論文 - 漆原　尚巳

Validation of algorithms in studies based on routinely collected health data: General principles

Ehrenstein V., Hellfritzsch M., Kahlert J., Langan S.M., Urushihara H., Marinac-Dabic D., Lund J.L., Sørensen H.T., Benchimol E.I.

American Journal of Epidemiology 193 （ 11 ） 1612 - 1624 2024年11月

最終著者, 責任著者,  ISSN  00029262

　概要を見る

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. In this paper, we aim to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy, gold/reference standards, study size, prioritization of accuracy measures, algorithm portability, and implications for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome, or covariate). Validation work should be part of routine maintenance of RWD sources. This article is part of a Special Collection on Pharmacoepidemiology.

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Prescribing Cascades of Loop Diuretics and Anti-vertigo Drugs Following Treatment with Gabapentinoids and Benzodiazepines: Prescription Sequence Symmetry Analysis of a Large-Scale Claims Database Including Japanese Older Adults

Omata R., Asami A., Hara A., Urushihara H.

Drugs - Real World Outcomes 11 （ 3 ） 529 - 540 2024年09月

最終著者, 責任著者,  ISSN  21991154

　概要を見る

Background: Gabapentinoids (GBP) and benzodiazepines (BZ) are commonly prescribed in older adults and their package inserts list edema and vertigo as adverse drug reactions. These adverse drug reactions may be treated with symptomatic drug therapies without discontinuing the culprit drugs or decreasing their dose, thereby initiating a prescribing cascade and often resulting in polypharmacy. Whether prescribing cascades occur in the treatment of edema and dizziness among Japanese patients treated with GBP and BZ has not been investigated, including treatment with mirogabalin, a class drug of GBP marketed in Japan. Objective: We aimed to investigate prescribing cascades with GBP-induced and BZ-induced edema and dizziness treated with loop diuretics (LD) and anti-vertigo drugs (AVD), respectively, among older adults. Methods: A prescription sequence symmetry analysis design was used to detect signals of prescribing cascades associated with edema and dizziness induced by GBP and BZ (exposure drugs). Loop diuretics and AVD were the outcome drugs used to identify prescribing cascades following the initiation of exposure drugs. The study population consisted of enrollees of a large-scale health claims database provided by DeSC Healthcare, Inc., between April 2014 and March 2021. Subjects eligible for a prescription sequence symmetry analysis were patients aged ≥ 65 years prescribed an outcome drug within 90 days before and after exposure drug initiation. A signal of a prescribing cascade was detected if secular trend-adjusted sequence ratios were statistically significant on comparison of the frequencies of outcome drug initiation before and after exposure drug initiation. Results: We identified 2671 patients with prescriptions of a GBP-LD combination, 4009 with a GBP-AVD combination, 8675 with a BZ-LD combination, and 9462 with a BZ-AVD combination. The adjusted sequence ratios for GBP-LD and BZ-LD cascades were significantly larger than one (adjusted sequence ratio [95% confidence interval], 1.69 [1.56–1.83]; 1.35 [1.29–1.41], respectively), indicating positive signals of prescribing cascades. No signal was detected for the GBP-AVD or BZ-AVD cascade (0.89 [0.83–0.94]; 0.90 [0.87–0.94], respectively). The adjusted sequence ratio for the mirogabalin cascade was higher than that for pregabalin (2.23 [1.84–2.71] vs 1.59 [1.46–1.73]). Conclusions: Our study provides good evidence that LD-prescribing cascades associated with edema would be a class effect of GBP and BZ. Edema emerging around 1 month after GBP initiation should be carefully differentiated from pathological edema, and undue LD prescription as a prescribing cascade should be avoided.

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Comparison of Regulations for Arsenic and Heavy Metals in Herbal Medicines Using Pharmacopoeias of Nine Counties/Regions

Inada I., Kiuchi F., Urushihara H.

Therapeutic Innovation and Regulatory Science （Therapeutic Innovation and Regulatory Science）  57 （ 5 ） 963 - 974 2023年09月

最終著者, 責任著者,  ISSN  21684790

　概要を見る

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.

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A quality management system aiming to ensure regulatory-grade data quality in a glaucoma registry

Wada S., Tsuda S., Abe M., Nakazawa T., Urushihara H.

PLoS ONE （PLoS ONE）  18 （ 6 June ）  2023年06月

最終著者, 責任著者,  ISSN  1932-6203

　概要を見る

Background Disease/patient registries are underutilized despite their multiple advantages over clinical trials in the clinical evaluation of drugs, such as the capacity for long-term curation, provision of patient outcome data in routine clinical practice, and provision of benchmark data for comparison. Ensuring the fit-for-purpose quality of data generated from such registries is important to informing regulatory decision making. Here, we report the construction of a quality management system aiming to ensure regulatory-grade data quality for a registry of Japanese patients with glaucoma to evaluate long-term patient outcomes. Methods The quality management system was established by reference to the risk-based approach in the ICH-E6 (R2) recommendations. The following three-component approach was taken: establishment of governance, computerized system validation (CSV), and implementation of risk assessment and control. Compliance of the system with the recommendations of regulatory guidelines relevant to use of the registry was assessed. Results Governance by academic collaboration was established. This was followed by the development of a total of 15 standard operating procedures, including CSV, data management, monitoring, audit, and management of imaging data. The data management system was constructed based on a data management plan, which specified data/paper flow and data management procedures. The electronic data capture (EDC) system was audited by an external vendor, and configured and validated using the V-model framework as recommended in the GAMP5 guideline. Informed consent, eligibility assessment and major ophthalmology measurements were determined as Critical to Quality (CTQ) factors. A total of 22 risk items were identified and classified into three categories, and operationalized in the form of a risk control plan, which included training sessions and risk-based monitoring. The glaucoma registry addressed most quality recommendations in official guidelines issued by multiple health authorities, although two recommendations were not met. Conclusions We established and configured a quality management system for a glaucoma registry to ensure fit-for-purpose data quality for regulatory use, and to curate long-term follow-up data of glaucoma patients in a prospective manner.

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Risk of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Associated With Antibiotic Use: A Case-Crossover Study

Fukasawa T., Urushihara H., Takahashi H., Okura T., Kawakami K.

Journal of Allergy and Clinical Immunology: In Practice （Journal of Allergy and Clinical Immunology: In Practice）  2023年

最終著者, 責任著者,  ISSN  22132198

　概要を見る

Background: Evidence is lacking on the association between antibiotic use and risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asians. Objective: We assessed the risk of SJS/TEN associated with different antibiotic classes in Japanese. Methods: We conducted a case-crossover study using a claims database. Firth conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of SJS/TEN associated with antibiotic use in a 56-day hazard period versus 3 control periods. We created 18 cohorts for each antibiotic class and calculated 56-day cumulative incidence per 100,000 new users. The association between antibiotic class and SJS/TEN was also evaluated in each case using the ALgorithm of Drug causality for Epidermal Necrolysis (ALDEN). Results: Our case-crossover study included 170 SJS/TEN cases. Increased ORs were observed for lincomycins (OR, 33.00 [95% CI, 3.74-4332.05]), trimethoprim-sulfamethoxazole (21.20 [6.73-105.98]), penicillins (14.39 [6.95-34.21]), glycopeptides (14.37 [3.17-136.10]), cephalosporins (7.06 [4.25-12.21]), aminoglycosides (6.55 [1.97-26.84]), quinolones (5.98 [3.34-11.20]), fosfomycin (5.40 [1.20-30.97]), carbapenems (5.09 [1.85-15.64]), tetracyclines (4.95 [1.78-15.27]), and macrolides (3.78 [2.13-6.83]). Cumulative incidence of SJS/TEN was 67.4 for trimethoprim-sulfamethoxazole, 86.2 for glycopeptides, and below 10.0 for the others. Despite the high incidence, only 2 cases had a probable causal relationship with glycopeptides. Conclusion: Some antibiotic classes, including lincomycins, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, were newly suggested to be associated with risk of SJS/TEN; considered together with the high incidence for trimethoprim-sulfamethoxazole and glycopeptides, these findings warrant caution in clinical practice.

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【薬剤疫学の医療への貢献】日本薬剤疫学会専門家認定制度「認定薬剤疫学家」について

漆原 尚巳, 大場 延浩

Precision Medicine(2434-3625) 5 （ 14 ） 1264 - 1266 2022年12月

研究論文（学術雑誌）, 筆頭著者

診療報酬請求情報データベースを用いた、妊婦における抗精神病薬使用実態調査

座古 梨央(慶応義塾大学 薬学部薬学科医薬品開発規制科学講座), 原 梓, 汐月 雄一, 漆原 尚巳

薬剤疫学(1342-0445) 27   S42 - S43 2022年11月

責任著者

高齢者におけるベンゾジアゼピン系睡眠薬・ガバペンチノイドによるめまい及び浮腫に関する処方カスケードの検討

小俣 理奈(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 漆原 尚巳

薬剤疫学(1342-0445) 27   S58 - S59 2022年11月

責任著者

医療情報データベース研究のためのアウトカム定義レポジトリ　Relevance of Outcome Definition Repository

漆原 尚巳

薬剤疫学(1342-0445) 27   S67 2022年11月

研究論文（学術雑誌）, 筆頭著者

The Kawasaki Aging and Wellbeing Projectのデータを用いた生活習慣病に関する診療報酬請求データによる疾患定義の妥当性の検討

猪澤 一樹(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 原 梓, 佐々木 貴史, 安藤 崇之, 阿部 由紀子, 色本 涼, 新井 康通, 漆原 尚巳

薬剤疫学(1342-0445) 27   S81 - S82 2022年11月

研究論文（学術雑誌）, 責任著者

BERTを用いた糖尿病治療薬における有害事象間の潜在的関連性の探索

八重樫 昇吾(慶応義塾大学 薬学研究科医薬品開発規制科学講座), 石川 智貴, 安藤 崇之, 原 梓, 大石 尚央, 漆原 尚巳

薬剤疫学(1342-0445) 27   S99 - S100 2022年11月

責任著者

大規模診療報酬請求情報データベースを用いた小児インフルエンザ外来患者に対する抗菌薬処方実態調査

鎗田 大地(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 木村 真也, 野口 亮, 漆原 尚巳

薬剤疫学(1342-0445) 27   S116 - S117 2022年11月

責任著者

日本・米国・英国における小児用医薬品の開発推進策と承認状況

諏訪 美月(慶応義塾大学 薬学部医薬品開発規制科学講座), 三宅 真二, 漆原 尚巳

臨床薬理(0388-1601) 53巻 （ 6号 ） 225 - 234 2022年11月

研究論文（学術雑誌）, 責任著者

Real-time survey of vaccine safety of the MRNA-1273 SARS-COV-2 vaccine in workplace vaccination at Keio university

Hara Azusa, Okumura Kaho, Inada Isa, Sugiyama Daisuke, Hoshino Takahiro, Yakoh Takahiro, Yokoyama Hirokatsu, Urushihara Hisashi

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY （Vaccines）  31 （ 9 ） 425 - 425 2022年09月

研究論文（学術雑誌）,  ISSN  1053-8569

　概要を見る

The mRNA-1273 Moderna COVID-19 vaccine was introduced to combat the COVID-19 global pandemic in 2020. Although the safety of the vaccine has been investigated worldwide, real-world safety data is scarce in Japan. An online, real-time survey of adverse events following immunization (AEFIs) with mRNA-1273 was conducted in the setting of a workplace vaccination program at the School of Pharmacy, Keio University from 26 June 2021, to 11 June 2022. Participants were requested to take four surveys during a seven-day follow-up period after each of the first, second, and third booster doses. The maximum number of responses, from 301 respondents, was obtained on day 0 (vaccination date) for the first dose. 98% of respondents reported local and systemic AEFIs for the second dose on day 1. No noticeable difference in local reactions was seen among the three doses. Females reported more AEFIs than males, and the young group (18–29 years) reported a higher rate than the middle age group (≥30 years) after the first dose. Age and gender differences in rates decreased at the second and third doses. This survey confirmed that the safety profile of mRNA-1273 in a real-world setting was similar to that derived from the clinical trials, and that the agent was well-tolerated.

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解説　2021年6月施行「人を対象とする生命科学・医学系研究に関する倫理指針」の概要について

漆原 尚巳

日本臨床腫瘍薬学会雑誌(2189-129X) 26   23 - 27 2022年07月

研究論文（学術雑誌）, 筆頭著者

リアルワールドデータを用いて行われた研究の評価項目に関する検討

阿左美 茜(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 原 梓, 漆原 尚巳

日本医薬品情報学会総会・学術大会講演要旨集24回    102 2022年06月

研究論文（その他学術会議資料等）, 責任著者

機械学習を用いた降圧薬および高脂血症用剤における潜在的リスクの予測

佐立 悠(慶応義塾大学 薬学部), 漆原 尚巳, 原 梓

日本薬学会年会要旨集(0918-9823)142年会    28 2022年03月

研究論文（学術雑誌）, 責任著者

大規模診療報酬請求情報データベースを用いた小児インフルエンザ外来患者に対する抗菌薬処方実態調査

安藤 梨花子(慶応義塾大学 薬), 原 梓, 木村 真也, 野口 亮, 漆原 尚巳

日本薬学会年会要旨集(0918-9823)142年会    27 2022年03月

研究論文（学術雑誌）, 責任著者

川崎市在住高齢者を対象としたウェルビイングコホートにおける使用薬剤数と医療・薬剤・介護費の関連についての検討　ベースライン調査

仙石 彩(慶応義塾大学 薬学部薬学科医薬品開発規制科学講座), 原 梓, 佐々木 貴史, 阿部 由紀子, 新井 康通, 漆原 尚巳

日本薬学会年会要旨集(0918-9823)142年会    27 2022年03月

研究論文（学術雑誌）, 責任著者

An NLP-Inspired Data Augmentation Method for Adverse Event Prediction Using an Imbalanced Healthcare Dataset

Ishikawa T., Yakoh T., Urushihara H.

IEEE Access （IEEE Access）  10   81166 - 81176 2022年

最終著者, 責任著者,  ISSN  2169-3536

　概要を見る

This paper proposes a data augmentation method for imbalanced healthcare datasets. This method was inspired by a data augmentation method in natural language processing (NLP) that generates synthetic sentences for training by replacing some words with similar words. The proposed method generates synthetic patient records by replacing patient backgrounds with similar backgrounds. In this paper, the cosine similarity of the distributed representations was used as the similarity metric between patient backgrounds. The distributed representations of the patient backgrounds were generated by the skip-gram model. To confirm the performance improvement with the proposed data augmentation method, the prediction performance of adverse events (AEs) caused by drug administration was experimentally evaluated on a real-world medical dataset with 1,510,137 records. The combination of the proposed data augmentation method and a conventional undersampling method resulted in an 80.0% improvement in accuracy and a 40.0% improvement in the precision and F1-score. The multifaceted evaluation demonstrated that the proposed method is effective, especially for predicting AEs with positive ratios ranging from 1.0% to 2.1%, which are difficult to predict with conventional machine learning methods but should be predictable in the medical field.

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Comparison of Regulations and Status of Promoting Drug Development and Authorization of Pediatric Indications among Japan, the United States and the United Kingdom

Suwa M., Miyake S., Urushihara H.

Japanese Journal of Clinical Pharmacology and Therapeutics （Japanese Journal of Clinical Pharmacology and Therapeutics）  53 （ 6 ） 225 - 234 2022年

最終著者, 責任著者,  ISSN  03881601

　概要を見る

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.

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Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims

Hara A, Hara K, Komeda T, Ogura E, Miyazawa S, Kobayashi C, Fujiwara M, Yoshida M, Urushihara H.

（Pharmacoepidemiol Drug Saf）  2021年12月

研究論文（学術雑誌）

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Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan

Hara A., Hara K., Komeda T., Ogura E., Miyazawa S., Kobayashi C., Fujiwara M., Yoshida M., Urushihara H.

Pharmacoepidemiology and Drug Safety （Pharmacoepidemiology and Drug Safety）  31 （ 6 ） 623 - 631 2021年12月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り,  ISSN  1099-1557

　概要を見る

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.

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Behavioral changes and hygiene practices of older adults in Japan during the first wave of COVID-19 emergency

Arai Y., Oguma Y., Abe Y., Takayama M., Hara A., Urushihara H., Takebayashi T.

BMC Geriatrics （BMC Geriatrics）  21 （ 1 ）  2021年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Background: On April 7, 2020, Japan declared a state of emergency due to the first wave of coronavirus disease 2019 (COVID-19) with the associated social distancing likely to have had a great impact on older adults’ lifestyle and health. This study aimed to explore the behavioral changes and personal hygiene practices in relation with background psychosocial and health characteristics of older adults during the COVID-19 emergency. Methods: A cross-sectional telephonic survey was conducted with the participants of the Kawasaki Aging and Wellbeing Project (KAWP), an on-going longitudinal cohort study of older adults aged 85 or older. The interviews were conducted using a structured questionnaire consisting of 11 closed questions regarding behavioral changes and personal hygiene practices during the state of emergency. Sociodemographic and health data were obtained from the KAWP baseline survey conducted 2.2 years before the telephonic survey. Results: Overall, 487 participants from the KAWP responded to the telephonic survey (response rate: 89.2%). 94.5% of the respondents reported no changes in basic lifestyle habits, such as eating, sleeping, smoking, and drinking, whereas 28.1% reported a decrease in physical activity, and 54.6% reported going out less frequently. One-third of the respondents reported a decrease in the number of people to converse with, as well as the amount of time to converse. For personal hygiene practices, 93.8% reported wearing a mask when they went out, and 50.3% reported an increased frequency of handwashing. Multiple logistic regression analysis revealed that engagement in physical activity at baseline (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.23–3.08), smartphone ownership (OR = 2.15, 95% CI = 1.33–3.47), and visual impairment (OR = 1.79; 95% CI = 1.10–2.91) were independently associated with decreased physical activity during the COVID-19 emergency. Female respondents and smartphone ownership were significantly associated with more frequent handwashing. Conclusions: The study revealed that older adults in an urban setting responded to the COVID-19 emergency with behavioral changes. The findings of this study have implications for the design of preventive strategies to maintain the health and wellbeing of at-risk older adults.

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Study factors associated with the incompletion of clinical trials that include pediatric patients: a retrospective analysis of the European Clinical Trials Database and a lesson from the European region

Tanemura N., Sasaki T., Sato J., Urushihara H.

Trials （Trials）  22 （ 1 ）  2021年12月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Background: Incomplete clinical trials for pediatric drug development result in a lack of adequate scientific evidence for providing appropriate medication to pediatric populations; this is especially true for Japan. Thus, using the European Clinical Trials Database (EudraCT), this study aimed to identify the factors related to the study design and administration that lead to incompletion of clinical trials that included pediatric patients. Methods: We focused on clinical trials that included patients under the age of 18 registered in the database, named as the European Clinical Trials Database between January 1, 2014, and December 31, 2018. Two groups of trials were identified: “all cases completed” and “not all cases completed,” reflecting whether they were completed in all participating countries/regions or not. To identify the factors of the occurrence of “not all cases completed,” a logistic regression analysis was performed to calculate the odds ratios and 95% confidence intervals. In total, 142 clinical trials (95 “all cases completed” and 47 “not all cases completed”) were analyzed. Results: The logistic regression analysis showed the number of countries in which a clinical trial was conducted to be the only significant factor (odds ratio: 1.3; 95% confidence interval: 1.1-1.5); this was identified as the primary factor for the occurrence of “not all cases completed” in the clinical trials that included pediatric patients. Conclusion: Our findings suggest that the feasibility of clinical trials that include pediatric patients, such as whether the countries in which the trial is to be conducted are suitable, must be considered prior to the trial.

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Lifestyle behaviors associated with the initiation of renal replacement therapy in Japanese patients with chronic kidney disease: a retrospective cohort study using a claims database linked with specific health checkup results

Hara A., Hirata T., Okamura T., Kimura S., Urushihara H.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine）  26 （ 1 ） 102 - 102 2021年12月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  1342078X

　概要を見る

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.

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日本・米国・英国における小児用医薬品の開発推進策と承認状況調査

諏訪 美月(慶応義塾大学 薬学部医薬品開発規制科学講座), 三宅 真二, 漆原 尚巳

日本臨床薬理学会学術総会抄録集(2436-5580)42回    1 2021年12月

責任著者

日本と欧州における希少疾病用医薬品の指定取り消し理由と開発の実態調査

野口 千鶴(慶応義塾大学 薬学部医薬品開発規制科学講座), 三宅 真二, 漆原 尚巳

日本臨床薬理学会学術総会抄録集(2436-5580)42回    2 2021年12月

責任著者

医療情報データベースを用いるためのOutcome Definition Repository(ODR)の構築　日本薬剤疫学ODR-Task Force報告

井上 慧哉(慶応義塾大学 大学院薬学研究科), 岩上 将夫, 小野 利展, 北島 行雄, 木村 友美, 佐藤 泉美, 杉田 玲夢, 杉山 大典, 原 梓, 宮崎 真, 米倉 寛, 漆原 尚巳

薬剤疫学(1342-0445) 26   S158 - S159 2021年11月

研究論文（学術雑誌）, 責任著者

医療情報データベースを用いた日本の抗菌薬による感染症治療の実態調査

雨宮 優理(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 田中 啓太, 漆原 尚巳

薬剤疫学(1342-0445) 26   S106 - S107 2021年11月

研究論文（学術雑誌）, 責任著者

有害事象予測に向けたElectronic Hospital Recordsに対する分散表現の適用

石川 智貴(慶応義塾大学 大学院理工学研究科総合デザイン工学専攻), 矢向 高弘, 漆原 尚巳

薬剤疫学(1342-0445) 26   S119 - S120 2021年11月

研究論文（学術雑誌）

抗菌薬・抗真菌薬の使用とスティーヴンス・ジョンソン症候群及び中毒性表皮壊死症のリスク

深澤 俊貴(京都大学 大学院医学研究科社会健康医学系専攻薬剤疫学分野デジタルヘルス学講座), 漆原 尚巳, 高橋 勇人, 川上 浩司

薬剤疫学(1342-0445) 26   S131 - S132 2021年11月

研究論文（学術雑誌）

三本の矢(マッチング、自己対照、トレンド分析)によるバロキサビルマルボキシルの出血リスク評価

米田 卓司(塩野義製薬 データサイエンス部), 原 梓, 原 華苗, 小倉 江里子, 藤原 正和, 宮澤 昇吾, 吉田 真奈美, 漆原 尚巳

薬剤疫学(1342-0445) 26   S137 - S138 2021年11月

研究論文（学術雑誌）, 責任著者

診療報酬請求データベースを用いた新型コロナウイルス感染症患者の重症化予測モデルの構築、及び重症化因子の探索

八重樫 昇吾(慶応義塾大学 大学院薬学研究科), 漆原 尚巳, 宮澤 孝慈, 市原 泰介, 山田 雄矢, 星野 崇宏

薬剤疫学(1342-0445) 26   S140 - S141 2021年11月

研究論文（学術雑誌）, 責任著者

慶応義塾大学薬学部におけるCOVID-19ワクチン職域接種サーベイランス(中間報告)

奥村 佳穂(慶応義塾大学 薬学部医薬品開発規制科学講座), 原 梓, 杉山 大典, 星野 崇宏, 矢向 高弘, 横山 裕一, 漆原 尚巳

薬剤疫学(1342-0445) 26   S143 - S144 2021年11月

研究論文（学術雑誌）, 責任著者

本邦における前立腺肥大症治療薬のアドヒアランス調査

前川 拓也(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 原 梓, 漆原 尚巳

薬剤疫学(1342-0445) 26   S145 - S146 2021年11月

研究論文（学術雑誌）, 責任著者

使用成績調査の代替としてのRWDを用いた医薬品の有用性評価に関する研究

川上 峻弥(慶応義塾大学 大学院薬学研究科医薬品開発規制科学講座), 星野 崇宏, 原 梓, 漆原 尚巳

薬剤疫学(1342-0445) 26   S154 - S155 2021年11月

研究論文（学術雑誌）, 責任著者

Believability of real-world evidence (RWE) for informed regulatory decisions

Leclerc Jacinthe, Brodovicz Kimberly G., Chang Stephen, Assimon Magdalene M., Urushihara Hisashi, Girman Cynthia J.

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 30   3 - 3 2021年08月

最終著者, 責任著者,  ISSN  1053-8569

Comparison of the incidence of bleeding between anti-influenza drugs among outpatients for the influenza virus infection: A retrospective study using an employment-based health insurance claims database in Japan

Hara Azusa, Hara Kanae, Komeda Takuji, Ogura Eriko, Miyazawa Shogo, Kobayashi Chiduru, Fujiwara Masakazu, Yoshida Manami, Urushihara Hisashi

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 30   182 - 183 2021年08月

最終著者, 責任著者,  ISSN  1053-8569

Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case–control and cohort studies

Fukasawa T., Takahashi H., Takahashi K., Tanemura N., Amagai M., Urushihara H.

Allergology International （Allergology International）  70 （ 3 ） 335 - 342 2021年07月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り,  ISSN  13238930

　概要を見る

Background: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. Methods: We conducted a matched case–control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. Results: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of “probable” or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated “unlikely” in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were “very unlikely”. Conclusions: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

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Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer

Maeda H., Takeda K., Urushihara H., Kurokawa T.

Cancer Reports （Cancer Reports）  4 （ 3 ）  2021年06月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Background: The purpose of this study was to investigate the correlation between overall survival (OS) and other clinical outcomes in patients with prostate cancer. Further, we conducted subgroup analysis in the correlation of OS. Aim: This study intended to investigate potential surrogate endpoints of OS for prostate cancer by examining the correlation between OS and the other endpoints. Methods: We performed a systematic review through a literature search by computer-based searches of the Medline database (January 1965 and May 2014). Results: The contents of 115 studies with endpoint as OS were analyzed in our study. Our results showed that 47.8% (55/115) of the studies used progression-free survival as an endpoint besides OS, followed by time to progression (43.5% [50/115]) and PSA response (40.9% [47/115]). Also, the relationship between OS and each surrogate endpoint was examined using the hazard ratio (HR) by a Bayesian hybrid model for random effect multivariate meta-analysis. Our results showed that the endpoint that had the highest correlation with OS was progression-free survival (PFS) with an estimated marginal correlation of 0.939 (95%CI: 0.900, 0.967). Furthermore, our stratified analysis identified PFS in castration-resistant prostate cancer patients (0.937), in sensitive patients (0.932), in none of chemotherapy patients (0.929), in first line of the chemotherapy (0.948), in patients who received no Docetaxel previously (0.942), in both symptomatic and asymptomatic patients (0.950), in patients who received only chemotherapy (0.956), and in phase III (0.960), time to progression (TTP) in castration-resistant prostate cancer (CRPC) patients (0.942), in metastasis patients (0.948), in both symptomatic and asymptomatic patients (0.953), in patients who received only chemotherapy (0.938), and in Phase III (0.927) as endpoints, which showed a lower limit for 95% CI of estimated marginal correlation ≥0.850 with overall survival. Conclusions: Our study suggests that PFS is a potential surrogate endpoint of OS in clinical trials for patients with prostate cancer. It also suggests potential surrogate endpoints for CRPC and locally advanced prostate cancer.

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Study factors associated with the incompletion of clinical trials that include pediatric patients: a retrospective analysis of the European Clinical Trials Database and a lesson from the European region

Tanemura N, Sasaki T, Sato J, Urushihara H.

Trials 2021年03月

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電子診療録由来の診療情報データベースを用いたコントロール不良の小児喘息患者を対象としたモンテルカストと吸入ステロイド薬の有効性比較可能性の検討

高橋 透(慶応義塾大学 院薬), 漆原 尚巳

日本薬学会年会要旨集(0918-9823)141年会    27 2021年03月

研究論文（学術雑誌）, 責任著者

大規模病院情報データベースを用いた認知症患者における抗精神病薬の使用実態調査

佐藤 應気(慶応義塾大学 薬), 漆原 尚巳

日本薬学会年会要旨集(0918-9823)141年会    27 2021年03月

研究論文（学術雑誌）, 責任著者

Behavioral changes and hygiene practices of older adults in Japan during the first wave of COVID-19 emergency

Arai Y, Oguma Y, Abe Y, Takayama M, Hara A, Urushihara H, Takebayashi T.

BMC Geriatr 2021年02月

研究論文（学術雑誌）

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Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case-control and cohort studies

Fukasawa T, Takahashi H, Takahashi K, Tanemura N, Amagai M, Urushihara H.

Allergol Int    335 - 342 2021年02月

研究論文（学術雑誌）, 共著

Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer

Maeda H, Takeda K, Urushihara H, Kurokawa T.

Cancer Rep (Hoboken) 2021年01月

研究論文（学術雑誌）

Regulatory Science Meets Epidemiology.

漆原 尚巳

薬剤疫学 （一般社団法人 日本薬剤疫学会）  26 （ Supplement ） S47 - S47 2021年

最終著者, 責任著者,  ISSN  13420445

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医療情報データベースを用いるための Outcome Definition Repository（ODR）の構築 ―日本薬剤疫学会 ODR-Task Force 報告―

井上 慧哉, 岩上 将夫, 小野 利展, 北島 行雄, 木村 友美, 佐藤 泉美, 杉田 玲夢, 杉山 大典, 原 梓, 宮崎 真, 米倉 寛, 漆原 尚巳

薬剤疫学 （一般社団法人 日本薬剤疫学会）  26 （ Supplement ） S158 - S159 2021年

最終著者, 責任著者,  ISSN  13420445

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• CiNii Research

欧米の動向を踏まえた、日本における抗てんかん薬の開発を目的とした小児臨床試験の有効性評価項目に関する実態調査

小坂 麻里子(慶応義塾大学 薬学部医薬品開発規制科学講座), 漆原 尚巳, 種村 菜奈枝

臨床薬理(0388-1601) 51   S366 2020年10月

研究論文（学術雑誌）, 責任著者

The first survey of gap between the actual labelling and efficacy information of functional substances in food under the regulatory processes in Japan

Tanemura N., Machii Y., Urushihara H.

Journal of Functional Foods （Journal of Functional Foods）  72 2020年09月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  17564646

　概要を見る

© 2020 The Author(s) To make well-informed choices, consumers need access to reliable and clear messages regarding the benefits of functional substances in food. This study identified foods with function claims (FFCs) in Japan that had a gap between actual labeling and efficacy information of functional substances not visible on their food package. Between April 1, 2015, to July 20, 2018, 1,310 FFCs were submitted to the regulatory agency and analyzed. The proportion of FFCs with a gap was highest in the health claim category of blood pressure management (79.5%), followed by neutral fat reduction in blood (75%) and suppression of blood sugar spikes (73.4%). These gaps are attributable to differences in food development strategy. Thus, to ensure the quality of benefit communication on FFC to consumers, scientific evidence regarding health claims of functional substances should be managed in an integrated manner.

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Real World Survey of Patient Engagement Status in Clinical Research: The First Input from Japan

Tanemura N., Sasaki T., Sato J., Urushihara H.

Patient （Patient）  13 （ 5 ） 623 - 632 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1178-1661

　概要を見る

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.

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自発報告に基づくシグナル検出ができること，できないこと ―その理論と実践―

漆原尚巳

医薬品情報学 21 （ 4 ） 135 - 141 2020年

研究論文（学術雑誌）, 単著, 筆頭著者, 最終著者, 責任著者, 査読有り

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Survey on off-label use of antineoplastic agents in pediatric patients using a large-scale medical database in japan

Kuroda M., Nakamura A., Tanemura N., Nakakuni M., Sato J., Urushihara H.

Japanese Journal of Clinical Pharmacology and Therapeutics （Japanese Journal of Clinical Pharmacology and Therapeutics）  51 （ 6 ） 307 - 316 2020年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  03881601

　概要を見る

A number of drugs without pediatric indication are used off-label in infants and children who are described as "therapeutic orphans". This practice is widespread and constitutes a global issue. We conducted a drug utilization study using a large-scale electronic medical record(EMR)database to explore off-label prescription of anticancer drugs in pediatric patients. The EMR database was provided by Medical Data Vision(MDV). The subjects of the present study were pediatric patients aged from 0 to 14 years who were prescribed anticancer drugs and enrolled in the database between January 2016 and December 2017. We surveyed the number of patients who were prescribed these drugs outside the approved age window. Of 700 pediatric patients included in this study, 277 patients(40％) were prescribed anticancer drugs off-label; especially, 182 patients were prescribed"cytotoxic antibiotics and related substances"according to the WHO ATC classification, predominantly pirarubicin(140 patients). Since pirarubicin has not been approved in overseas countries, it is difficult to apply for pediatric indication utilizing the development promotion schemes such as the"public knowledge-based application(kouchi-shinsei)", and other drug development schemes have to be considered. Only a few subjects(0 to 3％)were prescribed anticancer drugs with pediatric indication but outside the approved age range. The prescribed doses［median(min-max)］of methotrexate and cytarabine were 15(2.8-21200)mg and 60(3-9000)mg, respectively. The dose ranges of these drugs were wide compared to the other drugs in the study. It was speculated that these high doses were probably used as high-dose therapy according to clinical guidelines, within the framework of clinical research. Considering that anticancer drugs generally have narrow safety margins, drug development for approval of pediatric indication should be promoted to provide safe and effective treatments for pediatric patients.

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大規模病院情報データベースを用いた小児患者における抗悪性腫瘍薬の適応外使用に関する実態調査

2. 黒田万由子, 中村彩夏, 種村菜奈枝, 中國正祥, 佐藤淳子, 漆原尚巳

臨床薬理 51 （ 6 ） 307 - 316 2020年

共著, 責任著者

機械学習を用いた医薬品の潜在的リスクの予測

西川 景太(慶応義塾大学), 種村 菜奈枝, 矢向 高弘, 漆原 尚巳

医療情報学連合大会論文集(1347-8508)39回     512 - 513 2019年11月

研究論文（学術雑誌）, 責任著者

Influenza vaccination effectiveness for people aged under 65 years in Japan, 2013/2014 season: Application of a doubly robust method to a large-scale, real-world dataset

Shibata N., Kimura S., Hoshino T., Urushihara H.

BMC Infectious Diseases （BMC Infectious Diseases）  19 （ 1 ） 586 2019年07月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り

　概要を見る

© 2019 The Author(s). Background: Influenza vaccination is recognized as a primary public health intervention which prevents the illness of patients and relieves the societal burdens of influenza for medical community as well as the economy. To date, no effectiveness study of influenza vaccination has been conducted including a large population with a wide age span, in Japan. Here, we evaluated the clinical effectiveness of influenza vaccination in a large Japanese population. Methods: We conducted a cohort study using a large-scale claims database for employee health care insurance plans. Vaccination status was identified using plan records for influenza vaccination subsidies. We excluded people aged 65 years or more because of the unavailability of vaccination records. Effectiveness of vaccination in preventing influenza and its complication was evaluated with doubly robust methods using inversed probability treatment weighting to adjust health conscious behaviours and other confounders. Results: During the 2013/2014 influenza season, 369,425 subjects with age range from 1 to 64 years were eligible. Vaccination rate was 39.5% and an estimated odds ratio (OR) for influenza onset was 0.775 after doubly robust adjustment. Age-stratified ORs were significantly reduced in all age groups; lowest in subjects aged 1 to 4 years (0.600) and highest in those aged 13 to 19 (0.938). ORs for all the influenza complication outcomes were also statistically significant (0.403-0.709). Conclusions: We confirmed the clinical effectiveness of influenza vaccination in people aged 1 to 64 years. Influenza vaccination significantly prevented influenza onset and was more effective in reducing secondary risks of influenza complications.

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悪性腫瘍に関する医師主導臨床試験の結果公表状況調査

八田朋大, 三宅真二, 山川直利, 漆原尚巳

レギュラトリーサイエンス学会誌 2019年

薬学部におけるレギュラトリーサイエンスの基礎となる医薬品開発教育の実態調査

崔允瑄, 三宅真二, 種村菜奈枝, 漆原尚巳

レギュラトリーサイエンス学会誌 9 （ 3 ）  2019年

Utility of a specific health checkup database containing lifestyle behaviors and lifestyle diseases for employee health insurance in Japan

Fukasawa T., Tanemura N., Kimura S., Urushihara H.

Journal of Epidemiology （Journal of Epidemiology）  30 （ 2 ） 57 - 66 2019年

共著, 最終著者, 責任著者, 査読有り,  ISSN  09175040

　概要を見る

© 2019 Toshiki Fukasawa et al. T. Background: The Japanese Ministry of Health, Labour and Welfare introduced Specific Health Checkups (SHC) to identify individuals at risk of metabolic syndrome (MS). This study aimed to describe the SHC database developed by the Japan Medical Data Center Co., Ltd. (JMDC) as a means of exploring lifestyle behaviors and lifestyle diseases among working generations. Methods: We conducted a retrospective, cross-sectional study of employees and their families using the JMDC-SHC database to describe the prevalence of lifestyle behaviors (smoking, exercise, dietary habits, drinking habits, and sleeping) and lifestyle diseases (MS, hypertension, dyslipidemia, and diabetes mellitus). Results were compared with data from the 2015 National Health and Nutrition Survey (NHNS) in Japan as a benchmark. Results: All 646,869 enrollees in the JMDC-SHC database were included, of whom 66.5% were men. Age ranged from 40–74 years. Compared with the results of the NHNS, the JMDC-SHC subjects were younger and had fewer MS components and a lower prevalence of diabetes and hypertension. Subjects in their 40s were most likely to have unhealthy lifestyle behaviors in all age groups (eg, smoking: 41.0% in men and 10.2% in women). The SHC group had more favorable behaviors overall, but underweight was more prevalent in the SHC females. Conclusions: The JMDC-SHC population showed different lifestyle and lifestyle disease profiles to the NHNS population, probably due to its different age, gender, and employment distributions. Development of healthcare policies and plans for working generations would benefit from the selection of an age-and employment-appropriate database.

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Secular trend in the incidence of thyroid cancer undergoing thyroidectomy among employed Japanese from 2005 to 2014: a retrospective descriptive study using an employment-based insurance claims database

Noguchi Y, Urushihara H, Sakata Y, Nagamune H, Daidoji K, Ishii M, Geary S

Journal of Thyroid Cancer 1 （ 2 ） 5 - 15 2019年

Pediatric off-label use of psychotropic drugs approved for adult use in Japan in the light of approval information regarding pediatric patients in the United States: a study of a pharmacy prescription database

Tanemura N., Asawa M., Kuroda M., Sasaki T., Iwane Y., Urushihara H.

World Journal of Pediatrics （World Journal of Pediatrics）  15 （ 1 ） 92 - 99 2019年

ISSN  17088569

　概要を見る

© 2018, Children's Hospital, Zhejiang University School of Medicine. Background: Off-label use of psychotropic prescriptions for pediatric patients has been increasing in Japan. This study sought to clarify pediatric patients’ off-label use of psychotropics approved only for adults in Japan. Methods: This retrospective study on psychotropic utilization employed a pharmaceutical health insurance claims database supplied by a pharmacy for the fiscal year 2016. Seven psychotropic drugs were examined. For each drug, we calculated the proportion of patients aged < 16 years or who were under the approved age limit set in the United States out of all patients. The maximum daily dose of each drug within the study period was plotted by age. Results: Data of 45,715 patients (female: 26,799, male: 18,916) with 331,920 prescriptions were examined in this study. For each drug, the proportion of pediatric patients aged < 16 years ranged from 0.15 to 1.1%, while the proportion of those under the approved age limit in the United States ranged from 0 to 0.27%. Olanzapine had the highest reported proportion. No drugs other than olanzapine were taken under the approved age limit in the United States. Conclusions: We identified the pediatric off-label use of psychotropics that were limited to adult use in Japan. The results indicated the possibility of referring to international guidelines or evidence in clinical practice, but these factors do not discount the existing problems with off-label use. More clinical trials within the pediatric population in Japan are needed to address the issue of off-label use and obtain useful and reliable information in the package inserts for rational use in future pediatric patients.

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Comparative effectiveness and safety of warfarin and dabigatran in patients with non-valvular atrial fibrillation in Japan: A claims database analysis

Koretsune Y., Yamashita T., Yasaka M., Ono Y., Hirakawa T., Ishida K., Kuroki D., Sumida T., Urushihara H.

Journal of Cardiology （Journal of Cardiology）  73 （ 3 ） 204 - 209 2019年

ISSN  09145087

　概要を見る

© 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.

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Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan

Fukasawa T., Takahashi H., Kameyama N., Fukuda R., Furuhata S., Tanemura N., Amagai M., Urushihara H.

PLoS ONE （PLoS ONE）  14 （ 8 ） e0221130 2019年

最終著者, 責任著者, 査読有り

　概要を見る

© 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.

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Medications and fall risk: a case-control study in nursing home residents in Japan

2. Park H, Satoh H, Miki A, Maki H, Asai K, Shiraishi A, Urushihara H, Sawada Y.

Aging clinical and experimental research 2019年

Medications and fall risk: a case–control study in nursing home residents in Japan

Park H., Satoh H., Miki A., Maki H., Asai K., Shiraishi A., Urushihara H., Sawada Y.

Aging Clinical and Experimental Research （Aging Clinical and Experimental Research）  32 （ 5 ） 885 - 892 2019年

ISSN  15940667

　概要を見る

© 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.

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Effects of polypharmacy and anticholinergic/sedative drugs on the physical/cognitive/ mental related outcomes of community-dwelling elderly people: The kawasaki wellbeing project

Tanaka A., Arai Y., Hirata T., Abe Y., Oguma Y., Urushihara H.

Japanese Journal of Geriatrics （Japanese Journal of Geriatrics）  56 （ 4 ） 504 - 515 2019年

ISSN  03009173

　概要を見る

© 2019, Japan Geriatrics Society. All rights reserved. Aim: To assess the burdens of polypharmacy and the drug burden index in community-dwelling elder people. Methods: The survey was conducted on 396 participants who participated in The Kawasaki Wellbeing Project from March to December 2017. We investigated the associations between the drug burden and the physical/cognitive/mental outcomes. The drug burden was determined by calculating the number of medications and the drug burden index (DBI) based on the use of anticholinergic and sedative drugs. A multivariate regression analysis was conducted for the outcome measures ADL, IADL, MMSE, J-CHS, and EQ5D5L after adjusting for the sex, age, number of diseases, education level, smoking history, and alcohol history. Results: A total of 389 subjects were analyzed, the mean age of the population was 86 years old, and 187 people (48%) were male. Polypharmacy was reported in 243 people (62%), and DBI exposure was reported for 142 people (36.5%). We found that this population was physically healthy, with a median ADL of 100, and had high quality of life, with a median EQ5D5L of 0.895. Polypharmacy was found to be related to the J-CHS (β: 0.04) and EQ5D5L (-0.01). The DBI was also related to the EQ5D5L (-0.04). Conclusion: These results showed that even though this population was healthier than the general Japanese elderly population, the drug burden of polypharmacy and high dosages of anticholinergic/sedative drugs exerted significant negative effects on frailty and the quality of life. Additional research should be conducted to investigate the long-term effects of polypharmacy and anticholinergic/sedative drugs on elderly people.

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Differences in efficacy evaluation endpoints in clinical trials for claiming reduction of post-prandial glycemic response between Japan and the European Union

Tanemura N., Ito K., Hamadate N., Koshizaka M., Urushihara H.

Critical Reviews in Food Science and Nutrition （Critical Reviews in Food Science and Nutrition）  60 （ 21 ） 3589 - 3593 2019年

ISSN  10408398

　概要を見る

© 2019, © 2019 Taylor & Francis Group, LLC. When evaluating the efficacy of foods with health claims (FHC), each country sets different standards for efficacy evaluation endpoints in clinical trials, which may result in a barrier, namely the case that the claim that is allowed in Japan cannot be used on the label in another region and vice versa. We aimed to investigate the efficacy evaluation endpoints used in clinical trials of FFCs containing ID and submitted in Japan, in reference to the EU requirements for substantiating the claim, namely “reduction of post-prandial glycemic responses”. We detected only one difference in efficacy evaluation endpoints, which was insulin levels. We found 67 such clinical trials cited in systematic literature reviews on finished products or functional substance(s). Of these, 43 (64%) trials lacked insulin assessment. Particularly, for foods that were claimed to reduce post-prandial glycemic responses, the EU does not consider a claim to be substantiated unless insulin levels have been evaluated. Our findings suggest the need for standardization of requirements for FHC between Japan and the EU. This consideration will strengthen the evidence for clinical significance of ID and allow products labeled with this health claim to be more widely distributed.

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Application of adaptive designs in clinical trials in Japan and the United States

Yamakawa N., Teramukai S., Hatta T., Urushihara H.

Japanese Journal of Clinical Pharmacology and Therapeutics （Japanese Journal of Clinical Pharmacology and Therapeutics）  50 （ 4 ） 149 - 156 2019年

ISSN  03881601

　概要を見る

© 2019 the Japanese Society of Clinical Pharmacology and Therapeutics(JSCPT) Clinical trials using adaptive designs(AD)are more flexible in study design and implementation compared to conventional fixed designs. In the US, the draft guidance documentËAdaptive Design Clinical Trials for Drugs and BiologicsÌwas issued by the FDA in 2010, and many studies using AD have been performed. On the other hand, the situation of practical application of AD to clinical trials in Japan has not been reported and no guidance has been issued. We investigated the use of AD in both Japan and the US by searching public clinical trial registration databases in both countries. Four databases were used for searching clinical trials carried out in Japan, and one database for the US. We included clinical trials using AD registered between January 1, 2013 and December 31, 2017. Twenty-four AD trials conducted in Japan and 97 conducted in the US were identified. The AD were used mainly in the early phase of clinical development. Of the 24 trials conducted in Japan, 23 were sponsored by pharmaceutical companies. In particular, AD were frequently used in clinical trials led by global pharmaceutical companies and overseas affiliate of Japanese companies. In the US, the numbers of domestic AD trials and multinational AD trials were almost the same, and some of them were led by academic institutions. These findings suggest that Japanese companies have limited experience in using AD, and that AD are not yet popular in Japan. Efforts to enhance understanding of AD, such as issuing guidance by regulatory authorities in Japan, are needed to promote diffusion of efficient clinical development using AD.

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地域在住高齢者におけるポリファーマシーと抗コリン作動薬及び鎮静作用薬が身体・認知・精神に与える影響の評価：The Kawasaki Wellbeing Project

6. 田中あさひ, 新井康通, 平田匠, 阿部由紀子, 小熊祐子, 漆原尚巳.

日本老年医学会雑誌 56 （ 4 ） 504 - 515 2019年

責任著者

Persistence of oral antidiabetic treatment for type 2 diabetes characterized by drug class, patient characteristics and severity of renal impairment: A Japanese database analysis

Kadowaki T., Sarai N., Hirakawa T., Taki K., Iwasaki K., Urushihara H.

Diabetes, Obesity and Metabolism （Diabetes, Obesity and Metabolism）  20 （ 12 ） 2830 - 2839 2018年07月

ISSN  1463-1326

　概要を見る

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Aim: To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. Materials and Methods: This retrospective, observational study extracted data from a large-scale hospital database (April 2008 to September 2016). Patients with T2DM aged ≥40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or α-glucosidase inhibitors [α-GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan–Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: ≥90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). Results: We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, α-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for α-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1–G4+), followed by BGs at stages G1/G2. Conclusions: The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+.

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【Real World Data(実臨床データ)を用いた臨床疫学研究】 Real World Dataを用いた薬剤疫学研究の薬事利用に関する一考察　GCP renovationにおける"Fit-for-purpose data quality"の実践

漆原尚巳 and 種村菜奈枝

医学のあゆみ 265 （ 11 ） 945 - 951 2018年06月

ISSN  0039-2359

　概要を見る

薬剤疫学は、各国における薬事制度に立脚し、おもに日常診療で得られるデータReal World Data(RWD)に基づき、医薬品の市販後安全性確保と適正使用に資するエビデンスの創生を目的とする学問である。しかし、この分野では新医薬品の承認審査への応用をめざすエビデンス創出についてはほとんど議論されてこなかった。2017年2月にICHが公表したGCP renovationでは、RWDを用いた観察研究を含むさまざまな研究デザインにより生み出されるエビデンスを薬事承認申請に用いる方針が示され、これらのあらたな研究デザインに関する規定が次世代のGCPに盛り込まれることが謳われている。本稿では、薬事上の意思決定において、利用目的に応じたデータ品質水準、Fit-for-purpose data qualityの観点から、RWDを利用する際に求められるデータ品質に関する考察を行う。(著者抄録)

Effectiveness of influenza vaccination for children in Japan: Four-year observational study using a large-scale claims database

Shibata N., Kimura S., Hoshino T., Takeuchi M., Urushihara H.

Vaccine （Vaccine）  36 （ 20 ） 2809 - 2815 2018年05月

最終著者, 責任著者, 査読有り,  ISSN  0264-410X

　概要を見る

© 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.

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Evaluation of randomized controlled trials of foods with functional claims request: The learning outcomes from studies in Japan

Tanemura N., Hamadate N., Urushihara H.

Journal of Functional Foods （Journal of Functional Foods）  42   248 - 253 2018年03月

ISSN  17564646

　概要を見る

© 2018 Elsevier Ltd A new system for foods with functional claims (FFC) was implemented in April 2015. The efficacy of FFC must now be proven by systematic review or randomized clinical trials (RCTs). The aim of this study was to establish the scientific reporting quality of RCTs on the efficacy of FFC and to identify areas that require improvement. The reporting quality of 33 RCT papers on 31 FFC that were received between April 1, 2015 and December 31, 2016 were analyzed by two experts with regard to consistency with the 29 Consolidated Standards of Reporting Trials (CONSORT) items. RCTs on FFC reported 13.8 (47.6%) of the CONSORT items, which is similar to those on FOSHU. There were 7 least reported items, including study design. Determining the reporting quality of FFC studies is an important way of identifying items that require improvement in future papers.

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医薬品に関する消費者・患者向けリスク・ベネフィットコミュニケーションの実態調査

山本健, 山本ライン, 宮田滉平, 漆原尚巳, 山本美智子

医薬品情報学 20 （ 3 ） 180 - 188 2018年

Nationwide survey on informed consent and ethical review at hospitals conducting post-marketing studies sponsored by pharmaceutical companies

Urushihara H., Murakami Y., Matsui K., Tashiroc S.

Yakugaku Zasshi （Yakugaku Zasshi）  138 （ 1 ） 63 - 71 2018年

ISSN  00316903

　概要を見る

© 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.

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The Long Road to Perfect Harmony

Urushihara Hisashi

the Medicine Maker （UK: Texere Publishing Limited）  2017年10月

レギュラトリーサイエンスの視点からみた医薬品と保健機能食品における有効性又は安全性の科学的根拠に必要な規制やその考え方の相違.

種村菜奈枝, 濱舘直史, 漆原尚巳

日本補完代替医療学会誌 （日本補完代替医療学会）  14 （ 2 ） 47 - 60 2017年09月

ISSN  1348-7922

　概要を見る

現在，健康寿命の延伸が重要とされ，セルフメディケーションが推進されている．その推進の一助として保健機能食品の活用が提案されている．しかし，食品が持つ機能性関与成分は多様であるため，科学的根拠を示すために必要な臨床試験における評価系を考察することは重要である．本稿では，保健機能食品の定義や制度変遷，及びその種類や特徴を解説した後で，安全性又は有効性の科学的根拠に関し医薬品との考え方の違いを解説する．今後，透明性のある明確化された基準に基づき保健機能食品に関する制度を成熟させていくことで，消費者の信頼を確保することができ，今後さらなる市場の活性化に繋がると確信する．

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抗コリン作動薬及び鎮静薬による薬剤負荷が超高齢者のアウトカムへ与える影響　The Tokyo Oldest Old survey on Total Health(TOOTH)

佐藤亮平, 新井康通, 阿部由紀子, 高山美智代, 漆原尚巳

日本老年医学会雑誌 54 （ 3 ） 403 - 416 2017年07月

責任著者

Bridge the Gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies

Urushihara H, Parmenter L, Tashiro S, Matsui K, Dreyer N

Pharmacoepidemiology and drug safety  （ 26 ） 1299 - 1306 2017年

共著

The need for consumer science and regulatory science research on functional foods with health claims - What should we do to harmonize science and technology with society?

Tanemura N, Hamadate N, Urushihara H.

Trends in Food Science & Technology （ELSEVIER SCIENCE LONDON）  67 （ 67 ） 280 - 283 2017年

共著,  ISSN  0924-2244

　概要を見る

Background: According to the Codex Alimentarius of the foods with health claims (FHCs), two major factors play a significant role in the ability for consumers to select functional foods and utilize them appropriately for health maintenance (Codex Alimentarius, 1997). These are: 1) food labeling based on scientific evidence that consumers are able to understand; and 2) standardized criteria for obtaining scientific evidence.
Scope and approach: We discuss the regulatory system for foods with health claims in the world and the need for consumer science and regulatory science research through reviewing the history and recent topics about the regulation on FHCs in Japan.
Key findings and conclusions: There are some differences in regulations on FHCs among countries participating in the Codex, which have been said sometimes to cause some troubles. These are: 1) despite of the lack of renewal system, Japan experienced the first revocation event regarding the approved Foods for Specified Health Uses category of FHCs in 2016; and 2) global export barriers. Therefore, the introduction of mutual recognition rules among countries has been desired in Japan for further international harmonization. However, its feasibility seems to be low because of the complexity caused by such differences on regulations among countries. When it happens, we expect that the global regulatory climates on FHCs may be better regulated by involving neutral academic researchers and the trained experts in the field of consumer and regulatory science of functional foods. As Japan is the first country to establish the FHCs regulatory system in the world, it should lead to discuss the introduction of mutual recognition rules with other countries immediately. (C) 2017 Elsevier Ltd. All rights reserved.

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製造販売後調査における被験者同意と倫理審査

漆原尚巳, 村上結香, 松井健志, 田代志門

YAKUGAKU ZASSHI （全国病院調査）  2017年

共著

新たな研究倫理指針「人を対象とする医学系研究に関する倫理指針」と研究倫理の枠組み

漆原 尚巳

月刊薬事 57 （ 13 ） 2173 - 2178 2015年12月

研究論文（学術雑誌）, 単著

Price difference as a predictor of the selection between brand name and generic statins in Japan

漆原 尚巳

HEALTH POLICY （ELSEVIER IRELAND LTD）  119 （ 5 ） 612 - 619 2015年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0168-8510

　概要を見る

Objectives: This study aimed to explore the predictors of the selection between brand name drug (BR) and generic drug (GE) and to clarify the quantitative relationship about selection.
Methods: We identified "incident users" who dispensed statins between April 2008 and June 2011 in commercially databases consisted of dispensing claims databases (DCD) of out-of-hospital pharmacies and hospital claims databases (HCD) of in-house pharmacies in Japan. Predictors of the selection between BR and GE, including price difference (PD), the price of BR, their interaction and percent change of the price of GE relative to BR were explored by logistic regression using DCD and HCD separately.
Results: We extracted records of 670 patients who have opportunity for selection both BR and GE. Logistic regression analysis demonstrated that PD, the price of BR, interaction between them, and prescriber affiliation were factors significantly associated with the selection in the DCD; logit (p) = 9.735 - 0.251 x PD - 0.071 x the price of BR+0.002 x PD x the price of BR -1.816 x affiliation + 0.220 x gender 0.008 x age + 0.038 x monthly medical fee. PD was inversely proportional to BR choice in DCD and lead to the opposite result in HCD. Numerical simulation of selection revealed that the quantitative relationships heavily depend on situations.
Conclusions: PD and the price of BR are predictors of the selection between BR and GE interactively in out-of-hospital pharmacies, but not in in-house pharmacies of medical facilities. Results may support policies which increase the power of out-of-hospital pharmacies for selection. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

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Prescription patterns and trends in anti-rheumatic drug use based on a large-scale claims database in Japan

漆原 尚巳

CLINICAL RHEUMATOLOGY （SPRINGER LONDON LTD）  34 （ 5 ） 949 - 956 2015年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0770-3198

　概要を見る

This drug utilization study aimed to investigate prescription patterns and trends for anti-rheumatic drug use in Japanese patients with rheumatoid arthritis (RA), clarifying if patients with RA in Japan are being treated according to EULAR recommendations and ACR guidelines. We used a large-scale claims database consisting of the medical claims of employee health insurance recipients, which included approximately one million insured people. The claims data for incident 5,126 patients with diagnosis codes of RA between January 1, 2005 and October 31, 2011 were analyzed. The number of patients who received disease modifying antirheumatic drugs (DMARDs) including biologics as initial therapy was 629 (12.3 %), while the others received non-DMARD therapy only. During the study period, use of methotrexate (MTX) and biologics as first-line drugs increased from 1.9 to 8.0 % and from 0 to 1.6 %, respectively (p &lt; 0.001 for both), while that of non-steroidal anti-inflammatory drugs (NSAIDs) decreased (p = 0.004). Time from first RA diagnosis to the start of treatment with DMARDs decreased significantly from 2005 to 2010. These findings suggest that many early RA patients in Japan do not yet receive aggressive treatment, albeit that this prescribing practice has gradually changed to better comply with clinical recommendations. The current, obsolete Japanese RA guidelines require urgent updating to reflect the most recent knowledge and care with effective treatment modalities.

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Domperidone With ORT in the Treatment of Pediatric Acute Gastroenteritis in Japan: A Multicenter, Randomized Controlled Trial

漆原 尚巳

ASIA-PACIFIC JOURNAL OF PUBLIC HEALTH （SAGE PUBLICATIONS INC）  27 （ 2 ） NP174 - NP183 2015年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1010-5395

　概要を見る

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.

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Cost-effectiveness analysis of EGFR mutation testing and gefitinib as first-line therapy for non-small cell lung cancer

Narita, Yusuke, Matsushima, Yukiko, Shiroiwa, Takeru, Chiba, Koji, Nakanishi, Yoichi, Kurokawa, Tatsuo and Urushihara, Hisashi

Lung Cancer 90 （ 1 ） 71 - 77 2015年

研究論文（学術雑誌）,  ISSN  0169-5002

　概要を見る

AbstractObjectives The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. Materials and methods Our analysis compared the ‘EGFR testing strategy’, in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the ‘no-testing strategy,’ in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. Results The incremental cost and effectiveness per patient of the ‘EGFR testing strategy’ compared to the ‘no-testing strategy’ was estimated to be approximately JP¥122,000 (US$1180; US$1 = JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the ‘EGFR testing strategy’ is cost-effective compared with the ‘no-testing strategy’ when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. Conclusion The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin–paclitaxel for the treatment for NSCLC in Japan.

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Utilization trends and management and prescription of oral anticancer medicines using nationwide pharmacy databases and a questionnaire survey of community pharmacies in Japan

Takizawa O, Urushihara H, Tanaka S, Doi Y, Arai M, Matsunaga T, Ogata N, Kawakami K

International Journalof Pharmacy and Pharmaceutical Research 4 （ 3 ） 150 - 163 2015年

研究論文（学術雑誌）, 共著, 査読有り

Medications associated with falls in older people: systematic review of publications from a recent 5-year period

Park H, Satoh H, Miki A, Urushihara H, Sawada Y

European Journal of Clinical Pharmacology （SPRINGER HEIDELBERG）  71 （ 12 ） 1429 - 1440 2015年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0031-6970

　概要を見る

Falls are an important public health problem in older people. Medication use is considered a risk factor for falls. This study systematically reviewed recent studies to determine the medications that might be associated with the risk of falling in older people.
We conducted a systematic review of prospective and retrospective studies identified through the MEDLINE and CINAHL databases that quantitatively assessed the contribution of medications to falls risk in participants a parts per thousand yen60 years old published in English between May 2008 and April 2013.
The search identified 1,895 articles; 36 articles met the inclusion criteria. Of the 19 studies that investigated the effect of polypharmacy on the risk of falling, six studies reported that the risk of falling increased with polypharmacy. Data on the use of antihypertensive medications including calcium channel blockers, beta-blockers, and angiotensin system blocking medications were collected in 14 studies, with mixed results. Twenty-nine studies reported an association between the risk of falls and psychotropic medications including sedatives and hypnotics, antidepressants, and benzodiazepines.
The use of sedatives and hypnotics and antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors appears to be related with an increased risk of falls. It is not clear if the use of antihypertensive medications is associated with the risk of falls in older people.

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Patterns and trends in diagnostic tests used for detection of colorectal cancer after screening with the immunochemical fecal occult blood test in Japan

Yamamichi J, Seto K, Hinotsu S, Nagata K, Kobayashi Y, Urushihara H, Kawakami K

Open Journal of Clinical Diagnostics 5   107 - 116 2015年

研究論文（学術雑誌）, 共著, 査読有り

医療上の必要性の高い未承認薬・適応外薬検討会議」において検討された適応外薬の申請形態

伊藤知美, 漆原尚巳, 松嶋由紀子, 中島慶太郎, 黒川達夫

臨床薬理 46(5)   233 - 241 2015年

研究論文（学術雑誌）, 共著, 査読有り

Responsiveness of the Japanese Osteoporosis Quality of Life questionnaire in women with postmenopausal osteoporosis

Urushihara Hisashi, Yoh K, Hamaya E, Taketsuna M, Tanaka K

Health Qual Life Outcomes 12   178 2014年12月

研究論文（学術雑誌）, 共著, 査読有り

Application of a self-controlled case series study to a database study in children

Ueyama H, Hinotsu S, Tanaka S, Urushihara H, Nakamura M

Drug Saf 37   259-268 2014年03月

研究論文（学術雑誌）, 共著, 査読有り

Academic clinical trials and drug regulations in japan: impacts of introducing the investigational new drug system.

Urushihara H, Kawakami K

Therapeutic Innovation & Regulatory Science 48(4)   463-472 2014年02月

研究論文（学術雑誌）, 共著, 査読有り

Pharmaceutical company perspectives on current safety risk communications in Japan.

Urushihara H, Kobashi G, Masuda H, Taneichi S, Yamamoto M, Nakayama T, Kawakami K, Matsuda T, Ohta K, Sugimori H

SpringerPlus 3(1)   51 2014年01月

研究論文（学術雑誌）, 共著, 査読有り

Utilization of antipsychotic drugs in elderly patients with alzheimer's disease seen in ambulatory practice in japan.

Urushihara H, Kobayashi S, Honjo Y, Kosugi S, Kawakami K

Science Postprint 1(1)   e00014 2014年01月

研究論文（学術雑誌）, 共著, 査読有り

Prescribing pattern of anti-Parkinson drugs in Japan: a trend analysis from 2005 to 2010

Nakaoka S, Ishizaki T, Urushihara H, Satoh T, Ikeda S

PLoS One 9   e99021 2014年

研究論文（学術雑誌）, 共著, 査読有り

Transaction cost analysis of the new drug application process: a case study of a multinational pharmaceutical company in japan.

Hamada S, Shibata A, Urushihara H, Sengoku S, Suematsu C, Kawakami K

Therapeutic Innovation & Regulatory Science 48(3)   371-7 2013年12月

研究論文（学術雑誌）, 共著, 査読有り

Biased safety reporting in blinded randomized clinical trials: meta-analysis of angiotensin receptor blocker trials.

Takabayashi N, Urushihara H, Kawakami K

PLoS one 8(9)   e75027 2013年09月

研究論文（学術雑誌）, 共著, 査読有り

Economic evaluation of pravastatin for primary prevention of coronary artery disease based on risk prediction from JALS-ECC in japan.

Onishi Y, Hinotsu S, Nakao YM, Urushihara H, Kawakami K

Value in Health Regional Issues 2(1)   5-12 2013年02月

研究論文（学術雑誌）, 共著, 査読有り

A survey of physicians' understanding of the regulatory systems for clinical trials in japan.

Yamauchi Y, Kawashima Y, Urushihara H, Uosaki F, Kobayashi Y, Hinotsu S, Nakagawa M, Kawakami K

General Medicine 14(2)   92-103 2013年02月

研究論文（学術雑誌）, 共著, 査読有り

Emergency authorization of medical products: regulatory challenges from the 2009 H1N1 influenza pandemic in japan.

Urushihara H, Matsui S, Kawakami K

Biosecurity and bioterrorism : biodefense strategy, practice, and science 10(4)   372-82 2012年12月

研究論文（学術雑誌）, 共著, 査読有り

Quality of life in raloxifene-treated japanese women with postmenopausal osteoporosis: a prospective, postmarketing observational study.

Yoh K, Hamaya E, Urushihara H, Iikuni N, Yamamoto T, Taketsuna M, Miyauchi A, Sowa H, Tanaka K

Curr Med Res Opin 28(11)   1757-66 2012年11月

研究論文（学術雑誌）, 共著, 査読有り

日本におけるオセルタミビルの処方と異常行動リスクに対する規制措置の影響-保険薬局データベースを用いた医薬品使用実態調査

漆原尚巳, 川上浩司

インフルエンザ （メディカルレビュー社）   （ 10月 ） 37-43 2012年10月

研究論文（その他学術会議資料等）, 共著

京大病院における採血時フルネーム名乗らせ確認の遵守向上の取り組み

長尾雅能, 杉山綾香, 足立由起, 漆原尚巳, 一山智, 川上浩司

医療の質・安全学会誌 7(3)   223-229 2012年09月

研究論文（学術雑誌）, 共著, 査読有り

Effect of HMG-CoA reductase inhibitors on blood pressure in hypertensive patients treated with blood pressure-lowering agents: retrospective study using an anti-hypertensive drug database.

Hashimoto S, Urushihara H, Hinotsu S, Kosugi S, Kawakami K

Eur Rev Med Pharmacol Sci 16   235-241 2012年02月

研究論文（学術雑誌）, 共著, 査読有り

Chromosomal variability of human mesenchymal stem cells cultured under hypoxic conditions.

Ueyama H, Horibe T, Hinotsu S, Tanaka T, Inoue T, Urushihara H, Kitagawa A, Kawakami K

J Cell Mol Med 16   72-82 2012年02月

研究論文（学術雑誌）, 共著, 査読有り

Increased risk of acute pancreatitis in patients with type 2 diabetes: an observational study using a japanese hospital database.

Urushihara H, Taketsuna M, Liu Y, Oda E, Nakamura M, Nishiuma S, Maeda R

PLoS one 7(12)   e53224 2012年01月

研究論文（学術雑誌）, 共著, 査読有り

Oseltamivir prescription and regulatory actions vis-&agrave;-vis abnormal behavior risk in japan: drug utilization study using a nationwide pharmacy database.

Urushihara H, Doi Y, Arai M, Matsunaga T, Fujii Y, Iino N, Kawamura T, Kawakami K

PLoS ONE 6(12)   e28483 2011年12月

研究論文（学術雑誌）, 共著, 査読有り

成22年度「レギュラトリーサイエンス推進調査研究事業」研究報告 日本版IND制度導入にむけての国際動向調査研究 -米国の研究開発事例をもとに-

川上浩司, 漆原尚巳

医薬品医療機器レギュラトリーサイエンス 42(9)   843-850 2011年09月

研究論文（学術雑誌）, 共著, 査読有り

Echocardiography for the detection of valvulopathy associated with the use of ergot-derived dopamine agonists in patients with parkinson's disease.

Nakaoka S, Ishizaki T, Urushihara H, Satoh T, Ikeda S, Morikawa K, Nakayama T

Intern Med 50   687-694 2011年02月

研究論文（学術雑誌）, 共著, 査読有り

The current status of umbilical cord blood collection in japanese medical centers: survey of obstetricians.

Tada N, Hinotsu S, Urushihara H, Kita F, Kai S, Takahashi T A, Kato S, Takanashi M, Ito K, Sawai H, Maekawa T, Kosugi S, Kawakami K

Transfusion and apheresis science 44   263-268 2011年02月

研究論文（学術雑誌）, 共著, 査読有り

Night-to-night variability of sleep latency significantly predicts the magnitude of subsequent change in sleep latency during placebo administration.

Ogawa A, Hinotsu S, Urushihara H, Kawakami K

Sleep Med 12   565-571 2011年02月

研究論文（学術雑誌）, 共著, 査読有り

Development safety update report and proposals for effective and efficient risk communication

Urushihara H, Kawakami K

Drug Safety 33(5)   341-52 2010年05月

研究論文（学術雑誌）, 共著, 査読有り

非(前)臨床試験の仕組み

漆原尚巳, 川上浩司

THE LUNG perspectives （メディカルビュー社）  17   241-244 2009年07月

共著

Raloxifene and stroke risks in japanese postmenopausal women with osteoporosis on post-marketing surveillance.

Urushihara H, Kikuchi N, Yamada M, Yoshiki F, Miyauchi A

Menopause 16   971-977 - 977 2009年02月

研究論文（学術雑誌）, 共著, 査読有り

外来患者の薬物治療への参加意識と事故回避行動への認識: 大阪府高槻市における質問紙調査

中村祥子, 漆原尚巳, 宮崎貴久子, 中山健夫

医療薬学 35(2)   113-123 2009年02月

研究論文（学術雑誌）, 共著, 査読有り

Heterogeneity in responsiveness of perceived quality of life to body composition changes between adult- and childhood-onset japanese hypopituitary adults with growth hormone deficiency during GH replacement.

Urushihara H, Fukuhara S, Tai S, Morita S, Chihara K

European Journal of Endocrinology 156   637-645 2007年02月

研究論文（学術雑誌）, 共著, 査読有り