OBJECTIVE：The purpose of this study was to examine the problems of tracking patients by single facility for diseases that may be provided by specialists and in collaboration with regional healthcare providers during drug treatment and the applicability of an administrative claims database in Japan as a possible solution to these problems. METHODS：This retrospective cohort study utilized data from the DeSC database (from June 2018 to August 2022). First, we reported the number of facilities visited by patients with chronic thromboembolic pulmonary hypertension (CTEPH) on drug therapy, the frequency of visits at each facility, and new prescriptions of pulmonary vasodilators to identify possible transfers and concurrent consultations during drug therapy. We then reported the number of new diseases with possible adverse events at the facility where antithrombotic prescriptions were initiated and at other facilities among CTEPH patients who visited multiple facilities. RESULTS：We extracted 106 patients of CTEPH patients that were prescribed anticoagulants (77 patients in the multi-facility group and 29 patients in the single-facility group). The mean frequency of visits was 10.1 months/year (standard deviation 2.5) in the single-facility group and 10.4 months/year (standard deviation 2.1) in the multi-facility group, respectively. Whereas, the frequency of visits to only the facility that antithrombotic prescriptions were initiated in the multi-facility group was about half, at 6.5 months/year (standard deviation 4.0). For pulmonary vasodilators, out of the 18 patients (19 events) in the multi-facility group who had the initiation of prescription for pulmonary vasodilators at a facility other than where antithrombotic prescriptions were initiated, 13 of the patients (14 events) did not have the same prescription confirmed at the facility where antithrombotic prescriptions were initiated. These results indicate that CTEPH is a reasonable disease for patients to visit multiple facilities during drug treatment. In the multi-facility group, the newly diagnosed diseases confirmed at facilities other than the one where antithrombotic prescriptions were initiated and not confirmed at the facility where the antithrombotic prescriptions were initiated were：18/19 events of bleeding, 0/1 event of interstitial pulmonary diseases, 17/19 events of upper gastrointestinal motility disorders, 1/1 event of thyroid dysfunction, and 0/0 event of retinal disorders. CONCLUSION：This study showed that there may be safety information that cannot be picked up solely by the facility where the drug prescription was initiated due to multiple facility visits associated with diverse treatments. In cases where specialists may collaborate with community health care providers to treat a target disease during drug treatment, the generation of safety information through a patient-traceable an administrative claims database should be considered for the implementation of appropriate pharmacovigilance activities.

Objective：Compared to research conducted under a controlled system such as a clinical trial, differences in characteristics among observers (medical care providers) can be an issue when conducting observational research in general or research using RWD in particular. In particular, systematic differences in observational behaviors (attitudes) by department may cause confusion in interpreting study results, so we aimed to quantify the differences in behaviors toward patient observation by department. Design：Descriptive aggregation using “Millennium medical record” Database. Basic statistics such as median values for the number of characters in the clinical summary, which is a free entry column, are obtained for each department. Based on the purpose of this study, it was judged that it was appropriate to omit the description after hospitalization because the number of characters described in the part of the clinical course up to hospitalization in the clinical summary was included in the character count. Results：The median number of letters in internal medicine was 503. The ratios of the median number of letters to the median number of letters in various departments were surgery (0.55), ophthalmology (0.57), psychiatry/psychosomatic medicine (2.85), pediatrics (1.19), obstetrics/gynecology (1.04), and dermatology, orthopedic surgery/plastic surgery (0.41), respectively. Conclusion：There are characteristic differences in the number of letters in the free entry items depending on the medical department.

When a randomized controlled trial (RCT) is infeasible, unethical, or untimely, causal inference from observational data can serve as an effective alternative for scientific and clinical decision-making. However, observational studies harbor methodological vulnerabilities―not only confounding due to lack of randomization, but also selection bias or immortal time, arising from flawed study designs―that can fundamentally distort effect estimates. Target trial emulation has gained prominence as a framework for addressing these challenges. This approach has two steps：(1) specifying the protocol of a hypothetical pragmatic RCT (the target trial) that would answer the causal question of interest, and (2) explicitly emulating that trial with existing observational data. Its greatest contribution is the elimination of ambiguous causal questions in observational studies, transforming them into well-defined causal estimands. In this article, we synthesize the conceptual foundations of target trial emulation and detail methodological considerations for its implementation. As an illustrative example, we describe an observational study that compared denosumab with oral bisphosphonates for cardiovascular safety and fracture-prevention effectiveness in maintenance dialysis patients with osteoporosis. The target trial framework offers a structured approach that prevents design-induced biases and clarifies the limitations inherent in observational data, thereby enabling epidemiologists who grapple with causal questions to draw more valid inferences.

Objective：We aimed to evaluate the important potential risks listed in the risk management plans of SGLT–2 inhibitors (SGLT–2i) using a real world database.Design: A cohort study of patients prescribed either SGLT–2i (exposure group) or DPP–4 inhibitors (DPP–4i, control group), using a large–scale health insurance database including claims and specific health checkup.Methods：The study population included the patients with type 2 diabetes between April 2014 and August 2021, and received either SGLT–2i or DPP–4i monotherapy, based on the claims in the database provided by DeSC Healthcare, Inc．The comparability between treatment groups was ensured by propensity score matching (PSM) and inverse probability treatment weighting (IPTW). The outcome events included liver disorder, malignant tumors, fractures, cardiovascular disease, acute pancreatitis, acute kidney injury, and lower limb amputation. Hazard ratios (HRs) were estimated using the Cox proportional hazards model, in addition to five types of bias analyses.Results：In the PSM population, the HRs (95% confidential interval [CI]) of the SGLT–2i group versus the DPP–4i group were 0.63 (0.28–1.44) for acute kidney injury, 0.75 (0.58–0.95) for fractures, 0.85 (0.67–1.07) for liver disorders, 0.87 (0.71–1.05) for cardiovascular diseases, 1.15 (0.88–1.51) for malignant tumors, 1.51 (0.71–3.19) for acute pancreatitis, and with no observation of lower limb amputation．In the IPTW population, the HRs (95% CI) of the SGLT–2i group versus the DPP–4i group were 0.72 (0.47–1.10) for acute kidney injury, 0.76 (0.67–0.86) for fractures, 0.91 (0.80–1.02) for liver disorders, 0.86 (0.78–0.94) for cardiovascular diseases, 1.04 (0.92–1.18) for malignant tumors, 1.81 (1.24–2.64) for acute pancreatitis, and 2.89 (0.69–12.1) for lower limb amputation. The ad hoc analysis of malignant tumors by type revealed several organ–specific statistically significant increases or decreases in HRs among the IPTW subjects; however, no significant overall HR for malignant tumors was observed. Some of the bias analysis revealed that there were significant decreases in HRs for acute kidney injury and liver disorders and a significant increase in HR for lower limb amputation.Conclusion：In comparison to DPP–4i, the use of SGLT–2i was not associated with overall risk of malignant tumors. Further confirmatory studies with fit–for–purpose design are warranted to verify the potential, increased or decreased organ–specific risks of malignant tumors by type and the results suggesting decreased risks of bone fracture and cardiovascular diseases, and an increased risk of acute pancreatitis.

Introduction：The first–line agent for the treatment of ulcerative colitis is 5–ASA (5–aminosalicylic acid). About 10% of patients taking 5–ASA are deemed to develop a condition called “5–ASA intolerance,” in which they have difficulty taking 5–ASA continuously due to adverse effects. The incidence of 5–ASA intolerance seems to be on the rise. We can provide safer treatment if we can identify patients at high risk of developing 5–ASA intolerance, but there are few prediction models for the 5–ASA intolerance.Objective：The purpose of this study was to develop and internally validate a prediction model for the 5–ASA intolerance among Japanese ulcerative colitis patients using real–world data.Methods：We analyzed data from January 2005 to March 2023 using the payer database held by JMDC Inc. Japanese patients aged 15 years and older who were diagnosed with ulcerative colitis and prescribed oral 5–ASA were included in the analysis. Index date was defined as the date 5–ASA was first dispensed. A prediction model was developed using a Cox proportional hazards model with the number of days from the index date to the occurrence of an event (5–ASA intolerance) as the outcome. Predictors were selected based on expert opinions and the results of Cox regression. Internal validity of the model was assessed from two points; 1) The model’s discriminative ability by optimism–corrected c–index with bootstrapping, 2) The model’s accuracy by a calibration plot.Results：The sample size was 9,520 with 931 events. The selected predictors were gender, age, oral 5–ASA brands, oral 5–ASA prescription dose, and the presence of a diagnosis of a certain disease (i.e. intestinal infection, influenza or pneumonia, iron–deficiency anemia, gastro esophageal reflux disease, gastric ulcer, and acute pancreatitis) within the past 1 year of the Index date. The optimism–corrected c–index was 0.5934. The calibration plot shows adequate fit.Conclusion：With the developed prediction model, we could identify patients with ulcerative colitis who are at high risk for 5–ASA intolerance.

OBJECTIVE：The purpose of this study was to examine the problems of tracking patients by single facility for diseases that may be provided by specialists and in collaboration with regional healthcare providers during drug treatment and the applicability of an administrative claims database in Japan as a possible solution to these problems. METHODS：This retrospective cohort study utilized data from the DeSC database (from June 2018 to August 2022). First, we reported the number of facilities visited by patients with chronic thromboembolic pulmonary hypertension (CTEPH) on drug therapy, the frequency of visits at each facility, and new prescriptions of pulmonary vasodilators to identify possible transfers and concurrent consultations during drug therapy. We then reported the number of new diseases with possible adverse events at the facility where antithrombotic prescriptions were initiated and at other facilities among CTEPH patients who visited multiple facilities. RESULTS：We extracted 106 patients of CTEPH patients that were prescribed anticoagulants (77 patients in the multi-facility group and 29 patients in the single-facility group). The mean frequency of visits was 10.1 months/year (standard deviation 2.5) in the single-facility group and 10.4 months/year (standard deviation 2.1) in the multi-facility group, respectively. Whereas, the frequency of visits to only the facility that antithrombotic prescriptions were initiated in the multi-facility group was about half, at 6.5 months/year (standard deviation 4.0). For pulmonary vasodilators, out of the 18 patients (19 events) in the multi-facility group who had the initiation of prescription for pulmonary vasodilators at a facility other than where antithrombotic prescriptions were initiated, 13 of the patients (14 events) did not have the same prescription confirmed at the facility where antithrombotic prescriptions were initiated. These results indicate that CTEPH is a reasonable disease for patients to visit multiple facilities during drug treatment. In the multi-facility group, the newly diagnosed diseases confirmed at facilities other than the one where antithrombotic prescriptions were initiated and not confirmed at the facility where the antithrombotic prescriptions were initiated were：18/19 events of bleeding, 0/1 event of interstitial pulmonary diseases, 17/19 events of upper gastrointestinal motility disorders, 1/1 event of thyroid dysfunction, and 0/0 event of retinal disorders. CONCLUSION：This study showed that there may be safety information that cannot be picked up solely by the facility where the drug prescription was initiated due to multiple facility visits associated with diverse treatments. In cases where specialists may collaborate with community health care providers to treat a target disease during drug treatment, the generation of safety information through a patient-traceable an administrative claims database should be considered for the implementation of appropriate pharmacovigilance activities.

Objective: To evaluate the real-world risk of hypocalcemia in Japanese patients with rheumatoid arthritis (RA) receiving disease-modifying antirheumatic drugs (DMARDs) newly initiated on denosumab (PRALIA®) versus those receiving DMARDs alone.Design: Observational cohort study utilizing data obtained from the Medical Information Database Network (MID-­NET®) in Japan.Methods: Patients were eligible if they had a prescription record for any DMARD during the study period (July 2016–­December 2020), with their RA diagnosis ＜30 days before the date of DMARD prescription. Primary and secondary outcomes included the incidence of hypocalcemia (serum calcium level ＜8.50 mg/dL), and severe hypocalcemia (serum calcium level ＜7.00 mg/dL), respectively. Data was classified according to denosumab-exposure versus non-exposure, with outcomes assessed during the follow-up period. Results: Overall, 4,222 patients (denosumab-exposed patients: N＝293; non-exposed patients: N＝3,929) met the study criteria. Hypocalcemia occurred in 4.8％（95％CI: 2.6-­7.9) of denosumab-exposed patients and 1.0％（95％CI: 0.7-­1.4) of non-exposed patients, for an adjusted risk ratio (RR) of 1.67（95％CI: 0.90-­3.10).Conclusion: The incidence of hypocalcemia was increased in denosumab-exposed patients compared with non-exposed patients with RA in this observational study utilizing data from MID-­NET®. As the adjusted RR of hypocalcemia with denosumab was modest, current risk management strategies outlined in the package insert are appropriate.

This document reports the results of a questionnaire survey conducted among pharmaceutical companies that are members of the Japan Pharmaceutical Manufacturers Association as part of a collaborative research project within the AMED Research on Regulatory Science of Pharmaceuticals and Medical Devices ‘Research for the promotion of the utilization of real-world evidence in the pharmaceutical regulatory system and the harmonization of international regulations, and for the proposal of an ideal system in Japan’ (Principal Investigator： Harumasa Nakamura, National Center of Neurology and Psychiatry). This survey is the first domestic attempt to clarify the current state of development and utilization of data for companion applications (CPs) in pharmaceuticals. It is expected that the widespread development and use of pharmaceutical CPs will enhance the collection of patient-reported outcomes (PROs), which in turn will foster the utilization of real-world data (RWD) under pharmaceutical regulations. In anticipation that the results of this survey will contribute to this promotion, we are publishing the entire questionnaire results in this report.