Preventive Effects of Bioabsorbable Anti-Adhesion Barriers on Bowel Obstruction After Colectomy in Colon Cancer Patients: A Retrospective Cohort Study Using an Insurance Claims Database.

PURPOSE: Postoperative adhesions can be prevented by the use of bioabsorbable anti-adhesion barriers. Although the occurrence of postoperative bowel obstruction is an important concern for patients, at the time of approval of anti-adhesion barriers, its effectiveness in preventing postoperative bowel obstruction had not been evaluated. We aimed to retrospectively evaluate the incidence of bowel obstruction after colectomy in patients with colon cancer using an insurance claims database. METHODS: This retrospective cohort study analyzed the data of colon cancer patients (between 2005 and 2017 from a national insurance claims database) who underwent colectomies to compare the proportion of individuals with postoperative bowel obstruction between the barrier and no barrier groups. RESULTS: Of the 587 patients who met the inclusion criteria, 308 and 279 patients were identified as the barrier and no barrier groups, respectively. The incidence of postoperative bowel obstruction was significantly lower in the barrier group (log-rank test, P = 0.0483). The cumulative incidence of postoperative bowel obstruction 37 months after the initial colectomy was 6.1% and 10.9% in the barrier and no barrier groups, respectively. Moreover, consistent results were obtained in the matched cohort. CONCLUSION: In colectomies for patients with colon cancer, the use of anti-adhesion barriers could significantly reduce the incidence of postoperative bowel obstruction. Evaluations using insurance claims databases could provide important information on outcomes following implementation of medical devices.

Regional Disparity in First-in-Class Anticancer Drug Development in the US, EU, and Japan.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 d) was significantly different (p = 0.043) from that in the US (4253 d), though it was not significantly different from that in the EU (4655 d). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

[Establishment of Mono-scaled Benefit/Risk Analysis of HPV Vaccine].

Decisions concerning approval of human papillomavirus (HPV) vaccines and their use are based on expert evaluation of the vaccines. However, the quantitative differences between vaccine benefits and risks are difficult for non-experts to understand. In this study, we developed a new method to calculate the benefits and risks of the HPV vaccines using disability-adjusted life year (DALY) as the mono-scaled weight for various benefits and risks relevant to the vaccines. We evaluated benefits as a gain of DALY values for cervical cancer and risks as the loss of DALY values for various adverse events by the vaccination. To calculate the loss of DALY values, we integrated all adverse events in the International Classification of Diseases chapters. The novel method reflected the men-women ratio of this epidemiological disease to a certain extent. Among the vaccinated women, 111372 and 477190 received a bivalent and quadrivalent vaccine, respectively. The DALY rate of cervical cancer was 148.7. The calculated benefit for the bivalent and quadrivalent vaccines was 149.1 and 638.8, respectively, and set as the theoretical maximum. The risk was calculated as 129.3 and 49.6 in the bivalent and quadrivalent vaccines, respectively. Since HPV vaccines prevent several other cancers, the benefit of the vaccination extends beyond the risk according to this new method.

Characteristics of the Compassionate Use Program in Japan: An Analysis of Expanded Access Clinical Trials from 2016 to 2021.

Compassionate use is a system that provides patients with exceptional access to investigational new drugs to treat life-threatening diseases that have no effective conventional treatments. The purpose of this study was to characterize and assess the current status of the compassionate use program's application in Japan by evaluating expanded access clinical trials (EACTs) conducted between 2016 and 2021. In this study, a data set containing all EACTs, and pivotal clinical trials (PCTs) conducted in Japan between February 2016 and April 2021 was obtained from the Pharmaceutical and Medical Devices Agency, systemically reviewed, and analyzed. During the 5 years since EACTs began in Japan, out of 2,031 PCTs, 31 EACTs were conducted in Japan. Twenty-four trials (77.4%) of the 31 EACTs used anticancer drugs and 5 of those trials (16.1%) were conducted in children. Furthermore, we conducted an EACT survey for drugs with a high degree of social and patient demands as recommended in the EACT notification. Among the 2,031 PCTs, we found 152 trials with high degree of social and patient demands. Of these, EACT was implemented in 17 trials (11.2%). Days from the start of the EACT to the submission of new drug applications and the approval were 9.0 (67.0-56.5) and 208.0 (172.8-308.8) days, respectively. Of the 31 EACTs conducted, 24 (77.4%) drugs have been approved as of August 2021. This first comprehensive study on EACTs clarified the current status and issues of Japan's compassionate use system and the 5 years since the program initiated.

Clinical development of anticancer drugs can be enhanced using efficacy data of small population clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Although there are accelerated approval pathways based on data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs, which were approved or whose development was terminated in small and large clinical trials, and verified whether small clinical trials could reflect the results for efficacy in large clinical trials. METHODS: All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression-free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression analysis, Spearman's correlation analysis, and paired sample t-test were performed. RESULTS AND DISCUSSION: A total of 61 comparable small and large clinical trials were identified. For all endpoints, statistically significant linear trends and correlation were detected (p < 0.001). There were no statistically significant differences in the median PFS and ORR between small and large clinical trials. The mean differences of both clinical trials were -0.102 months and -1.531%, respectively. WHAT IS NEW AND CONCLUSION: Even when the sample size of the clinical trial was increased, the efficacy data of anticancer drugs could not be changed significantly. These results supported the accelerated approval pathway based on the promising efficacy data of small populations in anticancer drug development.

Impact of expedited programs in the United States, as foreign regulatory factors, on clinical development time in Japan.

WHAT IS KNOWN AND OBJECTIVE: Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development. METHODS: In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs. RESULTS AND DISCUSSION: The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time. WHAT IS NEW AND CONCLUSION: US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

Lag Time for New Innovative, First-in-Class, Drug Approval in Japan.

Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee's request. First-in-class drugs were developed at the Committee's request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

Characteristics of drugs approved in Japan without conducting confirmatory clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. METHODS: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. RESULTS AND DISCUSSION: Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. WHAT IS NEW AND CONCLUSION: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

Evaluation of Drug Lags in Development Initiation, New Drug Application and Approval Between Japan and the USA and the Impact of Local Versus Multi-regional Clinical Trials.

BACKGROUND: Drug time lags occur between the date that new drugs are first approved, often in the USA, and approval is granted in other countries. Multi-regional clinical trials (MRCTs) are a key strategy for simultaneous global development and regulatory submission of new drugs. However, no studies have evaluated the impact of MRCT versus local development on key time points in the drug development lifecycle between the USA and Japan. It is important for pharmaceutical companies planning drug development in Japan to understand when they can start development, when they can catch up in case of development initiation delay, length of time the development period might take, and amount of time that market exclusivity is lost, if Japan does not participate in the MRCT. OBJECTIVE: The aim of this study was to investigate differences in drug lag in development initiation, New Drug Application (NDA) submission and drug approval, as well as differences in the development and review periods, by local trials and MRCTs between Japan and the USA. We also assessed the advantages and disadvantages of MRCTs for these lags in Japan. METHODS: We analyzed drug approvals in Japan between 2016 and 2020 and divided them into local and MRCT groups. Lags in development initiation, NDA submission, and approval of new drugs were calculated by subtracting each date in Japan from the corresponding date in the USA. Our study period was divided into three periods based on the International Conference on Harmonization (ICH) E17 guideline, published in 2017, and the guideline for the Phase I trials in the Japanese population prior to MRCTs, published in 2014. In addition, subgroup analyses by therapeutic area, regulatory background, modality, capital style, and sales ranking (2020) were conducted. RESULTS: We analyzed 174 approvals in Japan and the USA. The differences in the drug lags for development initiation, NDA submission, and approval between the local and MRCT groups were 4.9, 3.5, and 3.2 years, respectively. All three lag times were shorter for the MRCT group than the local group. A development initiation lag in the local group has expanded since publication of the guidelines. CONCLUSIONS: For the people of Japan, important drug lags were identified in development initiation, NDA submission, and drug approval dates between local trials and MRCTs that include Japan. It is difficult to recover fully from the delay caused by local development, and it is important to understand the further expansion of drug lags, in cases where Japan is not involved in the MRCT.

Burden of caring for Alzheimer's disease or dementia patients in Japan, the US, and EU: results from the National Health and Wellness Survey: a cross-sectional survey.

AIMS: The growing prevalence of Alzheimer's disease (AD) worldwide has sparked the implementation of national policies to support the growing burden among caregivers of AD/dementia patients. This study aims to quantify and compare the burden of AD/dementia caregivers and evaluate how different living arrangements might impact health outcomes among caregivers in Japan, five European countries (5EU), and the United States (US). MATERIALS AND METHODS: This is a cross-sectional study based on existing data from the 2018 National Health and Wellness Survey. Health outcome measures included health-related quality of life (HRQoL), health state utilities, work productivity and activity impairment (WPAI), and measurement of depression and anxiety amongst AD/dementia caregivers and non-caregivers. Pairwise comparisons between AD/dementia caregivers in Japan, 5EU, and the US were conducted. Multivariate analysis was used to compare across groups within each region, with adjustment for potential confounding effects. RESULTS: A higher proportion of caregivers of AD/dementia patients in Japan were 65 years or older as compared to 5EU and US. On the contrary, female caregivers were significantly higher in the US than Japan and 5EU. The HRQoL and health state utilities index scores amongst AD/dementia caregivers were highest in Japan and lowest in the US. Caregivers in Japan incurred the lowest WPAI among the three regions. The proportion of AD/dementia patients reportedly living in an institution was highest in Japan as compared to the US and EU. Notably, US caregivers whose patients lived in an institution experienced significantly less caregiving burden as compared to caregivers whose patients lived in the community. CONCLUSIONS: The caregiving burden among AD/dementia caregivers was substantial across the three regions, with similarities and differences between the West and Japan. The lower caregiving burden in Japan was potentially associated with national policies supporting long-term healthcare and institutionalized nursing care facilities for AD/dementia patients.

Humanistic burden among caregivers of patients with Alzheimer's disease or dementia in Japan: a large-scale cross-sectional survey.

AIMS: As the population in Japan is rapidly aging, the prevalence of dementia, particularly Alzheimer's Disease (AD), is expected to increase, resulting in a growing need for caregivers. This study aims to quantify and compare the humanistic burden of caregivers of AD/dementia patients with caregivers of patients with other conditions in Japan. MATERIALS AND METHODS: This cross-sectional study used data from the 2018 Japan National Health and Wellness Survey (NHWS). Outcome measures included the Short-Form 12-item Health Survey (SF-12) for health-related quality-of-life (HRQoL), EuroQol 5-dimension scale (EQ-5D) for health states utilities, impact of health on productivity and activity, and evaluation of depression and anxiety. Multivariate analysis was used to compare across groups, with adjustment for potential confounding effects. RESULTS: A total of 805 caregivers of AD/dementia patients, 1,099 other caregivers, and 27,137 non-caregivers were identified. Both AD/dementia caregivers and other caregivers had lower HRQoL and EQ-5D scores, higher total activity impairment, and more caregivers tended to experience anxiety than non-caregivers. There were no significant differences in the involvment in basic and instrumental activities of daily living (ADL) between AD/dementia caregivers and caregivers of other conditions. Notably, AD/dementia caregivers were more involved in making treatment decisions and finance management than other caregivers. Among AD/dementia caregivers caring for one patient, 395 patients lived in the community and 282 in an institution. AD/dementia caregivers whose patients lived in the community were more significantly involved in basic and instrumental ADL. Caregivers of patients with both AD/dementia and cancer had higher caregiving burden than caregivers of patients with either condition. CONCLUSIONS: Caregivers of AD/dementia patients in Japan reportedly experienced significant humanistic burden which is associated with patients' living arrangements and the presence of an additional chronic condition. Therefore, provision of effective care/support is essential to relieve the burden experienced by the caregivers.

Alternative New Mono-scaled Quantitative Benefit-Risk Assessment of Human Papillomavirus Vaccine in Japan.

BACKGROUND: The human papillomavirus (HPV) vaccine coverage is very low in Japan since the government suspended the active encouragement of the vaccination. We aimed to conduct a benefit-risk assessment of HPV vaccination and explore different consequent scenarios to identify potential improvements to the current Japanese immunization program. METHODS: To calculate social benefit-risk of HPV vaccine, we used the Markov model to represent the natural history of HPV and adverse events (AEs) using disability-adjusted life year (DALY) as the outcome. Benefits and risks were calculated as the sum of negative and positive outcomes corresponding to all preventable diseases and AEs associated with HPV vaccination, respectively. The benefit-risk balance in 2050 was estimated using published data. RESULTS: Our model was confirmed by published cervical cancer incidence and mortality rates. The benefit-risk balance in 2050 showed that the most effective scenario was the introduction of 9-valent HPV vaccine targeting female individuals aged 10-29 years for routine vaccination starting in 2020, although there is possibility of increased risks of AEs for the vaccinated age group post resumption of recommendations. CONCLUSION: Our benefit-risk assessment of HPV vaccine helped estimate various scenarios pertaining to HPV vaccination and identify the best strategy regarding HPV vaccination. This benefit-risk assessment approach may be used for other vaccines and vaccination programs.

Factors associated with humanistic burden and indirect cost among patients with cancer in Japan.

AIMS: Patients with cancer experienced reduced health-related quality-of-life (HRQoL), increased work productivity and activity impairment (WPAI), and indirect costs. With the current emphasis on economic evaluation of health technology in Japan, it is important to understand how indirect costs correlate with HRQoL and patient characteristics. It is also crucial to assess the patient characteristics associated with the HRQoL, WPAI, and indirect costs among patients with any types of cancer. MATERIALS AND METHODS: This cross-sectional study used data from the 2017 Japan National Health and Wellness Survey (NHWS). Respondents self-reported their HRQoL and WPAI by answering validated SF-12v2 and WPAI questionnaires, respectively. Indirect costs were derived using the human capital method. Correlation between HRQoL components and indirect costs were assessed using Spearman's rank-order correlation. Correlation between patient characteristics and HRQoL, WPAI, and indirect costs were analyzed using generalized linear models. RESULTS: A total of 1,540 patients with any types of cancer, 254 with breast cancer, and 144 with colorectal cancer were included in the analyses. There was significant negative correlation between the indirect costs and HRQoL components among patients with any types of cancer. Patients with lower comorbid burden, higher household income, employed, married, or living with partner, never smokers, and exercised tended to have higher HRQoL. Being never smokers, having lower comorbid burden, normal weight, and exercised were associated with lower WPAI measures. Additionally, patients who were older, not married, not obese, and not smoking tended to incur lower indirect costs. CONCLUSIONS: The negative correlation between HRQoL and indirect costs among patients with cancer emphasized the needs to improve health outcomes and reduce indirect costs of patients. The factors associated with cancer burden identified in this study provide insights to allow targeted intervention to improve HRQoL and lessen the WPAI and indirect cost among cancer patients in Japan.

Weather Fluctuations May Have an Impact on Stroke Occurrence in a Society: A Population-Based Cohort Study.

BACKGROUND: Stroke has been found to have a seasonally varying incidence; blood pressure, one of its risk factors, is influenced by humidity and temperature. The relationship between the incidence of stroke and meteorological parameters remains controversial. OBJECTIVE: We investigated whether meteorological conditions are significant risk factors for stroke, focusing on the fluctuation of weather elements that triggers the onset of stroke. METHODS: We collected ambulance transportation data recorded by emergency personnel from Gifu Prefecture. We included cases where the cause of the transportation was stroke and excluded cases of trauma. We combined these data with meteorological data as well as data on average temperature, average air pressure, and humidity provided publicly by the Japan Meteorological Agency. Our target period was from January 2012 to December 2016. RESULTS: In the 5-year target period, there were 5,501 occurrences of ambulance transportation due to stroke. A seasonal tendency was confirmed, since ambulance transportation for stroke occurred more frequently at low temperatures (p < 0.001). Temperature (odds ratio: 0.91; p < 0.001) and humidity change (odds ratio: 1.50; p = 0.016) were identified as risk factors for ambulance transportation due to stroke. An increase in temperature incurs a lower risk than a decrease (odds ratio: 0.58; p = 0.09), although there is no statistically significant difference. CONCLUSIONS: Meteorological effects on the frequency of ambulance transportation due to stroke were studied. A lower temperature and radical humidity change were identified as risk factors for ambulance transportation due to stroke, and a decrease in temperature was also associated. We speculate on the possibilities of using meteorological data to optimize the assignment of limited medical resources in medical economics.

A population-based study of the humanistic burden among cancer patients in Japan.

Aims: Understanding the burden of cancer in Japan is becoming increasingly important to address the socio-economic consequences of the disease. This study broadly examined the cancer burden in terms of: Health-Related Quality of Life (HRQoL), work productivity and activity impairment (WPAI), stress-related comorbidities, and indirect costs in patients diagnosed with (i) any type of cancer, (ii) breast cancer, (iii) colorectal cancer, compared to controls without cancer.Materials and methods: This cross-sectional study used data from the 2017 Japan National Health and Wellness Survey (NHWS). Patient outcomes included self-reported stress-related comorbidities, HRQoL assessed by Short Form 12-item Health Survey and EuroQoL 5-dimension scale (EQ-5D), and work productivity and indirect costs assessed by WPAI questionnaire. Multivariate analysis was performed to compare outcomes across groups. An ad-hoc analysis compared respondents currently and currently not receiving prescription medication (Rx).Results: A total of 1,540 patients with any type of cancer, 254 with breast cancer, 144 with colorectal cancer were included in the analyses and compared to 28,070 controls without cancer. After adjusting for potential confounding effects patients with any type of cancer had significantly lower mental component summary scores (45.70 vs. 46.45, p = .003), physical component summary scores (48.95 vs. 50.02, p < .001) and EQ-5D index (0.77 vs. 0.79, p < .001), and significantly increased absenteeism (5.13% vs. 2.68% p < .001) compared to controls. No significant differences were detected for indirect costs. Breast cancer patients had significantly increased odds of anxiety and migraine. Colorectal cancer patients had significantly increased odds of insomnia. Patients currently receiving Rx had significantly lower HRQoL and higher WPAI than both controls and cancer patients not receiving Rx.Conclusions: Japanese cancer patients experience a significantly decreased HRQoL, increased absenteeism and higher odds ratio for stress-related comorbidities. This has implications for future policy making and Health Technology Assessment in Japan.

Humanistic and economic burden among caregivers of patients with cancer in Japan.

Aims: As the number of cancer patients increases in Japan, and people are living longer with cancer, the need for caregivers of cancer patients is expected to increase substantially. This study intended to reveal the humanistic and economic burden among caregivers of cancer patients, and to compare it with the burden among caregivers of patients with other conditions (other caregivers) and non-caregivers.Materials and methods: This cross-sectional analysis used data from the Japan National Health and Wellness Survey 2017. Outcome measures included the Short Form 12-item Health Survey for health-related quality of life (HRQoL), EuroQol 5-dimension scale (EQ-5D) for health states utilities, Work Productivity and Activity Impairment questionnaire for the impact of health on productivity and activity, and indirect costs. Multivariate analysis was used to compare across groups, with adjustment for potential confounding effects.Results: A total of 251 caregivers of cancer patients, 1,543 other caregivers, and 27,300 non-caregivers were identified. Caregivers of cancer patients (average 48.0 years old) tended to be younger than non-caregivers (51.5) and other caregivers (54.4) and had the highest education level (57.8% completed university education). Fewer non-caregivers had stress-related comorbidities than caregivers. Non-caregivers had significantly higher EQ-5D index scores than caregivers (average 0.81 vs. 0.73 vs. 0.74). Caregivers of cancer patients had significantly lower mental component summary scores than non-caregivers (40.18 vs. 46.70), and the difference indicated a clinically meaningful decrease in HRQoL. Caregivers of cancer patients had significantly higher presenteeism (37.31% vs. 20.43%), total work productivity impairment (38.85% vs. 21.98%), and activity impairment (40.94% vs. 25.78%) than non-caregivers. Additionally, caregivers of cancer patients had significantly higher total indirect costs (36.34% vs. 20.03% of average annual income).Conclusions: These results have implications for future healthcare planning, suggesting the importance of healthcare systems in Japan to consider the substantial burden borne by caregivers of cancer patients.

Japan's health care system faces a perfect storm.

Although Japan has implemented a universal health care system that is universal in terms of free access to health care services, it is managed by fragmented and financially insecure insurance societies that have cumulative deficits even with government subsidies. In terms of insurance premiums, the system is regressive to low-income and unstable workers, and the social benefit scheme only captures 1.6% of this population. The Japanese government is continuously instituting new health care policies to reduce growing health care expenditures. Recent health care reforms may improve economic efficiency, but the changes remain limited to controlling access to health services and pricing measures.

Evaluation of the effectiveness of caspofungin against febrile neutropenia and the factors related to the alteration in its plasma concentration.

Caspofungin (CPFG) is an echinocandin antifungal agent that inhibits the synthesis of ß-1, 3-D-glucan, a critical component of the cell wall of target fungi. Several clinical studies have confirmed the efficacy and safety of CPFG in patients with febrile neutropenia (FN); however, there are no reports available in Japanese patients with FN. Therefore, we investigated the therapeutic efficacy and pharmacokinetics of CPFG as an empirical therapy in a Japanese hospital. Twenty-four Japanese patients, who were diagnosed with FN at Gifu University Hospital from February 2014 to August 2017, were enrolled. Blood samples were collected at the end of CPFG dosing (0.5 h after the infusion) on day 1 and immediately prior to the next infusion on days 2, 3, and 4. The concentration of CPFG in plasma was measured by high-performance liquid chromatography. The efficacy was assessed by five of the component endpoints, and safety was monitored according to the Common Terminology Criteria for Adverse Events. CPFG showed an excellent effect against FN (75%, 18/24), without any serious hepatic or renal toxicity. Regarding the pharmacokinetics, the plasma concentration of CPFG was significantly correlated with body weight; although, no correlation was observed between the plasma concentration of CPFG and the other factors investigated, such as gender or laboratory results. These results suggest the high efficacy, safety, and tolerability of CPFG as an empirical antifungal therapy for Japanese patients with FN.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Health Technology Assessment in Japan: A Pharmaceutical Industry Perspective.

BACKGROUND: Japan has been preparing to implement a Health Technology Assessment (HTA) process in 2018. Through a 2-year pilot program implemented in 2016, the government examined the criteria for applicable products and the necessary infrastructure to review both the content and quality of the data and to conduct cost-effectiveness assessments to be incorporated into the current Japanese reimbursement and pricing scheme. A survey of the pharmaceutical industry was conducted to understand the current landscape and to identify issues and challenges of implementing HTA in Japan. METHODS: A semi-structured 19-item questionnaire was designed, and a survey was conducted via face-to-face or phone interviews. Answers were transcribed in English after the interviews and confirmed by e-mail. The survey focuses on pharmaceutical companies that develop new innovative products to be associated with the planned HTA. RESULTS: Differences between Japanese and global pharmaceutical companies were observed in terms of dedicated HTA teams in place, the use of quality of life data, and relationships with external vendors. Addressing a shortage of HTA professionals in Japan is critical to implement HTA. The survey found that list prices compared to those proposed by companies was an issue. CONCLUSIONS: Although the government decided to implement HTA for the pricing scheme in 2018, a shortage of experts and researchers remains a challenge. Findings suggest HTA should not be used solely to reduce pharmaceutical spending, as the impact by the HTA implementation will be temporary and discourage innovation.