Regular Article
Comparison of Oncology Drug Lag in Japan and South Korea Based on the Interval between the U.S. Approval and the Local Approval
2025 年 48 巻 1 号 p. 11-16
詳細
2025 年 48 巻 1 号 p. 11-16
Drug lag is a serious issue for patients with life-threatening diseases such as cancer. Japan and Korea have been facing a large drug lag, despite having a large market and a good clinical trial environment. We analyzed drug lags for anticancer drugs between these countries, using the information on 82 anticancer drugs approved in the United States between 2017 and 2022. The national health insurance coverage status was also investigated. The approval lag, defined as the number of days from the date of approval in the United States to the date of approval in the country of interest, was used as the indicator of drug lag and was calculated for each drug. The median for all drugs was estimated using the Kaplan–Meier method, with the lag for locally unapproved drugs treated as censored data. The median approval lag in Japan and Korea for all drugs, including locally unapproved drugs, were 1547 d (4.2 years) and 1000 d (2.7 years), respectively. The approval lags for the approved drugs were 216 and 655 d in Japan and Korea, respectively. All drugs approved in Japan were covered by national health insurance whereas many drugs recently approved in Korea were not yet covered. The overall drug lag in Japan was greater than that in Korea due to the high number of unapproved drugs in Japan. In Korea, more drugs have been approved; however, it generally takes longer for them to become widely available to the public.
Many drugs are authorized for marketing in more than one country and the timing of approval varies. The time from a drug’s first marketing authorization in the world, typically in the United States (U.S.), until the marketing authorization in another country is called “drug lag.”1) Patients in countries with long drug lags have delayed access to innovative medicines, and their impact on health outcomes is particularly serious for those with life-threatening diseases such as cancer.2)
Drug lag is an issue in both Japan and South Korea. Japan has the world’s third largest pharmaceutical market, spending approximately 88 billion U.S. dollars in 2020.3) Both Japanese and non-Japanese companies conduct clinical trials in Japan, with approximately 5000 trials registered in 2021.4) South Korea also has a relatively large market as a single country, spending 16 billion U.S. dollars in 2020, and, unlike Japan, it is still growing rapidly.3) South Korea is active in clinical development and has participated in many multinational clinical trials.5) However, in the past, the performances of Japan and South Korea in terms of drug lag were not as good as those of other developed countries. According to a report from the Organization for Economic Co-operation and Development (OECD), the average drug lags in Japan and South Korea in 2004 were 1417 and 1427 d, respectively, ranking 38th and 39th out of 40 countries, respectively.6)
In Japan, the Ministry of Health, Labour, and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have implemented countermeasures to alleviate drug lag, including the promotion of multinational clinical trials to support the marketing authorization of new drugs and an increase in PMDA’s capacity to shorten the review period. Owing to these countermeasures and efforts by academia and industry, the drug lag in Japan decreased from the late 2000s to the early 2010s.7,8) However, it has increased again since the late 2010s. The drug lag for anticancer drugs was shortest in 2018 and increased slightly in 2019 and 2020.9) Our previous study showed that the drug lag of anticancer drugs in 2017–2022 was longer than that in 2011–2016, owing to an increase in unapproved drugs.10) In many studies, the participation of Japan in a pivotal trial for marketing authorization in the U.S. (hereinafter, the U.S. pivotal trial) was associated with a shorter drug lag.7,11) The percentage of unapproved drugs has been increasing since 2016.12) The increase in unapproved drugs is often referred to as “drug loss.” Both “drug lag” (time lag between the first approval in the world and the approval in Japan) and “drug loss” (drugs are not approved and often their development has not started in Japan) cause access gap to new medicines in Japan.
The South Korean government has also made efforts to establish an infrastructure for clinical trials. The Regional Clinical Trial Centers program was launched in 2004 with large core sites to cover many clinical trials. The Korean National Enterprise for Clinical Trials (KoNECT) was established in 2007 to advance the country’s clinical trial capabilities. With these efforts, clinical trial activity in South Korea, particularly multinational trials, grew in the 2000s.13) In 2018, 679 clinical trials were approved by the Korean Ministry of Food and Drug Safety (MFDS), of which 289 were multinational trials.14) Drug lag in South Korea decreased in the early 2010s from a median of 5.84 years in 2007 to 1.72 years in 2013.15)
Both Japan and South Korea are developed countries located in East Asia, with large pharmaceutical markets and good clinical trial environments. Therefore, these countries have some common conditions and could be good references for comparison. The present study aimed to compare the latest status of drug lag in Japan and South Korea using data from all anticancer drugs approved in the U.S. in a given period, regardless of whether they were approved in Japan or South Korea. The study was performed with a specific focus on anticancer drugs, as cancer is a life-threatening disease, and the drug lag in anticancer drugs has a significant impact on public health. We also investigated how often Japan and South Korea participated in the U.S. pivotal trials. Furthermore, the national health insurance (NHI) coverage status of the drugs was investigated, as new drugs cannot be prescribed in regular clinical practice if they are not covered by the NHI, and it is considered an important factor in determining access to new drugs in both countries.
This study included new molecular entities (NMEs) approved for cancer treatment by the Center for Drug Evaluation and Research (CDER), part of the U.S. Food and Drug Administration (FDA), between 2017 and 2022. Products for cancer care with no antitumor effects, such as drugs used to alleviate the side effects of chemotherapy and those used for diagnostic purposes, were not included.
Data SourcesData were collected from the websites of the regulatory agencies. A list of NMEs approved by the CDER is available on the FDA website.
The FDA’s review report, PMDA’s review report (if the drug was approved in Japan), MFDS’s review report (if the drug was approved in South Korea), and clinical trial information on ClinicalTrials.gov were the main sources of key information, such as the date of new drug application (NDA), date of approval, pivotal trial for marketing authorization in each country, and participation of Japan and/or South Korea in the U.S. pivotal trial. For drugs that were given accelerated approval and subsequently regular approval, the date of accelerated approval was used as the date of approval in the U.S. Publications from clinical trials were also used to supplement missing information. The data search was performed in September 2023. When the date information was incomplete and only year and month were available, the date was assumed to be “15th.”
The NHI coverage status and the date of start of coverage in Japan were checked using information from the Central Social Insurance Medical Council (Chuikyo). The list of drugs covered by the Korean NHI is available on the website of the Health Insurance Review and Assessment Service (HIRA) and was used to check the NHI coverage in South Korea. The date of the start of coverage in South Korea was not available.
Outcome Measures and Statistical AnalysisThe approval lag, defined as the number of days from the date of approval in the U.S. to the date of approval in the country concerned, was calculated for products that met the selection criteria and were used as a primary outcome measure to represent the drug lag in Japan and South Korea. The median approval lag was calculated using the Kaplan–Meier method. The approval lag for products not approved in Japan or South Korea (cutoff date: 31 July 2023) was treated as censored data in the analysis for that country. If the date of approval in Japan or South Korea was earlier than that in the U.S., the approval lag was handled as 0 (considered no approval lag for the drug). The median approval lag was calculated for subgroups based on the participation of Japan or South Korea in the U.S. pivotal trial, as well as for all selected drugs. A log-rank test was performed to assess the differences between the two countries.
The median U.S.–Japan approval lag for drugs approved in Japan and the median U.S.–Korea approval lag for drugs approved in South Korea were also calculated. Differences between these countries were tested using the Mann–Whitney U test. The health authority review period, defined as the number of days from the date of submission to the date of approval, was investigated for all drugs approved in Japan and South Korea, and the median was calculated for each country. Differences were tested using the Mann–Whitney U test.
The local clinical development strategy was classified into the following four categories based on the pivotal trial for marketing authorization in the country of interest and summarized for each country: (1) participating in a multinational clinical trial, (2) use of overseas clinical trial data with a local bridging clinical trial, (3) use of overseas clinical trial data with no local bridging clinical trial, and (4) performing a local pivotal clinical trial. A bridging clinical trial is defined as a local clinical trial to assess the consistency of efficacy, safety, and clinical pharmacology between the local and global populations, and support the extrapolation of data from the global pivotal trial for local approval.
The time from marketing authorization to the start of NHI benefits in Japan was calculated for each drug, and the median was calculated. The NHI coverage in South Korea as of 01 November 2023 was summarized by the year of approval in South Korea.
Statistical analyses were performed using StatsDirect version 3.3.6 (StatsDirect Ltd., Wirral, U.K.).
From 01 January 2017 to 31 December 2022, 293 NMEs were approved by the FDA CDER. Of these, 82 were approved for cancer treatment with antitumor effects and were included in the analyses.
The local approval status and local clinical development strategies are summarized in Table 1. In Japan, a majority of drugs were approved using the “joining a multinational trial” strategy, and a small portion of drugs were approved using overseas clinical trial data with a local bridging clinical trial. Participating in a multinational trial was also the main local clinical development strategy in South Korea; however, approvals based on overseas clinical trial data are also common. Notably, no local bridging clinical trial was conducted for these approvals.
| Japan | South Korea | |||
|---|---|---|---|---|
| Drugs approved in the U.S. 2017–2022 | 82 | |||
| Drugs approved in Japan/South Korea | 32 | (39.0%) | 48 | (58.5%) |
| Local clin dev strategy for drugs approved in Japan/South Korea | ||||
| Participating in a multi-national clinical trial (incl. U.S. pivotal clinical trial) | 25 | (78.1%) | 34 | (70.8%) |
| Overseas data with local bridging clinical trial | 6 | (18.8%) | 0 | (0%) |
| Overseas data without local bridging clinical trial | 0 | (0%) | 14 | (29.2%) |
| Local pivotal clinical trial | 1 | (3.1%) | 0 | (0%) |
The Kaplan–Meier curves for the time to approval in Japan and South Korea after U.S. approval are presented in Fig. 1. The median U.S.–Japan approval lag was 1547 d (95% confidence interval [CI]: 1244–2331), which was longer than the median U.S.–Korea approval lag (1000 d [95% CI: 729–1172]). The log-rank test suggested a considerable difference in the likelihood of approval in Japan and South Korea, although it was not statistically significant (p = 0.082, hazard ratio = 0.68 [95% CI: 0.44–1.05]).
The curve for Japan initially drops more quickly than the 1 for South Korea; however, it becomes rather flat later and is overtaken around a 2-year time point.
The median approval lag for drugs approved in the country of interest showed an opposite trend (Table 2). The median U.S.–Japan approval lag was significantly shorter than the median U.S.–Korea approval lag (216 vs. 655 d, Mann–Whitney U test: two-sided p = 0.0002). The median health authority review period was also shorter in Japan (267 vs. 358 d, Mann–Whitney U test: two-sided p < 0.0001).
| Japan | South Korea | |
|---|---|---|
| Median approval lag for all drugs (Kaplan–Meier method) | 1547 (n = 82) | 1000 (n = 82) |
| Median approval lag for drugs approved in the country of interest | 216 (n = 32) | 655 (n = 48) |
| Median health authority review period | 267 (n = 32) | 358 (n = 42)* |
*Date of submission in South Korea was not available for six drugs.
The subgroup analyses of the approval lag with or without participation in Japan or South Korea in the U.S. pivotal trial are presented in Fig. 2. In both countries, the approval lag was significantly shorter with participation in the U.S. pivotal trial. Japan showed a greater difference, and the hazard ratio for drugs without Japan’s participation in the U.S. pivotal trial was 0.091, which was smaller than the corresponding hazard ratio for South Korea (0.324). Table 3 summarizes the local approval status with and without U.S. pivotal trial participation. In Japan, only 8 of 53 drugs have been approved for the group with no U.S. pivotal trial participation. The trend in South Korea was similar, with a lower number of approved drugs for the group without U.S. pivotal trial participation, but still, 15 out of 39 drugs were approved.
The difference between groups is significant in both countries. In Japan, most drugs are left unapproved in the group without participation in the U.S. pivotal trial, and the difference between groups is greater than that in South Korea.
| Japan | South Korea | |||
|---|---|---|---|---|
| Drugs approved in the U.S. 2017–2022 | 82 | |||
| Drugs for which Japan/South Korea participated in U.S. pivotal trial | 29 | (35.4%) | 43 | (52.4%) |
| Drugs approved in Japan/South Korea | 24 | (82.8%) | 33 | (76.7%) |
| Drugs not approved in Japan/South Korea | 5 | (17.2%) | 10 | (23.3%) |
| Drugs for which Japan/South Korea did not participate in U.S. pivotal trial | 53 | (64.6%) | 39 | (47.6%) |
| Drugs approved in Japan/South Korea | 8 | (15.1%) | 15 | (38.5%) |
| Drugs not approved in Japan/South Korea | 45 | (84.9%) | 24 | (61.5%) |
All 32 drugs approved in Japan are included in the Japanese NHI database. The median time from marketing authorization to the start of NHI coverage was 58 d (range: 49–90) (data on file). The availability of the NHI for the reimbursement of drug costs in South Korea is summarized in Table 4, with the number and percentage of drugs covered by the year of approval in South Korea. The NHI is available for most drugs approved by the first half of 2020. The percentage of covered drugs was low for drugs that were approved later. None of the drugs approved in the last half of 2022 or later are covered by health insurance.
| Year of approval in South Korea |
Number of drugs approved |
Number of drugs covered |
Percentage of drugs covered |
|---|---|---|---|
| 2018 H2 | 2 | 2 | 100.0% |
| 2019 H1 | 5 | 4 | 80.0% |
| 2019 H2 | 1 | 1 | 100.0% |
| 2020 H1 | 5 | 4 | 80.0% |
| 2020 H2 | 5 | 2 | 40.0% |
| 2021 H1 | 2 | 0 | 0.0% |
| 2021 H2 | 7 | 1 | 14.3% |
| 2022 H1 | 7 | 3 | 42.9% |
| 2022 H2 | 7 | 0 | 0.0% |
| 2023 H1 | 7 | 0 | 0.0% |
Drug lag is a common issue in Japan and South Korea; however, the data from our study highlight some differences between these countries. The U.S.–Japan approval lag for all drugs approved in the U.S. was far longer than that for drugs that were locally approved, suggesting that the main issue causing the long approval lag was the high number of unapproved drugs. This is a likely reason why the Kaplan–Meier curve for the U.S.–Japan approval lag initially dropped quickly but became rather flat afterward. It was suggested that the hazard for Japan approval events was not constant, resulting in the reversal of the two curves midway through the observation period, and no significant difference in the log-rank test. The percentage of unapproved drugs in Japan and South Korea was 61.0 and 41.5%, respectively. The percentage in the EU in the same period (2017–2022) was 30.5%,10) suggesting room for improvement in these Asian countries, particularly in Japan. Another issue is that the chance of drug approval is quite small when Japan does not participate in a U.S. pivotal trial. Our previous study also suggested that the chance of local approval was smaller for drugs developed by relatively small non-Japanese companies, such as U.S.-based emerging biopharma companies.10)
In South Korea, there is still a reasonable chance of drug approval when South Korea has not participated in the U.S. pivotal trial. However, the U.S.–Korea approval lag for drugs approved in South Korea was longer than that for drugs approved in Japan. Furthermore, newly approved drugs are generally not covered by the NHI for 1–2 years after approval in South Korea.16) This means that most Korean patients need to wait for extra time to use new drugs at an affordable price, while all drugs are reimbursable in Japan for up to 3 months after approval.
One major difference between Japan and South Korea is the use of overseas clinical trial data as pivotal evidence to decide on marketing authorization. In Japan, a bridging study is necessary to extrapolate overseas data to assess the efficacy and safety of Japanese patients. Conducting a bridging study used to be the main local clinical development strategy for approval in Japan. Among the 50 anticancer drugs approved in Japan between 2001 and 2016, 39 were approved by the bridging strategy, and only 11 used data from multinational clinical trials.17) The data from the present study indicate that the use of multinational clinical trials for local approval has become more common, whereas a bridging study has not been conducted for many drugs. This could be due to an increase in the number of drugs for rare cancers or cancers with rare gene alterations18,19) for which it is difficult to enroll sufficient patients in a single-country trial. Companies may be reluctant to justify additional investments for such trials. Therefore, drugs for which Japan has not participated in the U.S. pivotal trial are often not approved in Japan.
In principle, a bridging study is required in South Korea to extrapolate overseas clinical data. However, drugs with orphan indications designated by the MFDS can be exempted from a bridging study.20) Therefore, even if South Korea has not participated in the U.S. pivotal trial of a drug, the drug may still be approved in South Korea using data from the pivotal trial, whereas approval in Japan is more difficult when Japan has not participated in the U.S. pivotal trial. In the present study, approximately 30% of the drugs approved in South Korea were approved based on overseas clinical data, and all these drugs were exempted from a bridging study. This is one factor contributing to the higher number of drugs approved in South Korea than in Japan.
Another key difference between the two countries is their participation in the U.S. pivotal trial. Japan participates in fewer U.S. pivotal trials than South Korea, even though drug approval in Japan is more heavily dependent on it. Japan’s participation in U.S. pivotal trials has become more common than before but was only 35.4% in the present study. One of the potential reasons for this low participation rate is the regulatory expectation of collecting safety and pharmacokinetic data from Japanese participants before Japan participates in a multinational, later-phase trial. When the phase 1 clinical development of a drug has already been conducted outside Japan, it is often difficult to initiate and complete a Japanese phase 1 trial before it becomes too late to enroll a sufficient number of Japanese patients in the U.S. pivotal trial. In December 2023, the MHLW issued a new regulatory notification to clarify the circumstances under which Japan might participate in a multinational trial without conducting a phase 1 trial on Japanese participants.21,22) It is expected to help increase Japan’s participation in U.S. pivotal trials and alleviate drug lag, with the caveat that a phase 1 trial may still be required based on a case-by-case assessment of the drug and target indication. Early participation of Japan in global clinical development, ideally from the first-in-human trial, is still desirable so that potential ethnic differences can be identified before planning later phase trials. Japan may also need a scheme to encourage the local clinical development of drugs for which it has not been able to participate in U.S. pivotal trials.
The Korean government is implementing new measures to improve access to new drugs. When a new drug is approved, its eligibility for NHI coverage is assessed by the HIRA based on its clinical efficacy and cost-effectiveness. In the past, drug price negotiations with the NHI Corporation took place after the HIRA assessment. Since January 2023, a process has been in place to allow assessment by the HIRA and negotiation with the NHI Corporation to be done in parallel, for drugs for life-threatening diseases. This is expected to reduce the turnaround time between drug approval and the initiation of health insurance coverage.
The present study has some limitations. The launch strategy of pharmaceutical companies could be affected by multiple factors, including the availability of local branches; these factors were not considered in the analysis. The dates for the start of health insurance coverage in South Korea are not available; therefore, the exact duration from drug approval to the start of coverage could not be calculated. The number of locally unapproved drugs may indicate the drug accessibility issue in both countries; however, there might be drugs with limited clinical utility, and it is not easy to quantify the impact of unapproved drugs on the health outcomes of patients in these countries.
Both Japan and South Korea still have a great degree of drug lag, with different trends. The main issue in Japan is the high number of unapproved drugs, whereas South Korea generally requires a longer time until drugs become widely available to the public. The governments of both countries are taking measures to address the potential causes of drug lag; therefore, the situation may change over a few years.
Yoshifumi Tachibana is an employee of Nippon Boehringer Ingelheim Co., Ltd. Jangsoo Yoon is an employee of LG Chem. Mamoru Narukawa has no conflict of interest.
