Policy Research Institute Drug Lag: An Analysis of Factors Contributing to the Long-term Lag of Japanese Approved Products

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We conducted a survey of drugs approved in Japan that were approved in the U.S. and Europe prior to the approval in Japan and were approved in Japan after a delay, to determine the actual situation, background, and factors that caused a long-term drug lag. As a result, it was estimated that additional studies in Japan after approval in the U.S. and Europe have the greatest impact on the occurrence of long-term drug lag, and that acquisitions and alliances also increase the probability of drug lag .

1. Introduction

The NIHS has analyzed the current status of drug lag*2. OPIR Views and ActionsNo.70 "Drug lag: Analysis of the actual lag situation of products approved in Japan " *3 reported that although the overall drug lag period has been shortening, some products with long-term drug lag remain, and that many long-term lag items have been approved in Europe, the U.S., and Japan by different companies. The report also noted that many of the long-term lag items were approved by different companies in Europe, the U.S., and Japan. The drug lags that remain for a long period of time are a direct disadvantage to patients suffering from illnesses due to the discrepancy from the global medical standards.

Yuya Imai et al. of Kitasato University reported that there are multiple factors behind the drug lag*4, citing the difference between originator companies and Japanese developers in their analysis focused on drugs approved in Japan, and the small projected sales amount as contributing factors.

In this news item, we analyze and discuss the impact of additional Japanese studies, market size forecasts, and product characteristics on the occurrence of long-term lag, in addition to a detailed analysis of the background and differences between the companies that obtained approval and their own and other development modes, such as acquisitions and alliances, for the most recently approved products.

Survey Methodology

This news report is based on the "Drug Lag: Analysis of the Actual Lag Situation of Products Approved in Japan" (hereafter referred to as "previous issue news"), which appeared on OPIR Views and ActionsNo.70, and further analyzes the factors in detail. The survey covered drugs that were approved in Japan between 2019 and 2022 as drugs containing new active ingredients and that were approved later in Japan than in the U.S. and Europe, resulting in a drug lag, in order to focus on recent trends among the drugs covered in the previous issue. The drug lag period was calculated by identifying the date of application for approval and the date of approval from the data published by the review authorities in each country. Specifically, analysis was conducted based on information published on the websites of the Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA). If the product was approved in both the U.S. and Europe, we used the information from the region where the product was approved at the earlier date. Since there are some products with significantly long approval periods and some with short approval periods due to special exceptions, we used the median value as the main basic statistic. In Europe, the approval information is based on the central review system, and may differ from the approval status in each country.

Items for which the Ministry of Health, Labour and Welfare (MHLW) has issued a call for development companies or a request for development by the "Study Council for Unapproved and Off-label Drugs of High Medical Need " *5 (hereinafter referred to as "Study Council") were excluded from the analysis in this survey, as they are affected by factors of unapproved drugs not developed in Japan.

The definition of in-house or acquisition/partnership in the form of development was defined as follows for this news. In-house" was defined as items that were consistently developed by one company (including parent-subsidiary companies) in Europe, the U.S., and Japan, referring to information in "New Drugs for Tomorrow (produced by Technomic). Acquisitions and alliances were defined as those in which a company that had obtained approval in Japan acquired a company or in-licensed a product under development. Acquisitions and alliances that had been approved in the U.S. or Europe for more than six years were classified as in-house.

Results

3-1. impact of differences in development format

OPIR Views and Actions In No. 70, we reported that the median lag period was longer for the cases where the acquiring company was different from the acquiring company in Japan and the U.S. than for the cases where the acquiring company was the same in Japan and the U.S. In order to explore this factor in more detail, we decided to investigate the status of corporate alliances related to development rights in Japan during the process of obtaining approval in Japan. Of the drugs approved in Japan between 2019 and 2022, 114 experienced drug lag: the median drug lag for the 114 drugs was 20.2 months, the minimum was 0.03 months, the maximum was 257.1 months, and the mean was 35.6 months. Of the 114 products, 63 (55%) were in-house developed products and 51 (45%) were acquired through acquisitions or partnerships with other companies. The median lag time for both in-house and acquired/partnered products was 10.5 months and 44.8 months, respectively ( Figure 1 ). This result compares with OPIR Views and ActionsNo. 70 and confirms a similar trend, with acquired/partnered products having a longer lag, even though the survey periods are different.

Figure 1 Number of drug-lag products approved in Japan by development type and lag period (median)
Note 1: Acquisitions and alliances are defined as drugs for which the Japanese development rights were acquired from outside the company up to five years prior to the year of approval in the U.S. or Europe. (The same applies to Figure 2 and thereafter.)
Note 2: Excludes 8 products that were solicited or requested by development companies at the review meeting.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)

3-2. Impact of Additional Japanese Participant Studies

When applying for approval in Japan, information on Japanese subjects is considered important in the review process, and in some cases, additional clinical trials are conducted to obtain information on Japanese subjects. The presence or absence of additional Japanese studies is expected to be a significant factor in drug lag, and Imai et al. of Kitasato University have reported that differences in development strategy can affect the length of development delays. In this news item, we surveyed the studies in which Japanese participants were identified among the evaluation studies listed in the "Clinical Efficacy and Clinical Safety Data and Summary of Review by the Agency" section in the PMDA's review report. The timing of the start of each study was compared with the approval in Europe and the U.S., and the presence or absence of additional studies was determined. Information that was not disclosed in terms of the timing of the trials was considered to be of unknown timing, as the content could not be verified.

The survey results showed that 38 (33%) of the products had additional Japanese participation studies conducted after approval in the U.S. and Europe, 75 (66%) had not, and 1 (1%) had unknown timing. The median lag period by the presence of additional trials was 53.1 months for those with additional trials and 9.8 months for those without additional trials ( Figure 2 ). This indicates that although more than 30% of all products are started after approval in the U.S. and Europe, trials involving Japanese participants create a long-term drug lag, with a median difference of slightly less than four years.

Figure 2: Items with or without additional Japanese participation trials after approval in the U.S. and Europe and lag period (median)
Note 1: One item with unknown timing is not shown in the lag period figure.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)

3-3. impact of the difference in corporate classification of companies approved in the U.S. and Europe

In recent years, the remarkable rise of emerging biopharmaceutical companies ("start-ups") in global drug development has been reported in various fields*6 *7 Therefore, we investigated the impact on drug lag for Japanese-approved products and categorized them according to whether the companies obtaining approval in the US or Europe are start-ups. The definition of start-ups in this news item is the same as that in OPIR Views and ActionsNo.70, and refers to companies that have been in business for 30 years or less at the time of approval and had sales of less than US$500 million in the year prior to approval, while pharmaceutical companies are defined as non-emerging companies.

The median lag period was 42.8 and 15.3 months for 33 (29%) and 81 (71%) of the products approved in the US and Europe, respectively ( Figure 3 ). The median lag period for each was 42.8 months and 15.3 months, respectively (Figure 3).

Fig. 3: Products and lag periods (median) by company category for companies approved in the U.S. and Europe
Note: Emerging companies are those that have been in business for 30 years or less at the time of approval and had sales of less than US$500 million in the year prior to approval. Pharmaceutical companies are defined as companies other than start-ups.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, "Tomorrow's New Drugs (Technomic Production)," and Evaluate Pharma (R) (as of September 2023)

3-4. impact of nationality of domestic development companies

OPIR Views and Actions In No. 70, we analyzed the difference in the nationality of the domestic development company (Japanese or overseas), and we also investigated the impact of this news on the long-term lag. The median lag period was 47.5 and 14.4 months for 38 (33%) and 76 (67%) of the items for which the domestic developer was a Japanese company and an overseas company, respectively. The median lag period was 47.5 months and 14.4 months, respectively. In the case of Japanese companies developing only for the domestic market, it is assumed that the lag period was influenced by the time required to introduce the product from European and U.S. approved companies through alliances.

Figure 4: Products and lag periods (median) by nationality of domestic developers
Source: Created at The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)".

3-5. relationship with market size forecast

The relevance of the lag period to the forecasted market size at the time of the NHI drug price listing in Japan was also verified with recent data from 2019 to 2022.

In the Central Social Insurance Medical Council (Chuikyo) document "Calculation of NHI Drug Prices for New Drugs," 35 items (31%) had a market size forecast (at peak) of 10 billion yen or more, while 70 items (61%) had a market size forecast of less than 10 billion yen. The median lag period (9.8 months) for vaccines forecasted to reach 10 billion yen or more and 28.9 months for those forecasted to reach less than 10 billion yen were not available as of November 2023, including vaccines related to novel coronavirus (COVID-19). ( Figure 5 ). Thus, long-term lags were observed for items with relatively small projected market size, and the number of items accounted for more than half of the total.

Fig. 5: Products and lag periods (median) by company category for companies approved in the U.S. and Europe
Note: Nine products included in the lag period figure without information are not shown.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and NHI drug price calculation data from the Chuikyo, Ministry of Health, Labour and Welfare

3-6. classification by other items

In addition, we also examined whether or not small molecule drugs are applicable, whether or not orphan drugs are applicable, and whether or not preferential measures are taken by the pharmaceutical affairs bodies at the time of approval in the U.S. and Europe. Figure 6 shows the median number of applicable drugs and the median lag period for each category, and no significant differences were observed.

Fig. 6: Products and lag periods (median) by company category for companies approved in the US and Europe
Note: Preferential treatment in the US and Europe refers to whether the product was designated as Breakthrough Therapy and Fast Track in the FDA or Accelerated Approval and PRIME in the EMA.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)

Logistic regression analysis

We used statistical methods to estimate the impact of acquisitions and alliances and other factors on long-term drug lag, and to compare the impact of these factors ( Table 1 ).

Table 1 Impact on lag period
Note: Hyphens in the table indicate that no analysis was conducted.
* P-value ＜0.1

In a logistic regression analysis (see OPIR Views and Actionsfor details*1) conducted on the probability of the lag period exceeding 24 months using data on 114 products, two factors were statistically significant: "acquired/partnered products" was significant (P value = 0.003) and "products for which additional studies with Japanese participants were conducted after approval in Europe and the US" was significant (P value = 0.000). Two factors were statistically significant (P value = 0.000).

At the same time, this analysis estimated a 5.9 times higher odds ratio of having a lag period of 24 months or longer for acquired/partnered products compared to in-house products. The odds ratio of having a lag period of 24 months or longer was estimated to be 41.7 times higher for products that underwent additional studies with Japanese participants after approval in the U.S. and Europe than for products that did not undergo additional studies.

Comparing the marginal effects of each, the odds of the lag period being 24 months or longer were estimated to be 21% higher for acquired/partnership products compared to in-house products, while the odds of the lag period being 24 months or longer were estimated to be 45% higher for products for which an additional Japanese participation study was conducted after US/European approval compared to products for which no such study was conducted. This result indicates that the impact of additional Japanese studies conducted after US/EU approval is particularly large.

To check the robustness of the analysis, a Cox proportional hazards model was also used. The results showed that "acquired/partnered products" was significant (P value = 0.080), and "items for which additional Japanese participation studies were conducted after approval in the US and Europe" was significant (P value = 0.000), both of which were statistically significant.

On the other hand, none of the other factors analyzed, including whether the company that obtained approval in the U.S. and Europe was an emerging company or not, were statistically significant in any of the models. The impact of each explanatory variable was evaluated using the additional Japanese study after approval in the U.S. and Europe as the explained variable in order to evaluate the impact of other explanatory variables for "items for which an additional Japanese study was conducted after approval in the U.S. and Europe," which had the largest impact in the logistic regression analysis. *1 In addition, the impact of the additional Japanese study after approval in the U.S. and Europe was evaluated as the explained variable in this analysis. 1 Of the 114 products analyzed in this news report, 105 products for which market size forecast data at the time of NHI drug price listing were publicly available were included. As a result, statistical significance was found for "projected sales of less than 10 billion yen" (P value = 0.036), "Japanese national of domestic development company" (P value = 0.002), "emerging company approved in the US or Europe" (P value = 0.034), and "not classified as orphan drug" (P value = 0.007), while statistical significance was found for "small molecule drug" and "drug for rare disease" (P value = 0.008). small molecule drug" and "not receiving preferential treatment at the time of approval in Europe and the U.S." were not significant (P-values = 0.788 and 0.960, respectively).

4. characteristics by development type

4-1 Relationship between development type and the presence or absence of studies with Japanese participants after approval in the U.S. and Europe

In order to gain a better understanding of the background and factors that influence long-term lag, the analysis was divided into in-house products and acquired/partnership products. OPIR Views and ActionsNo.70 also conducted a detailed investigation because differences in lag periods were visible in cases where the company obtaining approval differed between Japan and the U.S. and Europe. Of the 63 in-house products, 9 (14%) had additional Japanese participation studies conducted after approval in the U.S. and Europe, and 54 (86%) had not. Of the 51 acquired/partnership products, 29 (57%) had undergone additional Japanese participation studies after approval in the U.S. or Europe, and 21 (41%) had not. The lag periods for in-house and acquired/partnership products are shown in Figure 7, with the median lag period being 51.3 months for in-house products and 54.8 months for acquired/partnership products. The survey results show a significant difference in the distribution of products, with most of the in-house products having completed the necessary studies prior to approval in the U.S. and Europe, while more than half of the acquired/partnered products had additional studies conducted after approval in the U.S. and Europe. The group of products that showed a long-term lag in acquisitions/partnerships had additional studies. Although the percentage of companies conducting additional studies in-house was low, the lag was long, suggesting that additional studies were a factor in the occurrence of long-term lag, regardless of whether the company was in-house or in an acquisition tie-up.

Figure 7 Number of items and lag period (median) by whether or not additional studies were conducted after approval in the U.S. and Europe (by development type)
Note 1: "Other" includes items for which the timing of study implementation is unknown.
Note 2: Three items included in "Others" are not shown in the lag period chart.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)

4-2 Relationship between development type and company classification of companies approved in the U.S. and Europe

We investigated the relationship between the type of development and the companies approved in the U.S. and Europe by company classification. Of the 63 in-house products, 8 (13%) were developed by start-ups and 55 (87%) were developed by pharmaceutical companies. Of the 51 acquired/partnered products, 25 (49%) were from start-ups and 26 (51%) were from pharmaceutical companies. The median lag periods are shown in Figure 8. While the median lag periods for in-house products were 18.3 months and 9.3 months for both start-ups and pharmaceutical companies, the median lag periods for acquired/partnered products were 43.1 months and 48.4 months for both start-ups and pharmaceutical companies, respectively.

The survey results indicate that although half of the acquired/partnered products were from emerging companies, many of the products were from pharmaceutical companies whose companies obtained approval in the U.S. and Europe. It is also possible that the lag period was influenced more by the development format of the acquisition or alliance than by differences between startups and pharmaceutical companies.

Fig. 8 (By type of development): Products and lag periods (median) of companies approved in Europe and the U.S. by company category
Note: Emerging companies are those that have been in business for 30 years or less at the time of approval and had sales of less than US$500 million in the year prior to approval. Pharmaceutical companies are defined as companies other than start-ups.
Source: Prepared by The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, "Tomorrow's New Drugs (produced by Technomic)," and Evaluate Pharma (R) (as of September 2023)

Impact of timing of acquisition of Japanese rights for acquired/partnered products

We investigated the impact of acquisitions and alliances on the lag period from a different angle. We categorized when the Japanese-approved companies acquired the rights to develop their products in Japan, using the U.S. and European approvals as the starting point for the drug lag period. As a result, 38 (75%) of the 51 acquired/partnered products acquired the right to develop in Japan before the US or European approval, and 13 (25%) acquired the right to develop in Japan after the US or European approval, with a median lag period of 30.6 months and 87.8 months, respectively ( Figure 9 ). In other words, the lag tended to be relatively longer when development rights in Japan were obtained after approval in the U.S. and Europe.

Furthermore, of the 13 products for which Japanese development rights were obtained after approval in the US or Europe, 11 (84%) had additional Japanese participation studies ( Figure 10 ).

Fig. 9 Items and lag period (median) between acquisition of Japanese rights and approval in the US and Europe for acquired/partnered products
Source: Created at The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)".

Fig. 10 Items by Japanese participation study between acquisition of Japanese rights and approval in the US and Europe
Source: Created at The Office of Pharmaceutical Industry Researchbased on publicly available information from PMDA, FDA, and EMA, and "Tomorrow's New Drugs (produced by Technomic)".

6. discussion and summary

In this news item, following OPIR Views and ActionsNo. 70, we conducted an additional survey of factors that induce long-term drug lag in Japan-approved products, focusing on differences in the form of development in Japan, such as whether the product is in-house or acquired/partnered.

Suggestion of item characteristics and factors of long-term lag

Analysis of the characteristics of products with drug lag in recent years showed that the median length of lag was long for the following categories: acquisition/partnership, with additional Japanese studies, startups, Japanese nationals, and market size less than 10 billion yen, although the percentage of products in each category was low (excluding those with market size of less than 10 billion yen). Logistic regression analysis on the probability that the lag period between US/EU approval and Japan approval exceeded 24 months showed that "acquired/partnership products" and "products for which additional studies with Japanese participants were conducted after US/EU approval" had a significant impact on the lag period.

A comparison of the marginal effects of the two influencing factors that were found to be significant indicated that the influence of conducting clinical trials in Japan after approval in the U.S. and Europe on the probability of the lag period being 24 months or longer was greater than that of acquisitions and alliances. The significant effect of acquisitions and alliances in addition to the presence of additional trials suggests that changes in development policy and strategy for the Japanese business, as well as the length of transaction procedures related to acquisitions and alliances, may have an impact on the long-term lag.

In the detailed analysis that followed, the percentage of additional Japanese studies was higher for items in acquisitions and alliances and lower for in-house studies, but these lags were long, suggesting that conducting additional Japanese studies is a factor in the long-term lag, regardless of the development format. In addition, the large proportion of acquisitions and alliances with additional Japanese studies suggests that for many products, development and business development in Japan were not anticipated prior to the acquisition or alliance.

On the other hand, the effect on the probability of the lag period exceeding 24 months was not significant for the emerging companies, Japanese nationality, and orphan drugs, but the effect on the probability of conducting clinical trials in Japan after approval in the U.S. and Europe was significant, which may be related to the long-term lag due to the impact of additional trials. The effect on the probability of conducting a clinical trial in Japan after approval in Europe and the United States was significant. Similarly, the impact on the probability of conducting clinical trials in Japan after approval in the U.S. and Europe was significant for products with a peak year market size forecast of less than 10 billion yen, suggesting that market size may be a factor in the decision to conduct additional clinical trials in Japan.

No statistical significance was found for either the prolonged lag or Japanese clinical trials after approval in the U.S. or Europe, whether the drug is a small molecule or a biotech drug, or whether the drug received preferential treatment at the time of approval in the U.S. or Europe, suggesting that the impact is low.

The following are possible reasons why the results of this news may differ from those of previous studies. The fact that the market size is less than 10 billion yen did not show statistical significance as an effect on the long-term lag (Cox proportional hazards model), but it was different in the target items because the years covered by the study, 2010-2020 and 2019-2022, were different, and the study conference items were excluded from the study in this paper. The study was different in that the years covered were 2010-2020 and 2019-2022. Compared to the previous study, the proportion of items with a market size of less than 10 billion yen was higher in this news, and in addition, the proportion of items with a market size of less than 10 billion yen and a drug lag of 24 months or less was higher (data omitted), which may have been the reason for the difference. Alternatively, the original model may have been too strongly influenced by the presence or absence of additional studies.

Direction of Solution

The most influential factor in the occurrence of the long-term lag was the presence of an additional study in Japan after the approval in the U.S. and Europe. Factors that increase the probability of the occurrence of the long-term lag include the presence of an acquisition or alliance, the fact that the Japanese application is filed by a Japanese company, and the fact that the U.S. and European development companies are emerging companies. Many of the products that are approved in the U.S. and Europe by emerging companies overseas are developed in Japan through acquisitions or alliances by Japanese companies, and it is assumed that additional studies on Japanese subjects will be added after the introduction of the product. This business development pattern may be one of the reasons for the long-term lag. Although further detailed investigation and analysis is needed to understand the background behind the addition of Japanese studies, it is easy to imagine that the Japanese region was not incorporated into the pivotal studies conducted by emerging companies in the U.S. and Europe*7. We believe that one of the directions to resolve this issue is for emerging companies to incorporate the Japan region into pivotal studies conducted by emerging companies in Europe and the U.S.

In the direction of eliminating drug lag/loss, the Ministry of Health, Labor and Welfare (MHLW)-led "Expert Panel on Comprehensive Measures to Achieve a Rapid and Stable Supply of Pharmaceuticals " *8 will be formed in 2022, and the "Study Group on the Regulatory Framework for Pharmaceutical Affairs to Enhance Drug Discovery and Ensure Stable Supply " *9 will be formed in 2023, with industry-academia-government collaboration. 9 and other groups have been launched to discuss the issue in industry, academia, and government. In order to promote the incorporation of Japanese regions into pivotal trials by European and U.S. companies, the issuance of a notice allowing the omission of Japanese Phase 1 prior to pivotal trials*10 and the establishment of the PMDA's U.S. Washington Office to promote pharmaceutical consultation for development in Japan*11 are useful pharmaceutical measures, as is the "expedited introduction" policy that provides incentives for early submission and approval in Japan. The establishment of an "additional fee for expedited introduction, " *12 which provides incentives for early application and approval in Japan, is expected to prove effective in the future as a useful NHI policy.

Another useful measure would be the early incorporation of requirements for Japanese rollout through acquisition and in-licensing by major pharmaceutical companies and Japanese pharmaceutical companies in the early clinical phase. Although the risk of not achieving a product in the early clinical phase is high, and therefore the acquisition and in-licensing process is challenging in the pharmaceutical industry, we cannot help but hope that the industry will continue its early acquisition and in-licensing efforts, keeping up with the current trends in science and technology.

( The Office of Pharmaceutical Industry Research Hiroshi Azuma, Senior Researcher)

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