Statistical analysts engaged in typical clinical trials often have to confront a tight schedule to finish massive statistical analyses specified in a Standard Operation Procedure (SOP). Thus, statisticians or not, most analysts would want to reuse or slightly modify existing programs. Since even a slight misapplication of statistical methods or techniques can easily drive a whole conclusion to a wrong direction, analysts should arm themselves with well organized statistical concepts in advance. This paper will review basic statistical concepts related to typical clinical trials. The number of variables and their measurement scales determine an appropriate method. Since most of the explanatory variables in clinical trials are designed beforehand, the main statistics we review for clinical trials include univariate data analysis, design of experiments, and categorical data analysis. Especially, if the response variable is binary or observations collected from a subject are correlated, the analysts should pay special attention to selecting an appropriate method. McNemar's test and multiple McNemar's test are respectively recommended for comparisons of proportions between correlated two samples or proportions among correlated multi-samples.

Background: Vardenafil is a phosphodiesterase type 5 inhibitor, used in erectile dysfunction. This study aimed to evaluate the pharmacokinetics and tolerability of vardenafil following a single oral administration in healthy male subjects. Methods: A randomized, double-blind, placebo-controlled, single dosing, dose-escalation study was conducted in 30 healthy subjects. A single oral dose of vardenafil or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 5, 10 and 20 mg. Serial blood and urine samples were obtained up to 48 hours for pharmacokinetic analysis. Vardenafil and its metabolite were detected by high performance liquid chromatography tandem mass spectrometry assay. Results: A total of 45 adverse events (AE) were reported in 22 subjects, including 5 AEs from placebo treatment, and all the AEs were mild, except one case of moderate nasal stuffiness. Vardenafil was absorbed after a single oral dose, with the $t_{max}$ of 0.5-1.0 hours. The $C_{max}$ and $AUC_{last}$ were $10.21{\pm}3.68$ ug/L($mean{\pm}SD$) and $18.08{\pm}7.44\;ug{\times}h/L$ in 5 mg dose group, $19.79{\pm}12.13$ ug/L and $38.61{\pm}21.04\;ug{\times}h/L$ in 10 mg dose group and $53.16{\pm}37.01$ ug/L and $110.05{\pm}69.65\;ug{\times}h/L$ in 20 mg dose group. Dose-linearity on $AUC_{last}$ and $C_{max}$ of vardenafil were observed in three dose groups. In all dose groups, the fraction excreted in urine was less than 1%. Conclusion: The vardenafil was tolerable over a single dose range of 5 - 20 mg. The pharmacokinetics of vardenfil after a single oral dose was explored and linear pharmacokinetic characteristics were observed over the dose range of 5 - 20 mg in healthy subjects.

배경: 레트로졸은 유방암 치료에 사용되는 경구용 비스테로이드성 aromatase 억제제이다. 방법: 이 연구는 건강한 성인 남성을 대상으로 무작위 배정, 단회 투여, 공개설계로서 두 치료군, 두 순서, 두 시기의 교차 시험법으로 진행되었다. 각 순서군에 13명씩 무작위 배정되어, 한군은 1기에 페마라$^{(R)}$정(대조약)을, 2기에 유한 레트로졸정(시험약)을, 다른 한군은 반대 순서로 두 시기 사이에 약 5주의 휴약기를 가지고 각각 2.5 mg정 1정씩 투여 받았다. 약동학 분석을 위한 혈액 검체는 공복 상태에서 투약 후 312 시간까지 얻어졌다. 레트로졸의 혈장 내 농도는 liquid chromatography-tandem mass spectrometry를 이용하여 측정하였다. 안전성 평가는 활력징후, 문진 및 신체검사, 심전도, 진단검사실 검사와 이상반응 모니터링을 통하여 이루어졌다. 결과: 총 26명의 피험자가 연구를 완료하였고, 약동학 분석에 26명의 자료가 모두 사용되었다. $C_{max}$와 $AUC_{last}$ 파라미터에 대한 시험약과 대조약의 기하평균비는 각각 0.92 (90 % 신뢰구간: 0.85 - 0.99)와 1.01 (90 % 신뢰구간: 0.97 - 1.04)였다. 보고된 중대한 이상반응은 없었으며, 임상적으로 유의한 변화도 관찰되지 않았다. 결론: 건강한 자원자에서 페마라$^{(R)}$정과 유한 레트로졸정의 약동학 특성과 안전성은 유사하였다.

Background: Olmesartan medoxomil is an angiotensin II receptor blocker commonly used in hypertension. First objective of this study was to evaluate the bioequivalence of two olmesartan formulations, Olmesartan 20 mg and 40 mg tablet (Yuhan, Pharmaceutical Corp. Seoul, Korea) as test drugs and $Olmetec^{(R)}$ 20 mg and 40 mg tablet (Daewoong, Pharmaceutical Corp. Seoul, Korea) as reference drugs. Second objective of this study was to evaluate the dose-proportionality of two formulations. Methods: Two studies (20 mg, 40 mg) were conducted as a randomized, open-label, 2-period, crossover design. Each subject received one 20 mg or 40 mg tablet of the reference or test formulation of olmesartan medoxomil in each study. Blood samples were obtained during the 48-hour period after the dose in each treatment period. Wash-out period was 1 week in each study. Concentrations of olmesartan medoxomil in plasma were analyzed using a liquid chromatography system with tandem mass-spectrometric detection (LC/MS/MS). The primary pharmacokinetic parameters were $C_{max}$ (maximum concentration) and $AUC_t$ (area under the concentration-time curve from time 0 to the last sampling time). Results: A total number of 40 healthy male volunteers participated in the study and 37 volunteers completed both treatment periods in 20 mg trial. All 40 participants completed both treatment periods in 40 mg trial. The 90 % CIs for the geometric mean ratios of the pharmacokinetic parameters (test:reference drug) were 0.93 ~ 1.04 for $AUC_t$ and 0.97 ~ 1.08 for $C_{max}$ in 20 mg trial. The 90 CIs were 0.94 ~ 1.02 for $AUC_t$ and 1.00 ~ 1.11 for $C_{max}$ in 40 mg trial. All parameters of two studies satisfy the range of bioequivalence criterion. Conclusion: The obtained results indicated that pharmacokinetic exposure to Olmesartan 20 mg and 40 mg tablet was bioequivalent to that of $Olmetec^{(R)}$ 20 mg and 40 mg tablet, respectively.

Background: Spontaneous adverse drug reaction (ADR) reporting data has been used for safety of post-market drug surveillance. A system has been required that is able to detect signals associated with drugs by analyzing the collected ADR data. Methods: We developed the web-based automated analysis system (ADR-detector). We used the data which reported ADR spontaneously between March 2009 and December 2010 to Korean Food and Drug Administration. We used 3 statistical indicators for evaluating ADR signals: proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). The ADR reports which were detected as significant signals based on the indicators have been reviewed. Results: Among 153,774 reports, 9,955 cases were related to 4 analgesics which were most frequently reported analgesic drugs during the study period. The numbers of ADR reports associated with each drug are as follow: 5,623 reports in tramadol (56.5 %), 1,720 reports in fentanyl (17.3 %), 1,463 reports in tramadol-combination (14.7 %), and 1,149 reports in ketorolac (11.5 %). Top 5 ADR were nausea (3,351 reports - 33.7 %), vomiting (1,755 reports - 17.6 %), dizziness (1,130 - 11.4 %), rash (412 reports - 4.1 %), and pruritus (354 reports - 3.6 %). 6,674 ADR reports were significant based on PRR and ROR, and 336 reports were significant based on IC. Conclusion: By using the automated analysis system, not only statisticians but also general researchers are able to analyze ADR signals in real-time. Also ADR-detector would provide rapid review and cross-check of ADR.

Background: This study was performed to evaluate the prevalence and risk factors on the adverse reactions caused by iodinated contrast media (CM) for computed tomography (CT) examination in a university hospital. Methods: Clinical and demographic data among outpatients with CM use were collected at 0000 University Busanpaik Hospital in Busan, Korea between 2008 and 2010. Adverse reaction rate was calculated by the number of adverse reaction among total outpatients with CM use, which was stratified by seasons and sex. The association of risk factors on adverse reaction was investigated using logistic regression model. Results: The total outpatients and events of administered CMs were 27,587 and 48,616, respectively. The administered CMs were iopromide, iohexol, iobitridol, and iodixanol. Adverse reactions occurred in 300 outpatients among the total outpatients (1.1 %). The number of outpatients administered CM more than twice were 8,348. Among them, outpatients who experienced adverse reaction(s) more than once and twice were 124 (1.5 %) and 26 (0.3 %), respectively. Adverse reaction rate was significantly different by sex(p=0.01). The other risk factors were cancer history (OR 2.57, 95 % CI 2.00-3.31) and previous CM administration (OR 1.89, 95 % CI 1.47-2.44). Urticaria was the most frequent symptoms. Conclusion: Total adverse reaction rate was 1.1 % with most common symptom in skin system. Related risk factors were female, cancer history, and previous CM administration. These results were similar to previous studies and will be contribute to clinical practice and future research especially in Koreans.

Background: Metformin is an effective oral antihyperglycaemic agent for type 2 diabetes mellitus, with a variety of metabolic effects. In addition to controlling blood glucose level, it has been appeared to decrease the long-period complications of diabetes, including macrovascular disease. Few reports have addressed the metabolite profiling of metformin. The study was to evaluate if targeted metabolic profiling approach is sensitive enough to predict the therapeutic effects of metformin after a single oral dose. Methods: A randomized, open-label, single-dose study was conducted in twenty eight healthy Korean male volunteers. To determine the concentrations of endogenous metabolites in their pre-dose and post-dose plasma samples, blood samples were collected before and at 2 and 6 h after a single oral dose of 500 mg metformin. Both Modular P/Modular D analyzer and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based metabolic profiling was performed. Results: We quantified pre-dose and post-dose creatinine, blood urea nitrogen (BUN), lactic acid, 7 amino acids (lysine, glutamic acid, alanine, valine, leucine, phenylalanine, tryptophan), and 5 lysophosphatidylcholines (14:0, 16:0, 17:0, 18:0, and 18:1) using autoanalyser and UPLC-MS/MS. The postdose levels of alanine, lactic acid, glutamic acid, lysine, valine, leucine, phenylalanine, tryptophan, and lysoPC (18:1) were slightly decreased with statistical significance, but there is no clinical significance. Conclusion: In order to explore the potential endogenous metabolites associated with the therapeutic effects of metformin, further study including non-targeted (global) metabolite profiling is needed.

Backgroung: In recent years, clinical trials have considerably increased and relevant education programs to clinical trials have been developed and implemented since 2008 in Korea. To enhance the quality as well as global competitiveness of clinical trial professionals (CTPs), a certification program of the human resource is needed. Accordingly, in Korea the first and the second certification examinations were implemented in February and October 2012, respectively. In this paper, introduction of the certification program of the human resource is described, and results of the cerification examinations and questionnaire survey are presented. Methods: Data including the examination results and questionaire survey was collected by cooperative officials in Korea National Enterprise for Clinical Trials. Applicants who were selected eligible for examination by the steering committee were asked to complete questionnaires provided with the test papers on the day of the certification examination. Results: In the first certification examination, a total of 221 eligible participants completed the examination. 99.5% of the participants responded the questionnaire survey. In the second examination, a total of 223 applicants participated. The examination consisted of 50 multiple-choice questions with cut-off score of 70 per cent score. 176 & 194 CTPs passed the first & second examinations respectively. Conclusion: This paper that described the results of the two cerification tests and questionnaire surveys might be helpful in establishment and activation of the certification program in the future. Quality improvement of CTPs and international competitiveness of clinical trial in Korea can be anticipated by the certification program.

Background: To evaluate the safety and effectiveness of rosiglitazone/metformin in patients with type 2 (non-insulin-dependent) diabetes Methods: A total of 982 patients were enrolled by 19 physicians from November 2003 to November 2010. Patients treated with rosiglitazone/metformin at least once, were included in safety assessment. The incidences of adverse events (AEs) and serious adverse events (SAEs) were estimated. The effectiveness of rosiglitazone/metformin was evaluated through change in fasting blood glucose (FBG), 2-hour postprandial glucose (2hr PPG), Hemoglobin A1c (HbA1c). Results: Of the 982 patients, 713 patients with the mean age of $56.4{\pm}11.5$ years were included in the safety assessment. A total of 130 AEs were reported from 110 patients (15.4 %). The most frequent AEs were upper respiratory infection (2.4 %), oedema (2.2 %), gastritis (1.3 %), and weight increase (1.1 %). The incidence of unexpected AEs was 5.9 % (42/713, 47 AEs). Three SAEs such as bacterial pneumonia, hyperglycaemia, chest pain were reported in 2 patients. As it is about effectiveness, patients showed statistically significant reductions after treatment of rosiglitazone/metformin in FBG, 2hr PPG, and HbA1c (P<0.001 by paired t-test, for all). Conclusion: Our data suggest that rosiglitazone/metformin is well tolerated and effective in Korean patients with type 2 (non-insulin-dependent) diabetes.