PMDA, the Japanese regulatory agency, has worked for reinforcing and enhancing its post-marketing safety measures as stated in the second mid-term (FY 2009-2013) plan. MIHARI Project-Medical Information for Risk Assessment Initiative was started in FY 2009 to develop a new safety assessment system for post-marketing drugs using Japanese electronic healthcare data in PMDA. In the second mid-term, we examined characteristics of some electronic healthcare data available in Japan including, claims data, hospital information system data and Diagnosis Procedure Combination (DPC) data in order to make efficient use of those databases for the purpose of drug safety assessment. In addition, some pilot pharmacoepidemiological studies for risk assessment and drug utilization were conducted by use of these electronic healthcare data. Based on the accumulated findings, knowledge, and experiences from the pilot studies, we established the framework by FY 2013 to implement pharmacoepidemiology-based safety assessment in PMDA. In the third mid-term (FY 2014-2018), one of the important mission is to apply this framework into the current risk management process of drug safety. For that purpose, cooperation with other divisions of PMDA such as Office of Safety and Office of New Drug is a key. Simultaneously, we will work to establish an access to another database and novel pharmacoepidemiological methods using electronic healthcare data. A large-scale electronic health record database (MID-NET) as well as national claims database are expected to be an important database in the future activities of MIHARI Project. Furthermore, in April 2015, PMDA established new office focusing on Medical Informatics and Epidemiology for further promotion of electronic healthcare data utilization in Japan. In this article, we describe history and past activities of MIHARI Project followed by future challenges.

PMDA started MIHARI project in FY2009 to enhance drug safety assessment by developing ways to utilize electronic medical information as additional data sources to spontaneous adverse drug reaction reports. The project has been established according to PMDA's second midterm plan. In this article, we will introduce latest two studies (pilot studies No. 4 and 5) using data of standardized electronic medical record(EMR) called SS-MIX (standardized structured medical record information exchange) data out of our several pilot studies. SS-MIX is a standard specification published by the Ministry of Health, Labour and Welfare. In these studies, anonymized SS-MIX data were provided by six collaborative hospitals respectively. In pilot study No. 4, we explored approaches for evaluating the impact of regulatory action which instructed relevant manufacturers to revise package inserts of sitagliptin phosphate hydrate (sitagliptin) to call physician's attention. The revision was about reducing dose of sulfonylurea (SU) to avoid serious hypoglycemia when it is prescribed concomitantly with sitagliptin. As indicators of the impact, we evaluated changes in proportion of concomitant use and average SU dose before and after the action and estimated the risk of hypoglycemia in concomitant users compared to SU alone users before and after the action. In conclusion, evaluating impact of the regulatory action using SS-MIX data was technically feasible; however, it was difficult to analyze with adequate accuracy due to limited size of the data. In pilot study No. 5, we examined validity of outcome definitions for hyperthyroidism which were applied to combinations of some data elements of SS-MIX data to identify the patients. Three types of outcome definitions were prepared; 1) definitive diagnosis of hyperthyroidism, 2) prescription of medication for hyperthyroidism, 3) prescription of medication for hyperthyroidism in or after the month in which definitive diagnosis of hyperthyroidism was given. Criteria for case ascertainment were determined according to relevant clinical guidelines. After the cases were ascertained, positive predictives values were calculated. The results suggested that using information on prescription of medication improves validity of definition of outcome. The findings from pilot studies in MIHARI project have been utilized in another project which PMDA is carrying forward now (EMR network project). The findings would be also helpful when we use data from this network. (Jpn J Pharmacoepidemiol 2013；18(1)：23-29)

Purpose and Method: It is known that people have insufficient recognition about hospital-based palliative care units (PCUs). Patients with cancer and their families are probably not well informed about PCUs on its admission. To understand the situation of patients and their families before and after PCU admission, a questionnaire survey was performed and evaluated by PCU nurses. Result: As a result, two points regarding PCU admission have become clear. First, about 55％ of the nurses reported that prior to PCU admission, patients and family members lacked proper information about PCUs; about 62% of the nurses felt that PCUs had not been appropriately explained to the patients; and about 37% of the nurses felt that family members had not received an appropriate explanation of PCUs at the time of PCU admission. Second, before PCU admission, the main concern of patients and their families was proper utilization of PCUs. After admission, their main concerns were the extent of treatment provided in the PCU and the progress of the disease. Conclution: These results suggest that appropriate information on PCUs, including the scope of treatment provided to patients and the requirements for PCU admission, is necessary for general ward staff as well as for the patients and their families prior to PCU admission.

Objective: The aim of this study was to establish the proper definitions of venous thromboembolism (VTE) and bleeding events for a healthcare database in Japan.
Study Design: Validation study.
Methods: The study comprised patients with VTE or who had undergone orthopedic surgery of the lower extremities and whose outpatient or inpatient medical information from April 1, 2008 to September 30, 2013 was available.  The source population of the database was derived from 100 acute-care hospitals.  The endpoints were VTE events (deep venous thrombosis [DVT], pulmonary thromboembolism [PE]) and bleeding events (bleeding requiring blood transfusion, intracranial hemorrhage, intraocular hemorrhage, upper gastrointestinal [GI] bleeding, and lower GI bleeding).  The frequent events with laboratory data were randomly extracted and evaluated, while all the infrequent events with laboratory data were extracted and evaluated.  Positive predictive value (PPV) was defined as the proportion of events judged to be clinical by medical experts of all the extracted events.  First, we conducted a test with a small number of cases and then revised the definitions of events.  Second, we extracted and evaluated data in 50 patients for VTE and bleeding events patients, based on which we defined the target PPV level between 60 and 70%.
Results: Of the 5,044,743 patients in the database, 36,947 patients underwent orthopedic surgeries of the lower extremities and 3,578 patients experienced a VTE event.  The PPV at the first evaluation was 80.0% (8/10) for DVT, 57.1% (4/7) for PE, and 27.3% (6/22) for bleeding events.  At the second evaluation using the revised definitions, the PPV were 75.0% (42/56) for VTE and 73.3% (33/45) for bleeding events.  Overall, the PPVs for VTE and bleeding events were over 70%.  The PPV of the VTE events were 76.9% (30/39) for DVT and 70.6% (12/17) for PE.  The PPVs of each type of bleeding event were over 70% except for intracranial hemorrhage (44.4%, 4/9).
Conclusion: The PPV was high for VTE events (75.0%) and bleeding events (73.3%).  The definitions used in this study are rational for the identification of VTE, DVT, PE, and bleeding events in the healthcare database in Japan.  The definition for each type of bleeding event should be investigated in further studies.

Objective: In this study, we evaluated the change in degree of recognition and understanding of palliative care as pharmacy students’ years advanced.
Methods: A questionnaire survey consisting of 11 items about recognition of narcotics and 27 items about understanding of palliative care was conducted with first- to fifth-year pharmacy students.  We divided the questions about the image of narcotics into groups and classified the questions about their knowledge of palliative care into the categories based on some reports.
Results: Among the three groups of questions about the image of narcotics, the degree of “right recognition of narcotics” increased, and those of “wrong recognition of narcotics” and “sense of resistance to narcotics” decreased as pharmacy students’ years advanced.  Additionally, questions about their knowledge of palliative care were categorized into three: “basic guidelines for cancer pain relief and methods of narcotic use,” “role of pharmacists in palliative care and support for patients,” and “pharmacologic characteristics of narcotics.”  Their degree of understanding of each category increased with an increase in years.  Both the recognition of narcotics and understanding of palliative care changed in the fourth- and fifth-grade year students compared to the first-, second-, and third-year ones.
Conclusion: These results suggest that the recognition and understanding of palliative care changed along the same trends as pharmacy students’ years advanced.  Therefore, it is important that pharmacy students acquire appropriate knowledge to play an active role in palliative care.

Objective: Macrolide therapy has been recommended as an effective treatment for pediatric otolaryngology patients with conditions such as chronic sinusitis and otitis media with effusion.  However, in many cases, a relapse may occur after cessation of treatment.  Therefore, patients are compelled to continue taking antibiotics.  In this paper, we examined the relationship between the duration of therapy and period to relapse on the basis of prescription information and literature research.
Methods: To evaluate the therapeutic doses, we investigated the clinical doses of erythromycin and clarithromycin used for pediatric patients in a community pharmacy from January 2009 to July 2009.  Further, we performed literature searches on the doses of both drugs using Igaku-Chuo-Zasshi databases (from 1983 to 2011) and compared the data obtained with the clinical doses.  Accordingly, the oral doses of macrolides were classified as a low dose or normal dose.  We analyzed the relationship between the administration period and the cessation period, which was defined as the period from the cessation of the treatment to relapse.
Results: Review of the 17 selected reports and the clinical doses showed that the maximum dose of erythromycin was 15 mg/kg/day and that of clarithromycin was 8 mg/kg/day during therapy.  When both cephem or penicillin antibiotics and low-dose macrolides were taken continuously during the administration period, a weak correlation was observed between the administration period and the cessation period.
Conclusion: These results may be useful for the appropriate use of antibiotics and for preventing relapse in pediatric otolaryngology patients.

Objective: To identify factors affecting adherence to medication, a subjective questionnaire survey was administered to schizophrenia patients regarding the prescribed antipsychotic formulations. Methods: We evaluated the patients’ satisfaction and dissatisfaction with prescribed antipsychotic formulations, and patients answered the Drug Attitude Inventory-10 Questionnaire (DAI-10). Inclusion criteria for patients are as follows:age between 20 and 75 years and taking antipsychotic agents containing the same ingredients and formulations, for at least 1 month. Results: In total, 301 patients answered the questionnaire survey. Tablets were found to be the most commonly used antipsychotic formulations among schizophrenia patients (n = 174, 57.8%), followed by long-acting injections (LAIs, n = 93, 30.9%). No significant differences in the formulation satisfaction level and DAI-10 scores were observed between all formulations. Formulations, except for LAI, were selected by physicians in more than half of the patients.Patients who answered “Decided by consultation with physicians” had significantly higher satisfaction levels and DAI-10 scores compared to those who answered “Decided by physicians” (4.11 ± 0.77 vs. 3.80 ± 1.00, p = 0.0073 and 6.20 ± 3.51 vs. 4.39 ± 4.56, p ＜ 0.001, respectively). Satisfaction levels moderately correlated with DAI-10 scores (r = 0.48, p ＜ 0.001). Conclusion No formulation had a high satisfaction level in all patients, and it is important to be reflect the patients’ individual preferences in pharmacotherapy. Shared decision-making in the selection of the formulations is seen to be useful for improving medication adherence.

Objective: To improve poor medication adherence in schizophrenic patients, long-acting injectable (LAI) antipsychotics are used. However, it has not yet become common in Japan. Recently, aripiprazole LAI was approved for alternative injection into the deltoid muscle in addition to the gluteal muscle. The acceptance for the proposal to switch from gluteal to deltoid injections of aripiprazole LAI was investigated. Methods: The subjects were 32 outpatients with schizophrenia who had continuously received aripiprazole LAI administration into the gluteal muscle for ≥ 6 months. In the patients who had continued deltoid injection for 3 months after switching, the changes in the pain and shame in comparison with gluteal injections were evaluated. Results: Switching to the deltoid injection was chosen by 17 out of 32 patients. Three months later, 9 patients were still receiving deltoid injections with highly rated satisfaction. The main reasons for switching to deltoid injections included the pain and shame associated with gluteal injections. The main reason for returning to the gluteal injection was the pain experienced from the injection in the deltoid. Conclusion The option to select the injected area was based on the amount of pain in the deltoid and gluteal sites, leading to the widespread use of aripiprazole LAI.

Objectives  High gestational weight gain (GWG) is associated with perinatal risks to mother and child. Research shows that non-Japanese Asian women have higher GWG than Japanese women. However, no studies have compared GWG in these two populations using GWG recommendations in accordance with Japanese and Institute of Medicine (IOM) guidelines. The study aim was to compare GWG in non-Japanese Asian and Japanese pregnant women.Methods  This was a retrospective observational study. All participants were aged ≥20 years and gave birth between September 2019 and the end of October 2020 at one perinatal medical center in Japan. Medical record data were analyzed for 170 non-Japanese Asian and 316 Japanese pregnant women. We used t-tests and chi-square tests to examine differences in age, parity, smoking status, antenatal checkups, pre-pregnancy body mass index, and GWG. Logistic regression analysis was used to estimate odds ratios (95% confidence intervals) for above- and below-recommended GWG by non-Japanese Asian and Japanese status. We also analyzed differences in delivery type, abnormal blood loss, and birth size according to GWG.Results  After adjustment for confounding factors, the multivariable-adjusted OR and 95% CI for GWG above the Japanese guidelines recommendations was 1.86 (1.23-2.81) and that for GWG above IOM guidelines recommendations was 2.46 (1.45-4.16) for non-Japanese Asian women, as compared with Japanese women. Conversely, the multivariable-adjusted OR and 95% CI for GWG below Japanese guidelines recommendations was 1.55 (1.03-2.32) and that for GWG below IOM guidelines recommendations was 1.87 (1.26-2.76) for Japanese women, compared with non-Japanese Asian women. Conclusion  Because Japanese women tend to be below recommended GWG and non-Japanese Asian women tend to be above recommended GWG, midwives need to provide careful guidance to reduce perinatal risks.

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.
Aged ; Alzheimer Disease/genetics* ; Dementia/genetics* ; Environment ; Female ; Humans ; Incidence ; Japan/epidemiology* ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Risk Factors