論文 - 漆原　尚巳

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

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© 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

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