene Therapy, and Gene-modified Cell Therapy. The number of clinical trials (number of clinical trial starts) was analyzed over time for each modality, with the time period divided into 3-year (36-month) increments based on the trial start date of each clinical trial. It should be noted that the most recent data covers the 29-month period from January 2021 to August 31, 2023, and thus cannot be directly compared to the number of clinical trials in the previous 36-month period.

In the analysis of the number of clinical trials in each country, when a clinical trial was conducted in multiple countries (e.g., international collaborative trials), it was counted as one trial in each country. Therefore, it should be noted that the total number of clinical trials in each country does not equal the total number of clinical trials globally. In the analysis of sponsor nationality by country of clinical trial, when there were multiple sponsors for a single trial, the number of sponsors was ^prorated9). In the investigation of clinical trial phases, when multiple phases were conducted as a single trial, they were considered as clinical trials in later phases and were counted (a Phase 1/2 trial was considered as Phase 2).

Results

The ranking of countries conducting clinical trials of small molecule drugs is shown in Table 1. The U.S. has consistently ranked first in the number of countries conducting clinical trials of small molecule drugs since 2012, and the number of trials has remained above 4,000 in each time period. This is the highest number among all the modality categories shown below. Excluding the U.S., the top-ranking countries are all in Europe, where the number of clinical trials is generally similar, with some fluctuation in ranking. China has improved its ranking significantly in recent years, rising from outside the ranks in 2012-2014 and 2015-2017 to fourth in 2018-2020 and second in 2021-2023. Japan's ranking was 12th, 11th, 13th, and 13th in each survey period, and remained at 1/7th to 1/8th throughout the survey period compared to the U.S., which has the largest number of clinical trials.

The ranking of countries conducting clinical trials of recombinant proteins is shown in Table 2. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for recombinant proteins since 2012, maintaining a scale of more than 600 trials in each period. Excluding the U.S., the top countries were European countries, with Germany always in second place, although there were some fluctuations in the ranking. As with small molecule drugs, China has improved its ranking significantly in recent years, rising from outside the ranks in 2012-2014 and 2015-2017 to 8th in 2018-2020 and 3rd in 2021-2023. Japan's ranking has fluctuated from 12th to 9th to 9th to 9th in each survey period, and the number of clinical trials remained about 1/6th that of the U.S. throughout the survey period.

The ranking of countries conducting clinical trials of antibody drugs is shown in Table 3. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for antibody drugs since 2012, and the number of trials in each of the three-year periods has been increasing steadily. Excluding the U.S., the top-ranked countries are all in Europe, a trend similar to that seen in small molecule drugs, etc. Among European countries, Spain's high ranking is characteristic. As with other modalities, China has also improved its ranking significantly in recent years, rising from outside the ranks in 2012-2014 and 2015-2017 to third place in 2018-2020 and second place in 2021-2023. Furthermore, the number of clinical trials has increased to about 60% of the size of the U.S. in the most recent period, which is unique compared to other modalities. Japan's ranking has been 15th, 10th, 12th, and 10th in each survey period, and the number of clinical trials remained at about 1/4 to 1/5 of that of the U.S. throughout the survey period.

Table 4 shows the ranking of countries conducting clinical trials of nucleic acid medicine. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for nucleic acid drugs since 2012, but the number of trials in the most recent period remained at 178 trials. However, the number of trials in each of the three-year periods has been increasing steadily, indicating that this is a modality that is rapidly gaining attention. Excluding the U.S., the top-ranked countries are all in Europe, a trend similar to other modalities, but Canada's position at the top of the list is unique. In a departure from the other modalities, China did not rank in the top 10. Japan's ranking has been 21st, 19th, 12th, and 12th in each survey period, and the number of clinical trials in recent years has been about 1/6 of that in the United States.

Table 5 shows the ranking of countries conducting clinical trials of cell therapy. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for cell therapy since 2012, and although the number of trials has been increasing steadily every three years, the growth has been slower than for nucleic acid medicine. The top ranking except for the U.S. differs significantly from the other modalities, with Korea's position in the top ranking being a distinctive feature. This result is consistent with the ^report10) that South Korea has been focusing on research related to stem cell-related technologies and has greatly increased the number of patent applications. China's ranking has also been consistently high, moving from 7th to 3rd to 3rd to 4th during the survey period. Japan's ranking has shifted from no results to 15th, 10th, and 10th in each survey period, and the number of clinical trials in recent years has remained below 1/10 of that in the United States.

The ranking of countries conducting clinical trials of gene therapy is shown in Table 6. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for gene therapy since 2012, but the number of trials in the most recent period was only 125. However, the number of trials in each of the three-year periods has been increasing steadily, suggesting that this is one modality that is rapidly gaining attention. Excluding the U.S., the top ranking countries are all European countries, most notably the U.K., which has been in second place in recent years. China has also moved up to 5th place in recent years. Japan's ranking has shifted from 20th to 11th to 12th to 14th in each survey period, and the number of clinical trials in recent years has remained at 9, which is less than one-tenth of the number in the United States.

Table 7 shows the ranking of countries conducting clinical trials of gene-cell therapy. As with other modalities, the U.S. has always ranked first in the number of countries conducting clinical trials for gene cell therapy since 2012, but the number of trials in recent years has remained at 178. Since 2015, China has remained in second place behind the U.S., and the number of trials has increased to a level approaching that of the U.S. Japan's ranking has shifted from 7th to 12th to 13th to 14th in each survey period, and the number of clinical trials in recent years has remained below not only the U.S. but also 1/10th of China's level.

Next, we analyzed in detail the status of gene therapy and gene-cell therapy from the most recent year, 2021 onward. The number of clinical trials of gene therapy in each country is shown in Figure 1 (corresponding to 2021.1-2023.8 in Table 6), and the ratio of sponsoring nationalities to clinical trials in each country is shown in Figure 2. Similarly, the number of clinical trials of gene-cell therapy is shown in Figure 3 (corresponding to 2021.1-2023.8 in Table 7) and the percentage of its sponsoring nationalities in Figure 4. Since it is possible that gene therapy and gene-cell therapy may advance to the approval process based on the results of Phase 2 trials, Figures 1 and 3 also show the sum of Phase 2 and Phase 3 trials as an indicator of late-stage clinical trials.

Gene Therapy

As shown in Figure 1, the majority of gene therapy clinical trials in all countries were Phase 2 or later stage clinical trials. In the Netherlands, Germany, Canada, Italy, France, and Spain, the percentage of Phase 2 or later trials was particularly high, exceeding 80%.

In the U.S., which has the largest number of clinical trials (125 trials), approximately 74% (92.7 trials) were sponsored by U.S. companies, research institutions, etc., accounting for the largest proportion. The next most common sponsoring nationalities were Switzerland (about 8%, 10.5 trials), followed by Japan (about 4%, 4.5 trials).

A higher percentage of trials conducted in Canada and Australia were conducted by U.S. sponsors, while the percentage of U.S. sponsors was relatively low in China, Germany, and France compared to the other countries. The U.S. sponsored trials were conducted in the U.S., Canada, the U.K., and Australia, in that order, and only 3.5 trials were conducted in Japan, the smallest among the top 12 countries.

As shown in Figure 2, focusing on the U.K., which has a large number of clinical trials and a large number of U.S. sponsored trials, a closer examination of the 19 trials conducted in the U.K. ^region11) reveals that 17 of these trials were conducted exclusively by U.S. sponsors, 4 trials were conducted as joint trials between U.S. and other country sponsors, and there were 21 trials in total ⁽ Table 2 ⁾. and a total of 21 trials were present (Table 8). Of these 21 trials, 3 were conducted in only 2 countries (the U.K. and the U.S.), 13 were conducted in more than 3 countries including the U.S. and the U.K. but did not include Japan, and only 2 trials included Japan. These results suggest that in gene therapy, international clinical trials tend to be conducted without incorporating the Japanese region.

The majority of clinical trials conducted in China were conducted by sponsors of Chinese nationality (70%, 14 trials), suggesting that Chinese companies and research institutions often conduct clinical trials in their own countries.

The second largest number of clinical trials after the U.S. was conducted by Swiss companies or research institutes, with the largest number of trials conducted in the U.S. region (10.5 trials), and the highest percentages of trials conducted in Japan, Germany, and Italy.

Gene-cell therapy

As shown in Figure 3, the proportion of late phase clinical trials after Phase 2 in gene cell therapy trials was polarized between countries with a high proportion of Phase 2 trials and countries with a low proportion of Phase 2 trials. China (19.7%), Japan (33.3%), Australia (33.3%), and the U.S. (42.7%) had low percentages of Phase 2 and beyond, falling below half.

In the U.S., which has the largest number of clinical trials (178 trials), approximately 82% (146.2 trials) of them were sponsored by U.S. companies, research institutions, etc., which accounted for the largest proportion. The involvement of non-US sponsors was limited, although there were a certain number of clinical trials conducted by sponsors from Switzerland, the UK, Japan, and France.

China was the region with a number of clinical trials approaching that of the U.S. (Figure 3), but the majority of these trials were conducted by sponsors of Chinese nationality (approximately 88%, or 129.5 trials), suggesting that Chinese companies and research institutions often conduct clinical trials in their own country.

In clinical trials conducted in European countries and the regions of Canada and Australia, a high percentage (about 50-70%) were conducted by sponsors from the United States, followed by the involvement of sponsors from Switzerland and the United Kingdom. For trials conducted in the Japan region, only about 39% were conducted by U.S. sponsors, and about 33% of trials were conducted by Japanese sponsors. The trend toward a higher proportion of home country sponsors was similar in Korea.

The regions in which U.S. sponsors are conducting clinical trials are the U.S., China, the U.K., and France, in that order, with Japan accounting for only 3.5 trials, the fewest among the 13 countries (Figure 4). In addition, as with gene therapy, focusing on the U.K., a close examination of trials conducted in the U.K. region by U.S. ^sponsors11) revealed that 11 of the 11.5 trials were conducted exclusively by U.S. sponsors, and one trial was conducted as a joint trial between U.S. and other country sponsors, for a total of 12 trials (Table 9). Table 9). Of these 12 trials, none were conducted exclusively in the UK region, 2 trials were conducted in the UK and several European countries but did not include the US, 1 trial was conducted in only 2 countries (UK and US), 7 trials were conducted in 3 or more countries including the US and UK but not Japan, and 1 trial was conducted in 3 or more countries including the US and UK but not Japan. Two studies were conducted in three or more countries including the U.S. and the U.K. and did not include Japan. These results suggest that even in gene-cell therapy, there is a tendency for international collaborative trials to be conducted without incorporating the Japanese region.

Conclusion and Discussion

In this paper, we counted the number of clinical trials conducted in each country for each modality of drug, and analyzed the comparison of the number of trials by country and the change in the number of trials over time. The results showed that the number of clinical trials in the U.S. was always the largest for all modalities. One reason for this may be that there are many pharmaceutical companies and research institutes in the U.S. that are promoting research and development in the U.S., but also because pharmaceutical companies in other countries are conducting clinical trials in the U.S., aiming to launch their products in the U.S. market, which is the largest market. The second and subsequent countries conducting clinical trials after the U.S. are generally European countries and Canada, but China's rapid rise in the rankings for many modalities in recent years is a distinctive feature. In particular, in the fields of antibody drugs and gene cell therapy, China has recently moved up to second place behind the United States. As reported in past Policy Research Institute News, Chinese companies have been active in drug development in recent years, especially in the development of anticancer drugs ^.5)12) In the field of antibody drugs, China has been the world's leading country in the development of immune checkpoint inhibitors. In the case of antibody drugs, such as immune checkpoint inhibitors, and in the case of gene cell therapy, such as CAR-T cells, there are many cases of their application as anticancer drugs, and the results of this survey were considered consistent with the fact that the number of clinical trials of antibody drugs and gene cell therapy in the Chinese region is increasing. According to Evaluate Pharma's classification of Indication, approximately 70% of the clinical trials conducted in China for antibody drugs and 90% of those for gene cell therapy are actually being developed as anticancer drugs.

Next, we turn to the status of clinical trials conducted in Japan. The small molecule drugs with the largest number of cases always remained in the top 10. According to a report in Policy Research Institute News No. 66, Japan ranks 14th in the number of clinical trials for all ^drugs12), a result that is roughly in line with the ranking of low-molecular-weight drugs in this survey. While it is not necessary to discuss this ranking in depth in this report, it should be noted that while Japan is a country with a large drug market, the Japanese region is not selected as a country to conduct clinical trials when seeking approval in the U.S. or Europe (generally, countries with a similar racial composition to the country seeking approval are selected as the country to conduct clinical trials), and the number of clinical trials for small molecule drugs in Japan is very similar to the number of clinical trials for small molecule drugs in the U.S. (Generally, countries with a similar racial composition to that of the country seeking approval are selected as clinical trial countries), Japan's clinical trial costs (cost per case) are higher than the global ^average13), and the speed of case accumulation is slower than in other ^countries14). However, the number of clinical trials conducted in Japan for small molecule drugs is consistently 1/7th to 1/8th of that in the U.S., and we will discuss the status of other modalities on the assumption that this is the standard. During the four periods covered by this survey, the number of clinical trials conducted in Japan for recombinant proteins remained at about 1/6 of that in the U.S., antibody drugs at about 1/4 to 1/5 of the U.S., and nucleic acid drugs, which were initially less than 1/10 of the U.S. level, have recently risen to about 1/6 of the U.S. level, suggesting that these modalities are being conducted at the same level as low molecular drugs. It is thought that clinical trials are being conducted at the same level as those for small molecule drugs in these modalities. On the other hand, the number of clinical trials for cell therapy, gene therapy, and gene-cell therapy has been rising in recent years, but is still below 1/10 of the U.S. level, suggesting that clinical trials for these three modalities are relatively few and somewhat stagnant in Japan.

In this report, we conducted a detailed survey of the phases and sponsor nationalities of clinical trials being conducted in each country, with a particular focus on gene therapy and gene-cell therapy.

Analysis of the phases of gene therapy clinical trials revealed a high proportion of Phase 2 and later phase clinical trials in many countries. This overall trend is consistent with the report by ^Keyi15). Among these countries, some countries, such as the Netherlands, Germany, and Canada, have a high percentage of late-stage clinical trials, and although it was not possible to clarify the factors behind this in this survey, it can be inferred that these countries are more likely to conduct the next phase of clinical trials based on the results of Phase 1 trials conducted in other countries.

Analysis of the phases of clinical trials for gene-cell therapy revealed that the percentage of Phase 2 and later clinical trials in each country was polarized. In the U.S. and China, where the number of clinical trials itself is large, the percentage of clinical trials after Phase 2 was relatively low. Considering the results of Fig. 4, it is likely that many of the seeds discovered in these countries are being evaluated through early-stage clinical trials within their own countries. Like the U.S. and China, Japan has a low percentage of clinical trials after Phase 2 (33.3%), but there are three early-stage trials conducted by home sponsors, which gives hope for the future that more Japanese seeds will be put to practical use for the first time.

The U.S. region, which has the largest number of gene therapy clinical trials, accounted for the largest percentage, with approximately 74% of these trials being conducted by U.S. sponsors. Furthermore, the U.S. was also the region with the largest number of clinical trials for gene-cell therapy, with approximately 82% of these trials conducted by U.S. sponsors, which, like gene therapy, accounted for the largest proportion. From the results of Figures 2 and 4, it can be inferred that most of the drug discovery seeds for gene therapy and gene-cell therapy are generated in the U.S., and U.S. sponsors place the highest priority on development within their own countries. The second largest region conducting clinical trials after the U.S. is European countries, while clinical trials in the Japanese region are limited. The survey results show that the number of clinical trials involving U.S. sponsors in Japan was only 3.5 for both gene therapy and gene-cell therapy, which is the smallest among the countries surveyed. It is possible that U.S. sponsors have been reluctant to conduct clinical trials in Japan because they perceive that there are still issues in the Japanese clinical trial environment. A number of groundbreaking new drugs have emerged from gene therapy and gene-cell therapy in recent ^years16). In order to create a medical environment in which Japanese patients can access the latest gene therapy and gene-cell therapy without delay, it will be necessary to further stimulate the implementation of clinical trials in Japan.

Conclusion

In Policy Research Institute News No. 65, the challenges for gene therapy (gene-cell therapy) in Japan include: (1) Improvement of basic research (support for research funding, increase of researchers, human resource development, etc.), (2) Development and relaxation of regulations (regulatory science research, Cartagena Act compliance, etc.), (3) Transrational Research, and improving experience in gene therapy R&D), (4) expansion of manufacturing and testing facilities (CMO, CDMO, CRO, etc.), (5) patent strategy (securing competitive patents), and (6) educational activities (increasing understanding among medical professionals, patients, the public, etc.) ^.1) The following six points were picked up. Resolving these issues one by one will not only expand the number of Japan's first drug seeds, but will also encourage the medical application of domestic and foreign drug seeds in Japan without delay, and help solve the drug lag and drug loss that have become problems in recent years. Although IPSJ News No. 65 introduced the recent progress in resolving these issues1), the results of this survey indicate that we still have a long way to go. At the 29th Annual Meeting of the Japanese Society for Gene and Cell Therapy17) held recently, a symposium was held on the theme of regulation, where people from the Pharmaceuticals and Medical Devices Agency (PMDA) introduced the efforts of the authorities to resolve issues in the development of gene therapy and gene cell therapy in Japan. as well as individual consultations with PMDA staff18). In conjunction with the timing of the conference participation by people from academia, venture companies, pharmaceutical companies, and other related parties, "The contents and procedures of the consultation services provided by PMDA for those who are considering the development of regenerative medicine products (including gene therapy products) in Japan and those who are considering consulting with PMDA in the future were introduced, as well as the details of PMDA's consultation services and procedures for development products. The purpose of the individual consultation meeting was to "introduce the contents and procedures of the consultation services provided by PMDA, and to exchange opinions on the content (scope) of the consultation and the organization of issues to be discussed within a general scope in order to implement efficient consultation regarding the development of products. It is hoped that policies targeting academia, venture companies, and pharmaceutical companies in Japan and abroad, such as those represented by this individual consultation meeting, will come to fruition and stimulate the development of gene therapy and gene-cell therapy in Japan in the future.

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