JPERM

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Hyponatremia is the most common electrolyte imbalance and usually induced by renal water retention due to the presence of factors contributing to increased antidiuretic hormone, low glomerular filtration rate and poor intake of salt and protein in the elderly population. Although symptom severity varies according to the severity, duration and rapidity of hyponatremia, mild chronic hyponatremia is associated with frailty, osteoporosis, cognitive impairment and gait disturbance. The syndrome of inappropriate antidiuretic hormone secretion and endocrinopathies such as hypothyroidism and adrenal insufficiency are major causes of hyponatremia, but medications have been considered as an important factor of water imbalance, and thiazide diuretics, psychotropic agents, anticancer chemotherapeutic drugs and vasopressin analogues are major hyponatremia-inducing drugs in clinical practice. Syndrome of inappropriate anti-diuresis (SIAD) is a main pathogenesis of drug-induced hyponatremia, but multifactorial factors are associated with hyponatremia in old patients. Clinicians should prescribe these potential drugs with caution, especially in those with risk factors for SIAD. The treatment of hyponatremia depends on the severity and type of hyponatremia, and all offending drugs should be discontinued and re-administration of these drugs is strongly discouraged.

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Reproducibility and transparency are fundamental scientific principles that enhance research efficiency, facilitate corrections, and strengthen the reliability of published literature. The clearer each stage of the research process is, the easier it is for reviewers to understand how evidence was obtained and to evaluate the validity of the methods used. This also helps in understanding differences between studies addressing similar topics. A recent evaluation has revealed significant discrepancies in the transparency of real-world evidence (RWE) studies, emphasizing the need for rigorous and internationally agreed-upon guidelines. To address this issue, the International Society for Pharmacoepidemiology (ISPE) and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) have formed a joint task force with key stakeholders to develop a harmonized protocol template for RWE studies, aimed at assessing treatment effects and guiding decision-making. The HARmonized Protocol Template to Enhance Reproducibility (HARPER) incorporates various sections, guidelines, and structures from four protocol templates developed by multiple stakeholders and international organizations for RWE studies, which have been thoroughly evaluated, integrated, and updated. HARPER assists in building a common understanding of intended scientific decisions through a unified format of text, tables, and visuals. To assist Korean researchers in developing clearer and more reproducible research designs, we present the development process and usage guidelines of the HARPER format, along with the final version template, all translated into Korean from the original English publication.

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The increasing development of new drugs for rare diseases has posed challenges to the use of randomization in clinical trials. Therefore, the importance of regulatory decision-making utilizing real-world data (RWD) and real-world evidence (RWE) to complementary and alternative clinical trials has become a focal point. The United States, Europe, and Japan have implemented relevant laws and regulations and are continuously developing guidelines in this field. In response to this trend, South Korea is also advancing its research on regulatory decision-making using RWD/ RWE. This study aimed to explore the current utilization status of RWD/RWE for complementing and alternating clinical trials by examining guidelines from the United States, Europe, Japan, and South Korea. Through a comparative analysis of guidelines from various countries, we have developed recommendations for essential guidelines tailored to South Korea. We expect this study to enhance rational and efficient decision-making in regulatory processes and lay the groundwork for establishing clinical research that utilizes RWD/RWE.

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Tuberculosis remains a significant public health issue globally despite being preventable and treatable. This study reviews domestic and international tuberculosis treatment guidelines, focusing on recommendations for preventing ethambutol-induced optic neuropathy, a serious side effect of a key anti-tuberculosis drug. This study reviews tuberculosis treatment guidelines published between January 2015 and June 2024, focusing on recommendations for managing ethambutol-induced optic neuropathy. A systematic search was conducted using major databases and health organization websites. Guidelines were selected based on specific criteria and evaluated using the AGREE II instrument, with strengths and limitations analyzed to identify potential improvements in monitoring strategies. This study analyzed six international and one domestic tuberculosis treatment guideline using the AGREE II instrument. Guidelines varied in development rigor and transparency, with WHO and ATS/CDC/IDSA guidelines demonstrating the most comprehensive methodologies. Four guidelines, including the domestic one, addressed ethambutol-induced visual impairment, recommending baseline and periodic vision assessments. Recommendations for monitoring and managing ocular side effects varied across guidelines, emphasizing the importance of patient education and prompt reporting of visual changes. Out of seven guidelines examined, only four, including the domestic guideline, provided specific recommendations. The study emphasizes the importance of early detection and prevention of permanent visual impairment, suggesting the need for more detailed criteria, monitoring frequencies, and advanced diagnostic methods, particularly for high-risk patients. Selective use of optical coherence tomography and angiography is recommended for early diagnosis and prevention of irreversible disability.

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Objective: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) are widely used to treat dyslipidemia. Several studies indicate that statin users have greater bone mineral density and a lower risk of fractures than non-users. However, a recent study indicated that high-dose statin use increased the risk of osteoporosis. Thus, we assessed the risk of osteoporosis of statin users compared with nonusers. Methods: This was a retrospective cohort study using the National Health Insurance Service database in Korea from 2011 to 2019. Patients aged ≥ 40 years and diagnosed with dyslipidemia (ICD-10, E78) between January 1, 2014 and December 31, 2015 were enrolled. Statin users were defined as patients with at least one statin prescription. The outcome was osteoporosis. Primary analysis was performed using Cox’s proportional hazard model after 1:1 exact matching and 1:1 propensity score (PS) matching (462,900 patients per group) to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: Statin users had a lower risk of osteoporosis versus non-users (HR: 0.92, 95% CI: 0.91-0.93); the subgroup analyses were consistent. In the subgroup analysis, the risk of osteoporosis in statin users versus non-users was 0.96 (95% CI: 0.95-0.97), 0.88 (95% CI: 0.87-0.89), and 0.75 (95% CI: 0.72-0.79) in the low, moderate, and high dose groups, respectively; the results were statistically significant at all doses. Conclusion: Statin use is significantly associated with a lower risk of osteoporosis compared to non-use of statins. In particular, as the dose increased, the risk of osteoporosis decreased, confirming a dose-response relationship.

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Objective: Ammonia generated during breakdown of L-asparaginase is elevated due to excessive production or hindrance of ammonia conversion to urea. While children are in condition of growth and have faster metabolic rate compared to adults, hyperammonemia is more critical and can potentially lead to neurotoxicity. We aimed to assess the incidence and risk factors of hyperammonemia in pediatric patients with leukemia or lymphoma during hospitalization after L-asparaginase administration. Methods: Electronic medical records of pediatric patients with leukemia or lymphoma who were hospitalized at Seoul National University Children's Hospital and received L-asparaginase between 2013 and 2022, were retrospectively reviewed. Ammonia level ≥ 200 μmol/L were defined as hyperammonemia. Risk factors for hyperammonemia were analyzed using chi-square tests. Results: Among 110 patients whose ammonia levels were measured after L-asparaginase administration, hyperammonemia was observed in 70 patients (63.6%). Among them, 32 patients (45.7%) experienced neurological symptoms including nausea, vomiting, dizziness, confusion, seizure. Ideal body weight percentage, acute lymphoblastic leukemia (ALL) standard risk group and 1952 induction regimen (p = 0.019, 0.018, 0.038) were found as risk factors. Patients classified as high-risk for leukemia treatment had a higher risk of neurological symptoms (p = 0.005). Conclusion: Hyperammonemia occurred in 63.6% of pediatric hospitalized patients administered L-asparaginase. Patients with overweight or in the standard risk group for ALL were more likely to develop hyperammonemia. The risk of developing neurological symptoms in the high-risk group for ALL was higher and treatment was necessary. Thus, consistent monitoring of ammonia levels in pediatric patients administered L-asparaginase is necessary to detect hyperammonemia.

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Objective: Real-World Data (RWD) and Real-World Evidence (RWE) complement the limitations of clinical trials and play a crucial role in drug development and approval processes. This study assesses the awareness of RWD/RWE in the Korean drug approval process, and investigates practical experiences and challenges. Methods: The survey collected 113 responses through both offline and online methods. The respondents were broadly classified into two groups: those utilizing it for academic purposes and those for profitgeneration purposes. Data were analyzed using SAS 9.4 software. Results: Data revealed that only 26% of respondents felt they could fully utilize RWD/RWE currently, while 40% believed they could do so within 12 years. Both groups recognized the importance of RWD/RWE, but there were significant differences in utilization perceptions. 80% of academic respondents positively evaluated RWD/RWE, while 48% of respondents from the pharmaceutical industry indicated that more time was needed (p-value=0.011). In academia, the proportion of those with and without RWD/RWE experts was similar. However, the pharmaceutical industry showed 1.75 times higher rate of lacking such experts (p-value=0.173). Major challenges identified included data accessibility and quality issues, with the industry particularly concerned about costs. Among those without plans to utilize RWD/RWE, the main obstacles cited were the absence of experts within research teams and inadequate laws and regulations. Conclusion: This study highlights the necessity of addressing data accessibility and quality issues, training specialized experts, and providing clear regulatory guidelines and support. Bridging the perception gap between academia and the industry requires solutions to improve data accessibility and reduce cost burdens. Regulatory agencies should strengthen the legal framework for RWD/RWE utilization and establish systems and guidelines to ensure data quality and consistency. By systematically investigating the awareness and utilization of RWD/RWE in the domestic drug approval process, this study identifies key barriers and proposes solutions to overcome them. Effective utilization of RWD/RWE is expected to significantly enhance the efficiency and safety of drug development and approval processes, driving innovation.

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Objective: This study aimed to classify medication errors during clinical trials by stage of medication use, identify error types, and analyze associated factors at a single institution. Methods: Data were collected from medication errorrelated reports, including ‘protocol violation reports’ and ‘near miss reports,’ from January 1, 2018, to December 31, 2022. Errors were categorized by severity using the Medication Error Index and classified by error type using the Sheikhtaheri and psychological classification methods. Contributing factors were analyzed in terms of human, organizational, investigational product, and clinical trial design factors. Results: A total of 62 medication errors from 46 reports were identified. Errors occurred across various stages: prescribing (19.4%), preparation (46.8%), administration (1.6%), site management (9.7%), and sponsor management (22.6%). Common errors included ‘wrong dose’ in prescribing (58.3%) and ‘wrong medication’ in preparation (31.0%). Severity classification showed that most errors were in categories B (45.7%) and C (52.2%). Near miss analysis revealed that 45.6% of errors were intercepted before reaching the patient. Contributing factors were primarily human (52.9%), followed by organizational (16.1%), investigational product (16.1%), and clinical trial design factors (14.9%). Psychological classification indicated 34.8% rule-based, 30.4% knowledge-based, 21.7% action-based, and 13.0% memorybased errors. Conclusion: Understanding medication errors and their contributing factors in clinical trials can provide valuable insights for improving medication safety strategies in the planning and execution of clinical trials.

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Objective: The clinical outcome of mycophenolate (MPA) combined with tacrolimus in pediatric liver transplantation (LT) are not well understood. This study aimed to evaluate the effectiveness and safety of MPA and tacrolimus combination therapy compared to tacrolimus monotherapy in this population. Methods: This retrospective cohort study included pediatric LT patients who received at least 30 consecutive days of either tacrolimus and MPA (± steroid) combination therapy and their propensity score matched patients on tacrolimus (± steroid) monotherapy between 2010 and 2021. Incidence of acute rejection and immunosuppressantrelated adverse events (AEs) were compared between the two groups. Results: Among 130 pediatric LT patients, 32 were assigned to each group. Within one-year post-transplant, there were no statistically significant differences in acute rejection (9.4% vs. 12.5%; p = 0.502) or overall AEs (84.4% vs. 65.6%; p = 0.149) between the combination and control groups. However, a significantly higher rate of AEs leading to immunosuppressant discontinuation was observed in the combination group (62.5% vs. 3.1%; p < 0.001). No significant differences were found in severe infections, cytomegalovirus infections, post-transplant lymphoproliferative disease, or renal dysfunction. Although tacrolimus exposure was similar, the concentration/dose ratio was lower in the combination group at 1 month (1.8 ± 5.4 vs. 3.4 ± 3.8, p = 0.040). Conclusion: While acute rejection and overall AE rates did not differ significantly between the two groups, the MPA combination group had a higher rate of therapy discontinuation due to AEs. Further studies with larger populations are needed to confirm these findings.

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Objective: Acid-suppressive therapy is commonly used for stress ulcers; however, concerns have been raised regarding its potential to increase the risk of Clostridioides difficile infection (CDI). This study aimed to compare the risk of CDI associated with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) among acid-suppressive agents. Methods: We conducted a meta-analysis to systematically evaluate the risk of CDI associated with PPIs compared to H2RAs. We searched 3 major databases up to April 30, 2024. The primary outcome was the incidence of CDI. Results: The meta-analysis of 14 articles involving 160,085 patients showed PPIs were associated with a 1.50-fold increase in the risk of CDI compared to H2RAs [95% CI: 1.22–1.85, I² = 39%]. In a subgroup analysis of 8 out of 14 studies, which included 88,393 critically ill patients, PPIs were linked to a 1.58-fold increase in the risk of CDI compared to H2RAs [95% CI: 1.10–2.27, I² = 61%]. In observational studies, PPIs were associated with a 1.55-fold increase in the risk of CDI [95% CI: 1.26–1.91, I² = 33%]. In randomized trials, PPIs were not significantly associated with an increased risk of CDI compared to H2RAs [OR 1.92, 95% CI: 0.51–7.25, I² = 41%]. Conclusion: Our findings indicate that PPIs are associated with a higher risk of CDI compared to H2RAs. Further well-controlled clinical trials are necessary to confirm these results.