Points of View Analysis of Global Trends and Development Lag of Phase 3 Development Products

Printable PDF

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

Introduction

The National Institute of Biomedical Innovation (NIBIO) has reported on the current state of new drug creation, including the number of new drugs approved each year and a breakdown of the modalities of new drug approval, in various ^{newsletters1) and 2)}. 2 ⁾ In Research Paper No. 77, Keyi analyzed the development pipeline trends, including the annual number of development pipelines by modality and the nationality/company classification of the companies that created the ^pipelines3).

In this paper, we focus on new drug candidate compounds in Phase 3 (hereinafter referred to as NMEs) and analyze and discuss them from various angles, including the originator company of the NME, its nationality, the region where the clinical trial is conducted, and the modality of the NME, as indicators that enable us to estimate trends in new drugs that will be launched in the near future. The analysis and discussion will be conducted from various angles, including the originator company of the NME, its nationality, the region where the clinical trial is conducted, and the modality of the NME.

In addition, in recent years, several news reports from the Policy Research Institute have compared the approval timing of new drugs in Japan, the U.S., and Europe, focusing on a single new drug, and have revealed that the number and ratio of unapproved drugs in Japan have been on the increase since the late 2010s. By comparing the development stages of Phase 3 drugs between countries conducting clinical trials, we may be able to identify signs of drug lag and drug loss in the future. This paper examines the possibility of inferring signs of drug lag and drug loss from this indicator by comparing the development stages in Japan and the U.S. regions.

Methodology and Results

Using Pharmaprojects, a pharmaceutical database, we investigated ^NMEs6) in the Phase 3 stage. The definition in the database was used to evaluate the originator company of the developed product and its corporate ^{nationality7)}, taking into account the accelerated global trend of clinical trial publication in the early ^2000s8) and the 2007 FDA amendment law that made the pre-registration of clinical trials mandatory in the U.S. ⁹⁾, In order to eliminate the influence of the data coverage of the database on the analysis results, the period after 2007 was selected for analysis.

Nationality of the Originator Company for Phase 3 products

Figure 1 shows the annual changes in the number of NMEs extracted as Highest status: Phase 310 ⁾. In the series of surveys, the number of NMEs developed as of May of each year was used for evaluation.

Figure 1 shows that the number of NMEs in Phase 3 has been increasing steadily, almost doubling over the past 10 years (from 442 in 2012 to 820 in 2022).

Next, in order to examine the origin of these NMEs, we sorted them by the nationality of the originator company. Figure 2 shows the annual trends of all NMEs by the nationality of the originator company, and also shows the trends when classified by two modalities: small molecule drugs and new modalities (other than small molecule drugs).

Figure 2 shows that the number of products developed by U.S. companies (hereinafter referred to as "U.S. company-origin products") has increased significantly, and the number of products originated by Chinese companies has also increased significantly in recent years, indicating that the overall growth is driven by the increase in products developed by U.S. and Chinese companies. As of May 2022, the top countries are USA (303), China (127), Japan (50), South Korea (42), Switzerland (42), UK (36), France (30), Germany (25), Italy (14), Israel (13), Canada (12), and the United States (14). (13), Canada (12), Denmark (12), and Sweden (12). In subsequent analyses, only the above 13 countries will be evaluated.

When the products developed are categorized into Chemical, synthetic (small molecule drugs) and Others (other new modalities)11), the U.S. always maintained the No. 1 position in small molecule drugs, and the number of products under development is on a gradual upward trend. Japan maintained the number two position until the mid-2010s, but in recent years it has been overtaken by China and remains in third place. As of May 2022, the number of small molecule drugs in development was USA (121), China (42), Japan (28), Switzerland (18), UK (17), Israel (16) South Korea (16), Germany (12), France (11), Canada (8), Italy (7), Sweden (4), and Denmark (3). In the new modality group, since biopharmaceuticals began to be commercialized one after another in the 2000s, the U.S. has maintained the No. 1 position at all times and has continued to grow steadily and significantly, surpassing small molecule drugs in the number of products currently under development. As of May 2022, the number of products developed by Chinese companies was more than double that of the third-ranked companies and below. As of May 2022, the number of products in development in the new modality group was USA (182), China (85), South Korea (26), Switzerland (24), Japan (22), France (19), UK (19), Germany (13), Denmark (9), Sweden (8), Israel (7), Italy (7), and Canada (4).

In order to examine which attributes were responsible for the increase in the number of products developed by U.S. companies, we evaluated the number of products developed by the 8 major U.S. pharmaceutical ^companies12) separately from those developed by other companies (Figure 3). In terms of the definition of originator in Pharmaprojects, products developed by subsidiaries acquired through M&A before 2012 are counted as products derived from the parent company.

The number of items originating from the 8 major companies remained stable at around 50 at all times from 2007 to 2022, and in recent years, the proportion of new modality groups slightly exceeded that of small molecule drugs; as of 2022, a total of 52 items originated from the 8 major companies, among companies not classified as the 8 major companies, Regeneron (9 products), Ionis Pharmaceuticals (6 products), Moderna (5 products), CSL Behring (4 products), and Novavax (4 products) had more products in Phase 3 development, in that order. The result that there was no significant change in the annual change in the number of items originating from the eight major companies confirms that the overall increase in the number of items is largely due to the contribution of other companies. Although there are a variety of companies in this group, ranging from small bio-ventures such as start-ups to small- to mid-sized pharmaceutical companies, the number and percentage of products developed that originated from companies other than the eight major companies at least tends to increase year by year. As of 2022, there will be 251 products developed by companies other than the eight major pharmaceutical companies, of which 194 products are developed by one company (detailed data omitted), and the increase in the number of products can be attributed to the increase in the number of companies.

The increase in the number of items developed by Chinese companies was reported by Shibuguchi in Policy Research Institute News No. ⁶⁰¹³⁾. In China, the "13th Five-Year Plan for National Economic and Social Development (2016-2020)," which involves science and technology innovation policy, and "China Manufacturing 2025," which describes future manufacturing industry development plans, position the biopharmaceutical business as one of the key national strategies and encourage its development. While this may be the reason for the increase in the number of development pipelines originating from Chinese companies, the report also points out that most of the new drug development by Chinese pharmaceutical companies is being conducted only in China, and it is necessary to keep a close eye on whether the number of products that can be developed globally will increase in the future. The "14th Five-Year Plan for National Economic and Social Development (2021-2025)" and "China Manufacturing 2025," which were issued after the "13th Five-Year Plan for National Economic and Social Development (2016-2020)," were translated into Japanese by the National Institute of Science and Technology Agency (JST). For more information, please refer to the full Japanese translations prepared and published by the Japan Science and Technology Agency (JST) ^{14) and 15)}.

Although the analysis results in Figure 2 reflect the latest trends since the above report, it was confirmed that the number of items under development has continued to increase significantly even in the most recent period. Therefore, we will analyze and discuss the degree of increase in the number of global products at this point in time. In Figure 4, we distinguish between those products developed solely in China and those developed in other countries, with regard to products originated by Chinese companies in the Phase 3 stage. As a result, we can confirm that the number of both types of products is growing, and at the same time, the ratio of products developed in other countries to the total number of products is increasing year by year. These facts, as well as the increase in the number of items originating from Chinese companies that are being developed in the U.S. region, as discussed later in Figure 5, suggest that Chinese companies are beginning to make their global expansion more audible.

Comparison of development stages in Japan and the U.S.

Since the U.S. has the largest market in the world, we conducted a survey on products currently in Phase 3 development in the U.S. based on the assumption that products developed for global development will be in Phase 3 development in the U.S. For the purpose of comparing the development stages between countries where clinical trials are conducted, even if a drug is already approved in another country, it is counted as long as it is in Phase 3 development in the U.S. The results are shown in Figure 5. The results are shown in Figure 5, In 2022, the top countries were USA (325), Switzerland (60), Japan (46), UK (40), France (30), China (24), Germany (19), Israel (15), South Korea (15), Canada (14), Italy (13) Denmark (12), and Sweden (12).

In terms of evaluation by modality, Japanese companies have always maintained the second position in small molecule drugs, confirming their strength in small molecule drugs, but in the new modality group, they are only around fifth, and are considered to be slightly behind companies from other countries in the development of biopharmaceuticals and other products. In Figure 5, which shows Phase 3 trends in the U.S. region, the recent rise of Chinese companies is less conspicuous than in Figure 2, which shows global trends. This is consistent with the fact that, as mentioned earlier, many products originating from Chinese companies are being developed only in China. However, an analysis focusing on the last seven years shows that the number of products originating from Chinese companies that are in Phase 3 trials in the US region has increased significantly (1 product in 2016 → 24 products in 2022, rising to 6th place by 2022), and from this we can infer that the global presence of Chinese companies will continue to grow in the future. This suggests that Chinese companies' global presence will continue to grow in the future. A close examination of the 24 items in 2022 shows that these items originated from a total of 21 companies16) , 8/24 items originated from start-ups established within the past 10 years, and 16/24 items originated from companies established within the past 20 years, indicating that many items originated from relatively new and small-sized companies. There were many items that originated from companies with relatively short history and small scale. There were many cases where a single company, even an emerging company, attempted to proceed alone to the approval stage. It can be inferred that, backed by China's national policy and aggressive venture investment, emerging companies are obtaining abundant development funds and pursuing independent development while utilizing outsourcing services such as CROs and CMOs/CDMOs.

Next, in order to predict the introduction of new drugs into Japan17) , we also conducted a survey of Phase 3 projects in the Japanese region (Figure 6). Similar to the aforementioned survey method for Phase 3 in the U.S., even if a drug is already approved in another country, it is counted as long as it is under Phase 3 development in the Japan region.

The number of Phase 3 products in Japan that originated in the U.S. was the highest among the Phase 3 products in the U.S., which is similar to the number of products in the U.S. in Phase 3 in Japan. However, Japanese company-originated items are second, far ahead of Switzerland, which is third, and also account for about 19% of the total (for items in Phase 3 in the U.S., the number of Japanese company-originated items is only about 7% of the total), suggesting that Japanese companies are the most active in their efforts to bring new drugs to the Japanese market. In 2022, the top countries are USA (108), Japan (41), Switzerland (20), France (12), Denmark (8), UK (8), Germany (6), South Korea (6), China (3), and Canada (3), China (3), Canada (2), Israel (2), Italy (3), and Sweden (2).

Next, in order to evaluate the degree of agreement between items in Phase 3 in Japan and the U.S., the development stage19) of items in Phase 3 in the U.S. region in the same year in the Japan region was investigated, and results were obtained for all developed items (Fig. 7), limited to items originating from Japanese companies (Fig. 8), and for items originating from Japanese companies The results were calculated for all developed products (Figure 7), for products originated by Japanese firms (Figure 8), and for products not originated by Japanese firms (Figure 9). Figure 10 shows the percentage of delayed development stages in the Japanese region for Figures 7 through 9, comparing the nationalities of the originating firms.

The results for all developed products (Figure 7) show that in the 2000s, there were few cases in which Phase 3 was implemented at the same time in both Japan and the U.S., and the percentage was less than 5%. The percentage of delayed development in Japan (i.e., the percentage of items in Phase 2 or earlier development in Japan) was around 80-90% in the 2000s, then gradually declined from around 2010, reaching about 70% in 2014. However, it has since gradually reversed to an increasing trend, reaching a level of about 75% in recent years.

The results of the analysis focusing on products originated by Japanese companies (Figure 8) show that approximately 50% of Phase 3 products developed in the U.S. in recent years have been approved in Japan, suggesting that a high percentage of products originated by Japanese companies have been preferentially launched in the Japanese market. The percentage of products in Phase 3 development in the U.S. that are late in development in Japan has been decreasing every year since its peak value of approximately 60% in 2002, and has fallen to approximately 20% in 2014. The fact that this indicator has declined indicates that the environment has improved significantly in terms of access to new drugs for the Japanese population. However, this percentage has been gradually increasing since 2014, reaching a level of about 35% in recent years.

The results of the analysis focusing on non-Japanese firm-origin items (Figure 9) showed generally similar trends to the results for all developed items (Figure 7), as these items represent the majority of all developed items. In the case of non-Japan-originated products, about 80% of the products developed in recent years were late in the development stage in the Japan region.

The inflection point for this trend was around 2014, when the development of the drug was delayed from the Phase 3 trial to the approval stage. The results of this study may be an indicator that we can detect signs of drug lag and drug loss ahead of time, taking into account that it takes several years from Phase 3 trials to approval. Figure 10. As shown in Figure 10, although the percentage of Japanese firm-origin products lagging behind in the development stage in the Japanese region is lower than that of products originated by foreign firms, the fact that this percentage has been on the rise since 2014 is common, suggesting that even Japanese firms are beginning to prioritize overseas markets. In addition, while this analysis evaluated differences in development stage from the perspective of the individual development product level (NME level), in recent years, more and more development products have multiple indications, so when analyzed from the perspective of the indication disease level, a delay in the development of one development product in the Japan region may lead to a delay in the development/approval of a product for multiple indications. Therefore, it is feared that a delay in the development of one product in Japan may lead to a delay in the development/approval of products for multiple indications.

Afterword

This paper analyzes products in Phase 3 development to predict trends in new drugs that may be approved in the near future, and also analyzes trends in international development lags.

While the number of newly approved drugs has shown an increasing trend in recent years ( 1), the number of products in Phase 3 development in the survey conducted in this paper has been increasing year by year, and was considered to show a generally similar trend. The increase in the number of products under development is particularly influenced by the increase in the number of products derived from U.S. and Chinese companies. In the U.S., the number of products developed by companies other than major pharmaceutical companies is increasing, and it can be inferred that the increase in the number of products under development is also attributable to the increase in the number of start-up companies. Although a high percentage of products developed by Chinese companies are still targeted at the domestic Chinese market, the percentage of products developed globally has been gradually increasing in recent years, and it is expected that the presence of Chinese companies in the global market will increase in the near future, including the appearance of drugs that rank high in the global drug sales ranking. It was thought that the presence in the global market would increase in the near future.

In a comparison of products in Phase 3 development in both Japan and the U.S., products originating from U.S. companies were the main development products in both regions, and the recent growth of new modalities such as biopharmaceuticals was particularly notable. In the Phase 3 development in the U.S., Japanese company-originated products accounted for only about 7% of the total (about 17% of U.S. company-originated products), while Japanese companies accounted for about 19% of the total (about 40% of U.S. company-originated products) in the Phase 3 development in the Japan region, suggesting that Japanese companies are prioritizing the Japan region over overseas companies in their clinical development to deliver new drugs. It can be inferred that Japanese companies are prioritizing the Japan region over overseas companies in their clinical development efforts to deliver new drugs. From the opposite perspective, it can be seen that for foreign-origin products, the priority is placed on overseas markets such as the U.S. market, and activities to bring new drugs to the Japanese market are put on the back burner.

The analysis of the development stage in the Japan region, especially the percentage of delayed development in Japan, for products in Phase 3 development in the U.S. region showed that the percentage of delayed development in Japan gradually decreased from the 2000s to 2014, but reversed and gradually increased from 2014 onward. This trend was reversed after 2014, with a gradual increase. This was true not only for items originating from foreign firms but also for items originating from Japanese firms; although not all items in Phase 3 development will be approved, assuming that the probability of approval is constant and does not depend on differences in development stages between Japan and the U.S., delays in the development stage in Japan can be considered Taking into account that it takes several years from the start of Phase 3 trials to approval, the results are similar to those reported in 4) that the number of unapproved drugs and the percentage of unapproved drugs in Japan have been increasing since the late 2010s. The situation where even Japanese companies are beginning to prioritize overseas markets is considered very worrisome from the perspective of the Japanese public's access to new drugs.

The reoccurrence of drug lag and drug loss is being discussed at the "Expert Panel on Comprehensive Measures to Achieve a Rapid and Stable Supply of Pharmaceuticals "21) , and we look forward to progress in the discussion and resolution of these issues. Drug lags and drug losses are now considered a social issue, and are being discussed again not only in the above-mentioned expert panel, but also at government meetings, academic societies, and the Central Council of Medical Examiners (Chuikyo). Regarding the case in which the government recognized in the Diet that "the drug lag is not necessarily growing," the web media reported that there is a discrepancy in understanding within the industry and the government22) . In order to ensure a common understanding among the parties concerned, the following issues should be carefully addressed: clarification of the definition of the term "drug lag," classification by type of lag (development start lag, prolonged development lag, application start lag, and review lag), and analysis of the factors that cause each type of lag to occur. The pharmaceutical industry needs to communicate to each stakeholder more clearly than it does now that "the factors behind the current resurgence of drug lag and drug loss are based on delays in the initiation of clinical trials. Once a common understanding of the issues is achieved, we must work to resolve them. From the standpoint of patients in Japan, the most important thing is to have access to innovative new drugs as soon as possible, which requires clinical trials to be conducted in Japan without delay. Although various analyses have been conducted on the reasons why development in the U.S. takes precedence over that in Japan23) , it can be said that the way to solve this problem in the future is to identify the factors that are delaying the clinical trial stage in Japan and carefully solve them one by one. It will be difficult to solve this problem with a single measure alone, and a drastic reform will be necessary, not by taking stopgap measures as an extension of the current various systems, but with a view to the overall healthcare system that is not limited to the pharmaceutical industry.

Return to News List

TOP