Oncology Drugs In Japan Research Articles

Comparison of safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials: meta-analysis of safety profiles.

No report has assessed the differences in adverse event (AE) profiles of anticancer drugs for all types of cancers in clinical trials involving Japanese patients. This study aimed to compare the safety outcomes of anticancer drugs in Japanese and non-Japanese patients in multi-regional clinical trials (MRCTs), regardless of the type of cancer or drug. All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched through the Pharmaceuticals and Medical Devices Agency website. The odds ratio (OR) for comparing the incidence of AEs between Japanese and non-Japanese patients was estimated using the Mantel-Haenszel method with a random effect model. Sixty-six multi-regional phase 3 trials were identified involving 43,712 patients. Severe AE, AE leading to dose reduction, and AE leading to dose interruption were significantly more frequent in Japanese patients than in non-Japanese (odds ratios [ORs] were 1.32 (95% confidence interval (CI): 1.13-1.53), 1.97 (95% CI: 1.66-2.31), and 1.63 (95% CI: 1.43-1.86), respectively). Serious AEs (SAEs) and AEs leading to death were significantly less frequent in Japanese patients (OR: 0.70 (95% CI: 0.62-0.77) vs. 0.56 (95% CI: 0.44-0.67), respectively). There were no differences in AEs leading to study withdrawal. The incidence of most AEs was significantly higher in Japanese patients. In Japanese patients, the incidence of SAEs and AEs leading to death was low, but severe AEs, AEs leading to dose reductions, AEs leading to dose interruption, and individual adverse events were high.

Assessment of Surrogate End Point Trends in Clinical Trials to Approve Oncology Drugs From 2001 to 2020 in Japan

A surrogate end point (SEP) is an end point used in clinical trials as an alternative for measuring the true clinical benefit. The use of SEPs in trials shortens their duration. To investigate the use of SEPs in clinical trials to support the approval of anticancer drugs and to determine whether confirmatory studies that use overall survival (OS) as an end point are being conducted in Japan. In this cross-sectional study, drug approvals and background information were obtained from publicly available information, such as the Pharmaceuticals and Medical Devices Agency website, for anticancer drugs approved in Japan from January 2001 to December 2020. Data analysis was performed from September 2021 to March 2022. Characteristics of approved oncology drugs in Japan, end points for pivotal clinical trials, and outcomes of confirmatory trials using OS as an end point following drug approval. There were 299 anticancer drugs approved in Japan during the study period. Of these, 142 (47.5%) were molecular-targeted drugs, the most common of which targeted non-small cell lung cancer. There were 111 (37.1%) anticancer drugs with orphan designation. From 2001 to 2005, OS was used as an end point in 1 approval (3.6%); however, from 2006 to 2020, OS was used in 86 approvals (31.7%). Of the 212 anticancer drugs approved on the basis of SEPs, confirmatory studies with OS as the end point were conducted for only 37 approvals (17.5%); for the remaining 175 approvals, studies are under way for 35 approvals (16.5%), were waivered for 75 approvals (35.4%), and were not conducted for 65 approvals (30.7%). Furthermore, in 20 drug approvals (9.4%), the conducted confirmatory studies were not effective in determining the OS, but the drugs were approved following re-examination. The findings of this study suggest that starting from 2005, the use of OS as an end point has increased in studies supporting the approval of anticancer drugs in Japan. However, even after 2005, approximately two-thirds of these approvals were SEP based. Postmarketing surveillance studies of the true end points are necessary to validate the use of SEPs.

Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population.

It is important to recognize regional and racial differences in drug efficacy and safety when performing multi-regional clinical trials (MRCTs). To understand regional differences, we compared the efficacy results in Japanese patients and the overall population in the MRCTs of anticancer drugs. All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched using the Pharmaceuticals and Medical Devices Agency web site to find phase 3 MRCTs for the analysis. As the supporting data source, a literature search was performed in PubMed and Google Scholar. Linear regression analysis was performed and Pearson correlation coefficients (r) were calculated to compare the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between Japanese patients and the overall population. Seventy MRCTs were identified. The correlation of hazard ratios (HRs) for OS between Japanese patients and the overall population was moderate (r = 0.45), and OS was 1.31 times longer in Japanese patients than in the overall population, although the correlation of median OS was strong (r = 0.91). The HRs for PFS were moderately correlated (r = 0.70) and the correlation of median PFS was strong (r = 0.90). The correlation of ORR was very strong (r = 0.96). The PFS and ORR were consistent between Japanese patients and the overall population. A longer median OS was observed in Japanese patients. Our results would be a useful reference when planning and conducting MRCTs that include Japan for global simultaneous drug development.

Influence of Expedited Programs in the United States on Oncology Drug Development in Japan.

Recent trends in globalization and the complexity of drug development have resulted in the possibility that expedited programs in one country may now influence drug development in another. We examined the effects of expedited programs in the United States on the development of oncology drugs in Japan. Among oncology drugs approved in Japan between 2007 and 2016, we analyzed those that were approved in both the United States and Japan. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information. We analyzed a total of 108 approvals for oncology drugs. The difference in the development start date between the United States and Japan for drugs granted Breakthrough Therapy designation was smaller than that for drugs without this designation ( P < .01). The development period in Japan for drugs granted Breakthrough Therapy, Accelerated Approval or Fast Track designations was significantly shorter than that for drugs without these designations ( P < .05). In addition, the development period of oncology drugs in Japan tended to be significantly shorter as the number of expedited program designations increased ( P < .006 for trend). The characteristics and the target disease of the drug that could be eligible for expedited program(s) in the United States, which was supported by the designation, were one of the factors influencing the development of oncology drugs in Japan.

Influence of Breakthrough Therapy Designation in the United States on Oncology Drug Development Timelines in Japan

The Breakthrough Therapy Designation (BTD) program was established in the USA in 2012 to expedite the development of new potential “breakthrough” drugs with promising early clinical evidence over available therapies. The majority of BTDs are oncology drugs, and previous research has reviewed the impact of this designation on drug development in the USA. Recent trends in the globalization of oncology drug development suggest that expedited programs in the USA may influence drug development timing in other countries. We examined the influence of BTD in the USA on the development initiation date, development period, and approval of oncology drugs in Japan. We analyzed oncology drugs approved in Japan between 2013 and 2017 that were also approved in the USA. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information. We analyzed 72 approvals for oncology drugs. The development periods for BTD drugs, both in Japan and in the USA, were shorter than those for non-BTD drugs. Additionally, the difference both in the development start date and in the approved date between the USA and Japan was smaller for BTD drugs than that for non-BTD drugs. BTD designation itself and/or the characteristics and target diseases of drugs that are eligible for BTD in the USA may constitute factors that facilitate a shorter development period, earlier development initiation and earlier approval in Japan.

578P - Current situation and problems of ‘drug lag’ for oncology drugs in Japan

578P - Current situation and problems of ‘drug lag’ for oncology drugs in Japan

Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag.

Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early-initiation BG strategy were significantly shorter than that in the late-initiation BG strategy. The findings in our study suggest that the late-initiation BG strategy may not contribute to shortening drug lag. Because the number of late-initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non-Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign-capital companies.

Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

Regulatory review time for approval of oncology drugs in Japan between 2001 and 2014. Considerations of changes, factors that affect review time, and difference with the United States.

In this study, we comprehensively and historically studied the review time of oncology drugs approved by the regulatory authorities in Japan with publicly available information. A total of 120 applications of oncology drugs were approved in Japan between April 2001 and July 2014. The review time peaked with 732.0 days (24.4 months) in 2005, and showed a tendency to decline gradually each year thereafter. After 2012, a significant reduction of the review time was seen in comparison to the median of 13-year median time. In addition, we compared the review time with that in the United States. The median review time lag with the United States was significantly peaked in 2005. After 2005, the review time lag with the FDA has decreased, but lag did not significantly reduce by 2014. We also examined factors influencing the review time in Japan with multiple regression analysis. It was found that the factors related to a use of overseas data and expedited program for accelerating the reviews influenced the direction of shortening the review time. We consider that regulatory authorities in Japan need to keep making efforts to reduce the review time further and eliminate the review time lag with the United States.

Acceptance of surrogate end points in clinical trials supporting approval of drugs for cancer treatment by the Japanese regulatory agency

BackgroundThis study investigated the historic use of different end points to support approval of drugs for cancer treatment in Japan. Patients and methodsAnticancer drugs approved between April 2001 and April 2014 were comprehensively investigated using publicly available information. ResultsBefore the revision of the guideline for oncology drugs in April 2006 in Japan, >80% of end points supporting approval were response rate and overall survival (OS) was not frequent. After the revision of the guideline in Japan, using OS in pivotal clinical trials applied for approval increased to more than approximately one-third of oncology drugs, although trials with an end point of response rate decreased. Regarding drugs for major cancers including non-small-cell lung cancer, gastric cancer, colorectal cancer, and breast cancer, survival was used as an end point in 44.0%, whereas surrogate end points were used in 56.0%. Exploration of potential factors for using surrogate end points other than survival carried out through determinations of odds ratios and 95% confidence intervals identified ‘orphan drug designation in Japan’ and ‘accelerated approval by the U.S. Food and Drug Administration’ as significant factors. ConclusionsThe revised guideline for oncology drugs in Japan requires the results of phase 3 studies with survival as an end point at the time of new drug application at least for major cancers. The regulatory agency in Japan also accepts surrogate end points as end points supporting approval besides survival; however, the number of surrogate end points has decreased after the revision of the guideline. We consider that accepting surrogate end points in the Japanese regulatory systems is important to approve oncology drugs quickly in Japan.

An Analysis of Guidance for Proper Usage Documents for Oncology Drugs in Japan

Pharmaceutical companies in Japan often provide a unique document called the Guidance for Proper Usage (GPU) to medical oncologists, in order to promote the proper use of an approved drug. The aim of the study was to examine the content of and current trends in the efficacy and safety data provided in GPU documents, in order to understand what pharmaceutical companies regard as important information for an oncologist to ensure proper usage of oncology drugs in Japan. Furthermore, this study analysed the influence of route of administration (oral or injection), drug class (cytotoxic or other), type of malignancy (haematological or solid malignancy) and the period of GPU publication (before and after April 2004) on the content of the GPU document. For the 103 oncology drugs approved for use in Japan, 59 GPU documents, covering 50 drugs, were distributed to medical oncologists and were compared by multivariate analysis over two consecutive time periods, from October 1994 to March 2004 and April 2004 to December 2010. For each document, we determined the total number of pages and the proportion of pages that provided drug and toxicity information and the results of registration trials, including postmarketing surveillance. The median number of pages in the GPUs was 48 (range, 11–98). The proportion of pages providing toxicity information, drug information (e.g. warnings, contraindications, instructions, and directions for indications and usage, dosage and administration) and the results of registration trials were 30%, 26% and 11%, respectively. After April 2004, the publication of GPU documents doubled, and the proportion of pages discussing the results of registration trials significantly increased (p = 0.002). The proportions of pages discussing toxicity information and the results of registration trials in molecular-targeted drugs were significantly greater than those for other types of drugs (p < 0.001 and p = 0.008, respectively), while the proportion of pages discussing drug information was significantly lower (p = 0.001). The number and length of GPU publications distributed by pharmaceutical companies in Japan has increased since 2004. Significant changes in content have included a reduction in the amount of information about drug administration and an increase in information on the results of pharmaceutical company-sponsored registrational trials. A further study is warranted to evaluate how often oncologists actually access GPU documents and what type of information could be most useful in medical practice in Japan.

Use of oncology drugs in Japan compared to France, Germany, Italy, Spain, Sweden, the United Kingdom, and the United States: A comparison based on data from 1999 to 2009.

e16585 Background: Drugs constitute a key element in the treatment of solid tumors and in haematology. We have analysed the access and uptake of oncology drugs in 8 countries over a 10 year period (1999-2009) based on sales data provided by IMS Health. Methods: In this analysis we study cancer drugs (ATC code L1+ L2A+B+ L4X) sub divided into a “mature” set of cancer drugs available in 1999 or before (approved for use in any of the study countries) and a set of “new” cancer drugs available in 2000 or later. We have also analysed their use in relation to burden of disease (mg use/ mortality case). Detailed data will be presented. Results: We see very different patterns of spending in countries studied. The table below illustrates the situation in 2009, but the pattern of spending is similar during the whole study period. The highest spending per capita is found in France. In Japan the spending on especially “mature” drugs is high. Spending on “new” cancer drug is strikingly low in the UK. These differences in spending may also be related to differences in cancer burden (cancer incidence here given as age standardized incidence; ASR), as well the cancer panorama (differences in case load of lung cancer, gastric cancer etc.). Conclusions: There are major variations in the spending on cancer drugs between countries in the study. Japan has a high spending on cancer drugs in relation to burden of disease, and this spending is especially high on “mature” drugs. The differences seen may reflect several factors, such as differences in approval times, reimbursement decisions, use of generic drugs, budget allocation, exchange rate fluctuations and differences in interpretations of scientific data. Country Per capita spending (USD) “mature drugs” (% of total) Per capita spending (USD) “new drugs” (% of total) Cancer incidence ASR France 41 (59) 29 (41) 430 Germany 28 (61) 18 (39) 377 Italy 26 (63) 15 (37) 427 Japan 45 (78) 13 (22) 287 Spain 32 (58) 23 (42) 321 Sweden 25 (68) 12 (32) 357 United Kingdom 20 (77) 6 (23) 382 United States 39 (61) 25 (39) 447

The notorious “drug lag” for oncology drugs in Japan

This study aimed to analyze the oncology "drug lag" (i.e., the delay in time required for the approval of oncology drugs) in Japan compared with that in the United States of America (US) or the European Union (EU) and to identify the factors associated with this lag. Using publicly available information, we collected data on 42 approvals of 30 oncology drugs in Japan, the US, and the EU that included dates of drug development initiation, submission, review, and approval. Lags in each step of the process were then examined and compared among the three regions. We found that median submission and approval lag times between Japan and the US were 20.0 and 29.9 months, respectively, while those between Japan and the EU were 14.9 and 21.3 months, respectively. The median review periods for Japan, the US, and the EU were 14.3, 6.0, and 13.2 months, respectively, and the median lag in initiation of oncology drug development between Japan and the US/EU was 38.9 months. The proportion of approvals for which Japanese Phase I registration trials started after corresponding approvals in the US were 39% compared with 47% for the EU. Multivariate analysis suggests that delays in the initiation of drug development and the extended length of the regulatory review period in Japan may contribute to the longer oncology drug lag observed in Japan compared with that of the US or EU.