論文

© 2019, Springer Nature Switzerland AG. Aim: Falls are a significant problem for older people, but are few studies of the risk of falling in residents of nursing homes in Japan. We aimed to investigate the risk factors for falls and the association of medication use and falls in nursing home residents in Japan. Methods: This case–control study reviewed the records of residents of who were ≥ 65 years of age and had fallen in 2012 and an age-, sex-, and facility-matched control group selected from 58 nursing homes in Japan. The odds ratios of potential risk factors and current medications were determined by conditional logistic regression. Results: A total of 1832 residents (916 cases and 916 controls) were included. Falls were significantly associated with an inability to walk without assistance or stand up without assistance, need for toileting assistance, visual impairment, insomnia, and dementia. Current prescription of antithrombotic, nonsteroidal anti-inflammatory, or antiparkinson drugs, muscle relaxants, antiepileptics, antipsychotics, antidepressants, opioids, selective serotonin reuptake inhibitors, and memantine was also associated with increased risk of falling. Conclusions: Many medications were associated with falls in nursing homes residents in Japan. To prevent these falls, caregivers should provide adequate care, and healthcare professionals should consider switching or dose reduction for these medications.

© 2018 The Pharmaceutical Society of Japan. Under the Japanese drug regulatory system, post-marketing studies (PMS) must be in compliance with Good Post marketing Study Practice (GPSP). The GPSP Ordinance lacks standards for the ethical conduct of PMSs; although only post-marketing clinical trials are subject to Good Clinical Practice. We conducted a web-based questionnaire survey on the ethical conduct of PMSs in collaboration with the Japanese Society of Hospital Pharmacists and pharmacists belonging to the Society. 1819 hospitals around Japan answered the questionnaire, of which 503 hospitals had conducted company-sponsored PMSs in 2015. 40.2％ of the hospitals had obtained informed consent from participating patients in at least one PMS conducted in 2015, the majority of which was in written form. The first and second most frequent reasons for seeking informed consent in PMSs were to meet protocol requirements, followed by the requirement to meet institutional standard operational procedures and the request of the ethical review board of the hospital. Ethical review of PMSs was conducted in 251 hospitals. Despite a lack of standards for informed consent and ethical review in PMSs, a considerable number of study sites employed informed consent and ethical review for PMSs. While company policies and protocols are likely to be major determinants of the ethical conduct of PMSs, the governmental regulatory agency should also play a significant role in implementing a standardized ethical code for the conduct of PMSs.

Background: The updated international draft guidelines, the “General Considerations for Clinical Studies, ICH E8 (R1)”, state that patient engagement ensures that all perspectives are captured in the research process; however, this is not well understood, specifically in Japan. Objective: This study examined the current status and perceptions of patient engagement in clinical research from the perspectives of patient groups, pharmaceutical corporations, and researchers in Japan, using anonymous self-administered questionnaires. Methods: Three online surveys were conducted with patient groups (n = 100), pharmaceutical corporations (n = 66), and researchers (n = 300) in May and June 2019. The main variables were the current status and the current perception of patient engagement in clinical research. Results: The response rate was 71% for patient groups and 85% for pharmaceutical corporations, and there were 300 valid responses (emergence rate: 4.9%) from researchers. Experiences with clinical research involving patient engagement were reported by 76.5% of the patients, 21.4% of the pharmaceutical corporations, and 51.7% of the researchers. Patient groups reported three major factors that negatively impacted their relationship with pharmaceutical corporations and researchers: (1) ‘lack of understanding of the benefits of partnering’; (2) ‘lack of transparency or openness’; and (3) ‘unclear or ill-defined processes’. Conclusions: Pharmaceutical corporations in Japan have less experience with patient engagement in clinical research than other stakeholders. A neutral connecting system among the stakeholders with a constructive co-learning system will allow effective involvement/engagement of patient groups for enhancing the effectiveness of clinical research.

Background: Chronic kidney disease (CKD) is an independent risk factor for progression to an end-stage renal disease requiring dialysis or kidney transplantation. We investigated the association of lifestyle behaviors with the initiation of renal replacement therapy (RRT) among CKD patients using an employment-based health insurance claims database linked with specific health checkup (SHC) data. Methods: This retrospective cohort study included 149,620 CKD patients aged 40–74 years who underwent a SHC between April 2008 and March 2016. CKD patients were identified using ICD-10 diagnostic codes and SHC results. We investigated lifestyle behaviors recorded at SHC. Initiation of RRT was defined by medical procedure claims. Lifestyle behaviors related to the initiation of RRT were identified using a Cox proportional hazards regression model with recency-weighted cumulative exposure as a time-dependent covariate. Results: During 384,042 patient-years of follow-up by the end of March 2016, 295 dialysis and no kidney transplantation cases were identified. Current smoking (hazard ratio: 1.87, 95% confidence interval, 1.04─3.36), skipping breakfast (4.80, 1.98─11.62), and taking sufficient rest along with sleep (2.09, 1.14─3.85) were associated with the initiation of RRT. Conclusions: Among CKD patients, the lifestyle behaviors of smoking, skipping breakfast, and sufficient rest along with sleep were independently associated with the initiation of RRT. Our study strengthens the importance of monitoring lifestyle behaviors to delay the progression of mild CKD to RRT in the Japanese working generation. A substantial portion of subjects had missing data for eGFR and drinking frequency, warranting verification of these results in prospective studies.

© 2018 Elsevier Ltd Background: To date, few large-scale comparative effectiveness studies of influenza vaccination have been conducted in Japan, since marketing authorization for influenza vaccines in Japan has been granted based only on the results of seroconversion and safety in small-sized populations in clinical trial phases not on the vaccine effectiveness. We evaluated the clinical effectiveness of influenza vaccination for children aged 1–15 years in Japan throughout four influenza seasons from 2010 to 2014 in the real world setting. Methods: We conducted a cohort study using a large-scale claims database for employee health care insurance plans covering more than 3 million people, including enrollees and their dependents. Vaccination status was identified using plan records for the influenza vaccination subsidies. The effectiveness of influenza vaccination in preventing influenza and its complications was evaluated. To control confounding related to influenza vaccination, odds ratios (OR) were calculated by applying a doubly robust method using the propensity score for vaccination. Results: Total study population throughout the four consecutive influenza seasons was over 116,000. Vaccination rate was higher in younger children and in the recent influenza seasons. Throughout the four seasons, the estimated ORs for influenza onset were statistically significant and ranged from 0.797 to 0.894 after doubly robust adjustment. On age stratification, significant ORs were observed in younger children. Additionally, ORs for influenza complication outcomes, such as pneumonia, hospitalization with influenza and respiratory tract diseases, were significantly reduced, except for hospitalization with influenza in the 2010/2011 and 2012/2013 seasons. Conclusions: We confirmed the clinical effectiveness of influenza vaccination in children aged 1–15 years from the 2010/2011 to 2013/2014 influenza seasons. Influenza vaccine significantly prevented the onset of influenza and was effective in reducing its secondary complications.

Domperidone is an antiemetic that is often prescribed for children with acute gastroenteritis in Japan. In this study, the authors assessed the efficacy of domperidone prescription in combination with oral rehydration treatment (ORT) in the treatment of vomiting during acute gastroenteritis in children during the early period. They performed a prospective multicenter randomized trial in Japan. Patients received either ORT or ORT and domperidone prescription. The primary outcome was the proportion of patients who had vomiting during the first 2 hours after randomization. A total of 56 children were eligible; 24 received ORT alone, and 32 received ORT and prescribed domperidone suppository. Results showed that 27.3% of children in the ORT group vomited as compared with 20.7% of children in the ORT and domperidone group (P = .41). In this study, it appears that domperidone in combination with ORT in the treatment of acute gastroenteritis does not reduce vomiting in the early period.

© 2018 The Authors Background: Antithrombotic therapy, including direct oral anticoagulants, is recommended in patients with non-valvular atrial fibrillation (NVAF) who are at intermediate-to-high risk of stroke. The aims of this study were to assess the patterns of oral anticoagulant (OAC) prescription in Japanese patients with NVAF and compare the effectiveness and safety of dabigatran and warfarin. Methods: This was a retrospective observational study of adults with NVAF who initiated dabigatran or warfarin between March 14, 2011 and June 30, 2016, using electronic claims data of approximately 12.94 million patients from 230 hospitals. Propensity score matching was used to derive equal patient cohorts. Outcomes included the combined incidence of stroke, systemic embolism, and intracranial bleeding (primary endpoint) and the incidence of major bleeding (secondary endpoint). Results: Overall, 400,884 patients were included. Among those prescribed an OAC, warfarin was the most common (34.3%). For the comparison of dabigatran and warfarin, 4606 patients were propensity-score matched in each cohort. Dabigatran recipients had lower incidences of stroke, systemic embolism, and intracranial bleeding [29.0 vs. 35.6 per 1000 patient-years; hazard ratio (HR), 0.72; 95% confidence interval (CI): 0.53–0.97; p = 0.031] and major bleeding (6.4 vs. 11.3 per 1000 patient-years; HR, 0.55; 95% CI: 0.30–0.99; p = 0.048). The most common type of bleeding in both groups was gastrointestinal and the incidence was lower in dabigatran recipients (1.6 vs. 6.4 per 1000 patient-years; HR, 0.24; 95% CI: 0.08–0.69; p = 0.009). Conclusions: In Japan, dabigatran was associated with a lower risk of stroke, systemic embolism, and intracranial bleeding and major bleeding compared with warfarin in patients with NVAF.

© 2019 Fukasawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.

Purpose: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. Methods: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. Results: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90–0.99 compared to other therapies). Conclusions: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Pediatric drug development is challenging due to various difficulties in clinical evaluation and inadequate economic return over development cost. The legislative measures have been taken in several countries, including the European Union（EU）and the United States（US）, to advance drug development in pediatrics because of its importance in disease management. We compared legislation related to promotion of pediatric drug development in the US, the United Kingdom（UK）and Japan. Next, we set the US, a pioneer in addressing off-label use in children, as the standard against which to compare the approval status of pediatric indications in Japan and the UK. According to the drug labels, we identified 72 products approved for pediatric indications in the US between January 2016 and April 2020 which were also approved for adults or children in both Japan and the UK. We calculated the percentage of products with pediatric indications and analyzed the development status of products without pediatric indications. In the UK, 83％（60/72）of products had pediatric indications. Of the 12 products without pediatric indications, four were investigated in clinical trials or planned to be developed for pediatric use. In contrast, the percentage of products with pediatric indications in Japan was 44％（32/72）, and of the 40 products without pediatric indications, only two were in development for pediatric use. All of the products reviewed by the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs of the Japanese Ministry of Health, Labour and Welfare were indicated for pediatric patients. In contrast, only about half（9/19）of the drugs with orphan drug designation had pediatric indications. With reference to the regulatory frameworks in the US and UK, the＂Designation of Pharmaceuticals for Specific Use＂, established in the 2019 revision of the Pharmaceuticals and Medical Devices Law（PMDL）, may offer the better means to promote pediatric drug development in Japan.

Introduction: Standardization is an import factor in ensuring the safety, efficacy, and quality of herbal medicines, and facilitates their international commerce. Heavy metal poisoning due to herbal medicines has been reported in many countries. Here, to better understand the current state of harmonization, we compared regulations for arsenic and heavy metals in herbal medicines across seven countries and two regions with two international standards. Methods: We studied the monographs of herbal medicines of seven countries and two regions, as well as the WHO guidelines and ISO standards. We then compared the limits and test methods adopted for elemental impurities in herbal medicines listed in the monographs and standards among countries. Results: The number of herbal medicines assessed amounted to over 2000. Limits and test methods adopted for elemental impurities in herbal medicines varied by country/region and organization. Although WHO recommends a uniform upper limit for lead and cadmium for all herbal medicines, some countries set unique upper limits for individual herbal medicines. ISO 18664:2015 lists only instrumental analysis methods, whereas Japan and India list only chemical methods. Conclusions: Many countries do not adhere to the WHO or ISO recommendations on elemental impurities in herbal medicines. These findings suggest the presence of differences in regulations for herbal medicines among countries/regions, likely rooted in cultural differences and policies aimed at maintaining the diversity of herbal medicines. Regulatory convergence by “loose harmonization” to internationally agreed standards appears a feasible option to maintain diversity and safety, and promote international trade in herbal medicines.