Perspectives on Adopting the Guideline for Multi-regional Clinical Trials in Korea: A Multi-stakeholder Survey

BACKGROUND@#With the globalization of drug development, multi-regional clinical trials (MRCTs) have emerged to facilitate rapid availability of medicines to patients worldwide. The present study aimed to has explored attitudes and perceptions towards adopting the Korean MRCT guideline.@*METHODS@#An online survey, consisting of 16 questions, classified into two subjects, was administered to stakeholders in Korea. Most quantitative components were measured using the Likert scales. A content analysis of the qualitative components was carried out to identify the keywords in open-ended responses.@*RESULTS@#A total of 94 survey responses were analyzed: 51 participants from pharmaceutical companies, 11 from clinical research organizations, and 21 from clinical trial centers. The content of the guideline was rated as appropriate for clarity, acceptability, and applicability (96.8, 96.8, and 93.6%, respectively). The local environmental impact of the systemic/political, academic/technical, and industrial/economical aspects of the guideline was rated as appropriate at 95.7, 97.9, and 91.5%, respectively. The suggested adoption period was 1~2 years (40, 42.6%). The concept and individuals' domestic circumstances were the key problems affecting the clarity, applicability, and local environmental impact of the guideline.@*CONCLUSION@#The Korean MRCT guideline was well-developed. Their overall impact on the local environmental impact of MRCTs in Korea was expected to be beneficial, but methods are needed to minimize the negative impacts. The findings of this study can inform the priorities for the future adoption of the guideline in Korea.

Effects of Tumor Necrosis Factor-alpha Inhibitors on the Incidence of Tuberculosis

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) inhibitors are used as a treatment in various immune-mediated inflammatory diseases (IMIDs). Tuberculosis (TB) risk is reported in several meta-analyses in patients treated with TNF-alpha inhibitors. The purpose of this study is to collect, review, and evaluate the TB risk in TNF-alpha inhibitors according to IMIDs indications and between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors. METHODS: A systematic literature search on systematic reviews and meta-analyses was performed in PubMed, MEDLINE, Cochrane library, and EMBASE. We identified meta-analyses that evaluated TB infection risk of TNF-alpha inhibitors in IMIDs patients. RESULTS: Thirteen meta-analyses including 41 study results were included in this umbrella review. IMIDs patients treated with TNF-alpha inhibitors had an increased risk of TB than control group (placebo with or without standard therapy patients) (relative risk ratio (RR) 2.057, 95% confidence interval (CI) 1.697 to 2.495). Among them, RA patients with TNF-alpha inhibitors had a higher risk of TB than control group (RR 1.847, 95% CI 1.385 to 2.464), and non-RA patients with TNF-alpha inhibitors had an increased risk of TB (RR 2.236, 95% CI 1.284 to 3.894). In subgroup analysis on TB risk between soluble-receptor TNF-alpha inhibitor and monoclonal-antibody TNF-alpha inhibitors in RA patients, the analysis indicated that monoclonal-antibody TNF-alpha inhibitors had higher risk of TB than solublereceptor TNF-alpha inhibitor (RR 2.880, 95% CI 1.730 to 4.792). CONCLUSION: This umbrella review confirms that the risk of TB is significantly increased in TNF-alpha inhibitor treated patients compared to control group.

Regulations and Guidelines for Planning and Design of Multi-regional Clinical Trials

OBJECTIVE: Multi-regional clinical trials have been widely used for accelerating global drug development by multinational pharmaceutical companies. In this study, we aimed to review and analyze the international trends in regulations and guidelines on multi-regional clinical trials by regulatory authorities and international organizations, such as International Conference on Harmonisation, for referring to policies, including development of domestic guidelines for multi-regional clinical trials. METHODS: The policies, regulations, and guidelines published by the US Food and Drug Administration, European Medicines Agency, Pharmaceuticals and Medical Devices Agency (Japan), and China Food and Drug Administration were searched, and the International Conference on Harmonisation E17 draft guideline was reviewed. RESULTS: The regulatory authorities in developed countries have developed and implemented regulations and guidelines on multi-regional clinical trials to promote simultaneous global drug development and evaluate the regional differences in drug safety and efficacy. International Conference on Harmonisation developed the draft guideline for planning/designing of multi-regional clinical trials in 2016, which recommends the general principles for strategy-related issues and design of multi-regional clinical trials, and for protocol-related issues, such as consideration of regional variability, subject selection, dose selection, endpoints, comparators, overall sample size, allocation to regions, collecting information on efficacy and safety, and statistical analysis. CONCLUSION: It is important to understand the international regulatory requirements for designing and planning of multi-regional clinical trials for global drug development. Moreover, it is necessary to prepare multi-regional clinical trial guidelines in accordance with the Korean regulation for clinical trials and drug administration.

Regulation of Pharmacogene Expression by microRNA in The Cancer Genome Atlas (TCGA) Research Network

Individual differences in drug responses are associated with genetic and epigenetic variability of pharmacogene expression. We aimed to identify the relevant miRNAs which regulate pharmacogenes associated with drug responses. The miRNA and mRNA expression profiles derived from data for normal and solid tumor tissues in The Cancer Genome Atlas (TCGA) Research Network. Predicted miRNAs targeted to pharmacogenes were identified using publicly available databases. A total of 95 pharmacogenes were selected from cholangiocarcinoma and colon adenocarcinoma, as well as kidney renal clear cell, liver hepatocellular, and lung squamous cell carcinomas. Through the integration analyses of miRNA and mRNA, 35 miRNAs were found to negatively correlate with mRNA expression levels of 16 pharmacogenes in normal bile duct, liver, colon, and lung tissues (p<0.05). Additionally, 36 miRNAs were related to differential expression of 32 pharmacogene mRNAs in those normal and tumorigenic tissues (p<0.05). These results indicate that changes in expression levels of miRNAs targeted to pharmacogenes in normal and tumor tissues may play a role in determining individual variations in drug response.

Clinical Outcomes of Multidisciplinary Team Care on the Regulation of Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) in Patients Undergoing Dialysis

BACKGROUND: Multidisciplinary team care (MTC) is a collaborative approach to treatment plan and ongoing care. We aimed to evaluate the clinical effect of MTC on the regulation of chronic kidney disease-mineral and bone disorder (CKD-MBD) complications in dialysis patients. METHODS: This retrospective observational study was approved by the institutional review board. Among patients who have undergone dialysis at admission, the patients admitted to the nephrology ward were allocated to MTC group, and the others to usual care (UC) group. The MTC group had collaborative care by nephrologists, nurses, pharmacists, and nutritionists. The endpoints were the regulation of corrected calcium (cCa) and phosphate (P), the percent of patients in target level of cCa-P product (cCa×P), and the prescription rate of non-calcium based P-binders. RESULTS: A total of 163 patients were included from January to December 2009. A significant difference was shown in the percentage of patients in target cCa×P level at admission (MTC vs. UC, 81.40% vs. 91.67%; P = 0.038), but there was no significant difference at discharge. During admission, the cCa and P levels of patients in only UC group were significantly changed. In addition, compared with UC group, patients in MTC group were more likely prescribed appropriate P-binders, when they had higher cCa×P levels than 55 mg²/dL² (P <0.001). CONCLUSION: It was found that MTC had beneficial effect on improving the regulation of CKD-MBD and the appropriate phosphate binder uses. Therefore, application of the MTC is anticipated to enhance quality of clinical care in chronic diseases.

Near-infrared Fluorescence Imaging Using a Protease-activatable Nanoprobe in Tumor Detection: Comparison with Narrow-band Imaging

BACKGROUND/AIMS: Advances in endoscopic technology seek to improve the accuracy of neoplastic tumor detection. Recently developed endoscopy devices such as narrow-band imaging (NBI) nevertheless have limitations in morphologic diagnosis. The purpose of this study was to investigate whether a novel imaging technique-near-infrared fluorescence (NIRF) imaging using a protease-activatable nanoprobe-could provide more accurate neoplastic tumor detection, compared to NBI. METHODS: Images of the intestines of Apc(Min/+) mice were obtained by NIRF using a matrix metalloproteinase (MMP)-sensing probe, which was based on a nanoparticle platform. Immediately after imaging, endoscopy with NBI capability was performed on the same excised intestine. Macroscopic and microscopic findings in the intestines were assessed, and MMP expression was analyzed by Western blotting and real-time polymerase chain reaction. RESULTS: Numerous tiny polypoid lesions were present in the intestines of aged Apc(Min/+) mice. These lesions included adenomas, lymphoid follicles, and protruding normal tissues. When using NIRF imaging with an MMP-activatable nanoprobe, adenomatous polyps showed higher fluorescence, compared to lymphoid follicles or adjacent normal tissues. The expression of MMP was higher in the adenomatous tissue than in the other tissues. The sensitivity and specificity for adenoma detection were 88.9% and 82.2%, respectively, when using NIRF imaging with a MMP-nanoprobe, compared to 77.8% and 66.7%, respectively, when using NBI (P<0.05). CONCLUSIONS: Near-infrared fluorescence imaging with a protease-activatable nanoprobe could aid in the differentiation of tumor characteristics. Clinical application of this approach may improve the endoscopic detection of neoplastic tumors.

Pleomorphic Adenoma of the Breast: A Diagnosis Using an Ultrasound-Guided Core-Needle Biopsy Case Report

Pleomorphic adenoma is a tumor rarely seen in the breast. To date, only about 70 cases have been reported in the literature. Many reports have used fine-needle aspiration biopsy in the preoperative diagnosis of these lesions. However, pleomorphic adenoma is sometimes mistaken for a malignant tumor because of its cytologic features. In this study, we present a 56-year-old woman with a palpable breast mass. Ultrasound indicated a 15 mm oval-shaped hypoechoic mass with complex echogenicity in the palpable region. Ultrasound-guided core needle biopsy (US-CNB) revealed a pleomorphic adenoma of the breast, which was confirmed through surgical excision. Although pleomorphic adenoma is rarely seen in the breast, results demonstrate the usefulness and accuracy of US-CNB in diagnosing pleomorphic adenoma of the breast.

Near-Infrared Fluorescence Imaging Using a Protease-Specific Probe for the Detection of Colon Tumors

BACKGROUND/AIMS: Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages. METHODS: We utilized two murine colon cancer models: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe. RESULTS: Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa. CONCLUSIONS: NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.