The Pharmaceutical Industry at a Glance Drug Lag: Analysis of the Lag Status of NMEs Approved in Japan

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Hiroshi Azuma, Senior Researcher, Pharmaceutical Industry Policy Institute

SUMMARY

1. Introduction

Drug lag refers to the time difference that occurs before a drug that can be used overseas is approved and used in Japan. Some drugs are approved in Japan but "delayed," while others are "unapproved" and have not yet been approved in Japan. The Pharmaceutical and Industrial Policy Research Institute (PIIPRI) has analyzed unapproved drugs and raised the issue of drug ^{lag/loss1)2)3)4)5)6)7).} Some unapproved drugs are still under development in Japan and are expected to be approved later than their counterparts overseas (drug lag (unapproval)), while others have no confirmed information on development in Japan (drug loss) (Figure 1). On the other hand, there are items that have been approved in Japan but are in drug-lag status, meaning that they are approved late in foreign countries, which is also a major problem for patients who are waiting for innovative new drugs as soon as possible. Shibukuchi et al. ⁸⁾ reported that the drug lag for drugs containing new active ingredients improved with the median lag period, but they have not yet analyzed the characteristics of the items by the difference in the length of the lag period. In this paper, we would like to reanalyze the current status of drug lag not only in terms of median drug lag but also in terms of drug lag for all items approved in Japan, and discuss issues that need to be addressed in order to completely eliminate the lag. Among the drugs for which a drug lag exists, we will focus on drugs approved in Japan that have been approved in other countries (Figure 1 highlighted area). We would like to clarify in advance that this is not an analysis of the drug lag as a whole or of drug losses. However, since the drugs are still under development, it is difficult to measure the lag period, and in some cases, the development may be suspended, resulting in drug losses. We believe that the characteristics of these items should continue to be examined in the future.

Survey Methodology

The survey in this paper was conducted using the following methodology. The survey covered items approved in Japan between 2013 and 2022 as drugs containing new active ingredients, and the lag periods were identified by identifying the dates of application and approval based on the data released 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). In cases where the product was approved in both countries, the information from the region where the product was approved at the earlier date was ^adopted9). The main basic statistic was the median value, because there are some items for which the period of coverage is significantly long or short due to special exceptions. In Europe, the approval information is based on the central review system, and therefore, it may differ from the approval status in each country.

The date of approval and the date of submission were determined based on the PMDA's review report, the FDA's Approval Letter, and the EMA's Approval Letter. However, the approval and submission dates are based on the PMDA's review reports, the FDA's Approval Letter, and the EMA's European public assessment reports (EPARs).

Results

3-1. Drugs with drug lag

From 2013 to 2022, 424 new active ingredients were approved in Japan. Of these, 301 (71%) were approved in Japan after the rest of the world, i.e., there was a drug lag. In addition, there were 9 (2%) drugs for which it was difficult to determine whether the drug lag occurred in Japan, the U.S., or Europe, and 9 (2%) drugs for which the approval dates in the U.S. or Europe could not be determined.

Figure 2 shows a year-by-year breakdown of the 301 drugs with drug lag from 2013 to 2022. As a result, between 19 and 46 items had drug lags. In the most recent two years, the number of European and U.S. first-line drugs was again 36, or 69% of the number of drugs approved in that year.

The 10-year trend shows that although there are fluctuations from year to year, drug lags still exist for many of the drugs approved in Japan, confirming that Japan continues to be ahead of Europe and the U.S. in the drug development ranking.

3-2 Drug lag period over time

In order to understand the actual drug lag period, we investigated the median lag period of drug lag in Japan, Europe, and the U.S. Figure 3 shows the median lag period of drug lag products in Japan and Europe. Figure 3 shows the number of drug-lag items and the median transition of the period of delay in approval (= drug lag) and the period of delay in submission for approval (= development lag) for each survey year.

As a result, the median drug-lag period from 2013 to 2016 was more than 30 months, but since 2017 the median has been in the 20-month range except for 2019, and in the latest year, 2022, the median was 16.4 months. Thus, the drug lag period can be viewed as a generally decreasing trend over the last decade.

In order to analyze the lag excluding the effect of the review period in each region, we compared the lag at the date of application for approval (development lag). A similar trend to the drug lag was observed, ranging from about 25.3 to 41.3 months from 2013 to 2016, but the lag period tended to shorten from 2017 to 2022, ranging between 14.0 and 22.6 months, except in 2019.

Figure 4 shows the distribution of drug lag periods by year. In each year, the median was smaller than the mean, suggesting that many items had shorter durations. In addition, the third quartile is smaller, suggesting that the number of items with long lag periods is decreasing.

In order to examine the breakdown of the median decrease, we examined the number of drug-lag items and their percentage of total drug-lag items by lag period, i.e., 12 months or less, 12 to 24 months, 24 to 36 months, and 36 months or longer, for two years at a time (Figures 5 and 6). The results show that the number of long-term lag items (36 months or longer), which accounted for 33 items and 55% of the total in 2013-2014, declined to 24 items and 33% in 2021-2022, while the number of short-term lag items (12 months or shorter), which accounted for 12 months or shorter, declined to 24 items and 33% in 2021-2022. On the other hand, the number of short-term lag items of 12 months or less increased from 18 items accounting for 30% in 2013-2014 to 28 items accounting for 39% in 2021-2022. In 2021-2022, 12 items accounted for 17% and 8 items accounted for 11% of the total, respectively. The median drug lag (solid line in Figure 4) has decreased over the past 10 years due to a decrease in the number of items with a lag longer than 36 months and an increase in the number of items with a lag of less than 36 months.

In order to understand the lag trend by stratum, we analyzed the median lag trend for the group of drugs with a lag longer than 36 months (Figure 7), and found that the median lag for the group of drugs with a lag longer than 36 months was shrinking, from 103.9 months in 2013-2014 to 53.8 months in 2021-2022, almost half of the previous year. In other words, apart from the reduction in median lag duration, a reduction in lag duration was also observed for long-term lag items, confirming an improvement in one issue of drug lag.

3-3. Analysis of Drug Lag Drugs by Company Category 3-4.

In order to understand the characteristics of the drug-lagged products, the analysis was divided by company category and analyzed in three-year timeframes in order to capture the general trends. First, we investigated whether the companies that obtained approval in Europe and the U.S. were the same or different from the companies that obtained approval in Japan. As shown in Figure 8, the number of products approved by each company was 57 and 56 in 2014-2016, 41 and 32 in 2017-2019, and 47 and 48 in 2020-2022, respectively, and for about half of the products in each age group, the company that obtained approval was different. In other words, approximately half of the drugs approved in Japan represent a shift in leadership of drug development between different companies. Figure 9 again confirms that there is a significant delay compared to applications for approval filed by the same company. The median lag time ranged from 9.3 to 13.3 months for approval by the same company, while the median lag time for approval by a different company ranged from 44.9 to 79.3 months, a difference of approximately 3 to 5 years. In addition, the drug lag for items approved by different companies was significantly reduced from 79.3 months in 2014-2016 to 44.9 months in 2020-2022, confirming the shortening of the lag over time. Of course, it is not difficult to imagine that the drug lag may be caused by the time required for product transfer and acquisition negotiations when the companies obtaining approval differ between Japan and the U.S. and Europe, but the results suggest that the development time of drugs led by different companies may have a significant impact on the overall drug lag reduction.

In order to investigate the causes of the shortening of drug lag over time for drugs approved by different companies in Japan, Europe, and the U.S., we conducted an analysis by company classification of emerging companies and pharmaceutical companies (Figure 10). For the purposes of this paper, emerging companies are defined as those that have been in business for less than 30 years 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 all other companies.

In the 2014-2016 period, 35 drugs were approved by foreign pharmaceutical companies, while 20 drugs were approved by foreign startup companies. In 2020-2022, 20 products were approved by foreign pharmaceutical companies, while 27 products were approved by foreign startups. The ratio of approvals by foreign pharma companies to foreign pharma companies has been increasing over time. In addition, one product was approved by Japanese pharmaceutical companies in Europe and the U.S. in 2014-2016 and one in 2020-2022, while no products were approved by Japanese emerging companies in Europe or the U.S.

Next, we investigated which of the following four categories (foreign pharmaceutical companies, foreign emerging companies, Japanese pharmaceutical companies, and Japanese emerging companies) had obtained approval in Japan for the items for which different companies obtained approval. Figure 11 shows the attributes of companies that obtained approvals in Europe and the U.S. in Japan, divided into overseas pharmaceutical companies (Figure a) and overseas emerging companies (Figure b). As an example, of the 35 drugs approved in Europe and the U.S. by foreign pharmaceutical companies, 46% were approved in Japan by 16 foreign pharmaceutical companies, 40% by 14 Japanese pharmaceutical companies, and 14% by 5 Japanese emerging companies from 2014-2016 (Figure 11a). In Japan, foreign and Japanese pharmaceutical companies were equally represented, with some Japanese start-ups gaining approval. In contrast, in the United States and Europe, for example, out of 20 drugs approved in 2014-2016, 4 drugs (20%) were approved by foreign pharmaceutical companies, 15 drugs (75%) by Japanese pharmaceutical companies, and 1 drug (5%) by Japanese start-ups. In Japan, Japanese pharmaceutical companies mainly led the development of products approved in the U.S. and Europe, followed by foreign pharmaceutical companies, and only a few Japanese startups (Fig. 11b). This result indicates that the trend of the destination of approved companies in Japan differs depending on the classification of approved companies in the U.S. and Europe, and that Japanese pharmaceutical companies are the main recipients in Japan of drugs derived from overseas emerging companies. Note that there was only one case in which the Japanese recipient of approval was an overseas emerging company in the 2020-2022 period for a product originating from an overseas emerging company (see Figure 11 Note 2).

Figure 12 shows the number of items and the drug lag period (median) in each category for the four patterns where the companies obtaining approval in Europe and Japan were different and the number of items was large: overseas pharma → overseas pharma, overseas pharma → Japanese pharma, overseas emerging → overseas pharma, and overseas emerging → Japanese pharma. The lag period (median) for the total number of items was reduced from 79.3 months in 2014-2016 to 44.9 months in 2020-2022, as shown in Figure 9. By pattern, the median lag periods (median) for overseas pharma to overseas pharma (35 products in total) were 94.2, 37.4, and 21.4 months; for overseas pharma to Japanese pharma (30 products in total), 41.9, 123.9, and 63.1 months; for overseas emerging to overseas pharma (16 products in total), the median lag period ( The median lag periods (median value) for overseas emerging → Japanese pharmaceuticals (43 products in total) were 65.0, 57.5, and 51.5 months. The largest decreases in lag period (median) between 2014-2016 and 2020-2022 were in the following order: Overseas → Overseas Pharmaceuticals, Overseas Emerging → Overseas Pharmaceuticals, and Overseas Emerging → Japanese Pharmaceuticals. The overall decrease in lag duration (median) was also large in number, suggesting a larger reduction in lag duration and a greater impact from overseas pharma → overseas pharma.

3-4 Analysis of Drugs with Drug Lag by Therapeutic Category

Drugs that experienced drug lag were analyzed by drug category (Fig. 13), and the largest number of drugs (73), accounting for 24% of the total, were anti-cancer drugs. This was followed by 42 systemic anti-infectives, 34 drugs for the nervous system, and 30 drugs for blood and blood-forming organs. In addition, in order to understand the changes over time in each area, we analyzed the trends by three-year category (Figure 14). The number of products in the top four therapeutic areas by year was 26, 20, and 21 for antineoplastics; 11, 13, and 15 for systemic anti-infectives; 9, 13, and 12 for neurological agents; and 15, 10, and 7 for blood and blood-forming organs agents. Looking at the median lag period by drug category, the median lag period for nervous system drugs ranged from 35.3 to 79.2 months, which is a characteristic example of a larger lag period than in other therapeutic areas. As a transition, it was confirmed that the lag period had been shrinking over time. On the other hand, the largest drug lag between 2020 and 2022 was 48.9 months for blood and blood-forming organ drugs, with a trend of 9.3-48.9 months, indicating that the lag was increasing over time. Antineoplastic agents, which accounted for the largest proportion of the drugs, showed a decrease in lag over time, from 32.8 to 21.3 months.

Despite the reduction in the lag period, the overall lag period from 2020-2022, shown in Figure 3, ranged from 16.4 to 24.1 months, suggesting that these diseases with a large number of items may be more prone to lag.

4. discussion and summary

In this paper, we have analyzed the actual drug lags that have occurred among the drugs approved in Japan in order to eliminate drug lags/losses. This chapter discusses the current status of drug lag in Japan based on the analysis.

In Chapter 3-1 of this report, we showed that drug lags have occurred in approximately 70% of all pharmaceutical products over the past 10 years (Figure 2). Considering that these drugs were developed and approved in Japan, it is not difficult to imagine that these drugs satisfy Japan's medical needs. We believe that a delay in the development of many of these drugs compared to their overseas counterparts should be avoided. The median lag period for the most recent year, 2022, was 16.4 months, which means that more than half of the new active ingredient-containing drugs have a lag of 16.4 months or longer. (There is still a need to shorten the lag period from the viewpoint of patient accessibility.

In Chapter 3-2, we analyzed the drug lag period and the approval delay period of development lag, and showed a trend toward shorter lag periods for drug lag. This fact is very gratifying because it represents an improvement in access to medicines. There is almost no difference from the development lag, i.e., the situation in Japan in recent years has been very substantial in terms of review period, and we can confirm reports that PMDA is conducting reviews more quickly than in the U.S. and ^Europe10). 10) We believe that this is due to the success of the PMDA's policy for approval and the efforts of developers to develop products on a global basis.

The above results suggest that the drug lag period can be explained almost entirely in terms of the development lag period, and that the shortening of the drug lag period contributes to the shortening of the development lag period. This means that drugs for which companies have deemed it worthwhile to obtain approval in Japan tend to be developed and approved more quickly than in the past. The median drug lag period in 2019, shown in Figure 3, stood out at 41.3%. A breakdown of the drug lag shows that 10 items had drug lags of 60 months or longer, twice as many as in the previous year. The reasons for the high number of these items in the same year were not investigated.

In Chapter 3-3, we analyzed the classification of development companies in order to find out the characteristics of items that experienced drug lag. The results showed that drugs approved by different companies in Europe, the U.S., and Japan had a significant impact. This can be seen as one aspect of the recent trend of shifting the leadership of drug discovery to startups. Furthermore, we confirmed that Japanese pharmaceutical companies are mainly responsible for obtaining approval in Japan for drugs that have been approved in the U.S. and Europe by emerging companies. The median drug lag period (51.5 months from 2020 to 2022) is still long, although a decreasing trend was observed over time. The study also confirmed that the drug lag period for drugs approved in Europe and the U.S. by foreign pharmaceutical companies and approved in Japan by different foreign pharmaceutical companies has also been significantly reduced. Although it was shown that the companies obtaining approval in Europe and the U.S. differ from those in Japan as a factor in the occurrence of drug lag, the timing and actual conditions of such alliances and collaborations have not yet been investigated. However, the reality that the lag period has been shortened over the past decade suggests that there may be clues to further shortening the drug lag and eliminating drug losses. The actual status of drug lag shortening in these alliances and collaborations is a subject for future research and analysis. This is an issue for future study, such as detailed investigation in relation to the timing and clinical stage of the movement of drug bearers to obtain drug approval.

In Chapters 3-4, analysis by therapeutic area was conducted. The number of items and lag periods for the four disease areas that ranked highest in terms of number of items were investigated, and it was confirmed that the lag period was long in the past in the areas of anti-cancer drugs and drugs for the nervous system, and that the lag period has shortened over time. These areas are areas where Japan has made progress in incorporating drugs into international clinical trials, and it is possible that this is one manifestation of the elimination of the drug lag between Europe, the U.S., and ^Japan3). On the other hand, compared to the median value for all items, there is still room for improvement in many items. In addition, an extension of the lag period for blood and hematopoietic agents was also observed in the last three years, but the reasons for this have not yet been identified.

Conclusion

The present analysis is limited in scope to the various drug lags, including drugs containing new active ingredients and drugs approved in Japan by 2022. Although the analysis showed improvement in these areas over the past 10 years, more than half of the items still have a lag of 16 months or more, which is an issue that needs to be improved. In addition to this, drug lags,

We would like to add that the following should not be overlooked.

The number of unapproved drugs in Japan has been increasing since 2016, reporting signs of growing drug ^{lag/loss1), 2)}. In order to deliver the medicines that patients in Japan are waiting for to the rest of the world without delay, we, the pharmaceutical industry, regulatory authorities, and medical professionals, must further strengthen our cooperation to realize policies to improve drug lag/loss.

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