• Communications for Statistical Applications and Methods
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• 제19권1호
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• pp.57-64
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• 2012

제 1상 임상시험에서 주목표는 부작용이 발생하지 않고 피험자가 견딜 수 있는 한도 내에서 최대 용량인 최대허용용량(Maximum Tolerated Dose; MTD)을 결정하는 것이다. 최대허용용량을 결정하는 방법에는 SM방법, CRM방법 등이 있는데 본 논문에서는 기존의 Stopping rule을 변형한 두 단계 MTD 추정방법을 제안하였다. 기존의 방법들을 본 논문에서 제안한 방법과 모의실험을 통하여 비교하였다.

• 생물정신의학
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• 제19권4호
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• pp.153-158
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• 2012

Understanding of a clinical trial is essential in developing clinical guideline and adopting evidence based practice. In designing and executing clinical trials, following ethical requirements should be considered : social value, scientific validity, fair subject selection, informed consent, favorable risk-benefit ratio, institutional review board, and respect for human subjects. According to the stage of drug development, purpose of trials, accumulated scientific data, clinical trials for drug development are classified as phase 1, 2, 3, and 4. Phases of clinical trials can be overlapped and the judgment of entering into the next phase should be considered highly strategically. In reading, evaluating and interpreting clinical trial reports, various skills and challenges exist. Patient sample composition, trial duration, selection of endpoints, responders and non-responders, placebo effect, patient recruitment, and extrapolation to the real world are the examples of those challenges. Treatment success will come from the well balanced approach of evidence based decision making and consideration of specific single case.

• 응용통계연구
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• 제27권1호
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• pp.13-20
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• 2014

제 1상 임상시험의 목적은 피험자가 견딜 수 있는 최대의 용량인 최대허용용량(Maimum Tolerated Dose; MTD)을 추정하는 것이다. 최대허용용량을 추정하는 방법으로는 SM방법, ATD방법, CRM방법 등이 있다. 본 연구에서는 제 1상 임상시험에서 멈춤규칙을 이용한 최대허용용량 추정법을 제안하였다. 제안한 최대허용용량 추정법은 연속재평가방법(Continual Reassessment Method; CRM)과 모의실험을 통해 비교하였다.

• Communications for Statistical Applications and Methods
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• 제18권2호
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• pp.179-187
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• 2011

제 1상 입상시험의 주된 목적은 신약의 최대허용용량(Maximum tolerated dose; MTD)의 추정이다. 본 논문에서는 실험으로 얻어진 Dose-toxicity data를 S자 모형에 적합 시켜 MTD를 추정하는 방법을 제안하였다. 멈춤 규칙(stopping rule)에 의해 MTD가 결정되는 방법과 미리 정해진 표본수에서 실험을 종료하고 MTD를 추정하는 기존의 추정방법을 본 논문에서 제안한 방법과 모의실험을 통하여 비교하였다.

• Journal of the Korean Data and Information Science Society
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• 제23권6호
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• pp.1085-1091
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• 2012

제 1상 임상시험의 주목적은 신약 후보 물질의 독성을 평가하여 부작용 및 안전하게 투여할 수 있는 약물의 적정한 용량인 최대허용용량의 추정이다. 기존에 최대허용용량을 추정하는 방법에는 표준방법 (Storer, 1989; Korn 등, 1994) 그리고 NM방법 (Lee와 Kim, 2012) 등이 있다. 본 연구에서는 많은 피험자들이 낮은 용량에 많이 할당되는 점을 보완하고 기존의 최대허용용량 추정법보다 적은 수의 피험자로 실험하기 위해서 기존 최대허용용량 추정법을 수정한 멈춤 규칙을 적용시킨 추정법을 제안하였다. 기존의 방법들과 새롭게 제시한 방법을 모의실험을 통하여 비교하였다.

• 대한기관윤리심의기구협의회지
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• 제5권1호
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• pp.14-20
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• 2023

Purpose: To obtain fundamental data on selection tools for an internal audit and develop a new guideline. We scored the indicated points from the internal audit, identified the research progress and problems that occurred, and confirmed the validity of the risk factors involved. Methods: Of the 63 internal audits conducted by Keimyung University Dongsan Hospital from 2014 to 2021, we analyzed 55 clinical trials with an inspection checklist. We excluded 8 that failed to transfer data and refused to comply with the internal audit. The statistical summary of the collected data was verified and interpreted by using frequency analysis and a chi-square test. Result: Of total 55 cases included in the internal audit, sponsor-initiated trial (SIT) was 63.6% (vs. investigator-initiated trial [IIT]), clinical trial for investigational drug was 71.0% (vs. nonclinical or clinical trial for investigational device), domestic multicenter trial was 60.0% (vs. single center or multinational multicenter trial), and trial requisition for MFDS approval was 69.1% (vs. exception for MFDS approval). The 10 areas of the clinical trial inspection checklist (reports, protection of subjects, compliance with protocols, records, management of investigational drug and/or device, delegation of duties, qualification of investigators, management of specimen, contract-agreement and approval of protocols, and preservation of recorded documents) were weighted between 2 to 5 points. The average of the total points was 16.09±13.2 and 20 clinical trials were above the average. As a result of comparing the average of the total points weighted by year, the highest score was in 2020. The 4 factors that play significant roles in determining the internal quality were (1) principal subjects that initiated the clinical trials (p=0.049), (2) type (p=0.003), (3) phase of clinical trials (p=0.024), and (4) number of registered subjects reported at the time of continuing deliberation (p=0.019). Of the 10 areas of the clinical trial inspection checklist, 'record' was the most inappropriate and insufficient. We found more indicated points; the quality of performance declined in IIT, nonclinical trials, and other clinical trials that were not in phase I1-IV4, and the study of more than 30 registered subjects at the time of continuing review. Conclusion: If an institution has an internal audit selection tool that reflects the aforementioned risk factors, it will be possible to effectively manage high-risk studies; thereby, contributing to an efficient internal audit and improving the quality of clinical trials.

• 응용통계연구
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• 제32권5호
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• pp.741-752
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• 2019

제1상 임상시험의 주목적은 최대허용용량(maximum tolerated dose; MTD)을 결정하는 것이다. MTD 결정을 통해 다음 임상시험에 사용될 용량이 제한되므로 투약용량 발견 시험이라고도 불리며 매우 중요한 단계이다. MTD를 결정하는 방법에는 대표적으로 DM 방법, SM 방법, CRM 방법이 있다. 본 논문에서는 기존 수정된 CRM 방법에 초기가속화 단계를 적용하여 낮은 용량에 다수의 피험자가 할당되는 문제점을 보완하는 새로운 MTD 추정 방법을 제안하였고 기존 방법들과의 비교를 위해 모의실험을 실시하였다.

• Journal of Acupuncture Research
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• 제15권2호
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• pp.183-198
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• 1998

This study was done in order to present clinical trial method for safety of herb-acupuncture. The results were summerized as follow: In case of western medicine, clinical trial divides into four phase 1. Phase I: Investigate safety and drug movement for health people. 2. The first phase II: Investigate safety, effectiveness for the limited patient. The late phase II: Investigate propriety of an applicable disease, the way to use and dose. 3. Phase III: Through the comparative, public trial, investigate a final, applicable disease and side effect. 4. Phase IV: After NDA, investigate safety and effectiveness for the wide patients. In case of herb-acupuncture, we have to investigate the following for safety and effectiveness 1. Drug dose: Decide with 1/2 or 1/3 of oral dosage or a basis of animal's of maximum dosage or a ratio of man and animal. 2. Toxicity: Examine blood, urine, liver function, EKG, after herb-acupuncture during acertain period of time. 3. Regional response: Estimate response of swelling, redness, pruritus. etc 4. Treatment effectiveness: After exactly diagnosis, estimate effectiveness with a objective guide post.

• Genomics & Informatics
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• 제16권3호
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• pp.52-58
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• 2018

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

• Communications for Statistical Applications and Methods
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• 제18권5호
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• pp.581-594
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• 2011

제 1상 임상시험 계획에서 신약제의 최대허용용량을 추정하기 위해 전통적 방법인 표준 3+3계획과 모형중심의 베이지안 방법을 적용시킨 연속재평가방법이 주로 사용되고 있다. 본 논문에서는 치료불응 또는 재발된 백혈병이나 골수형성 이상증후군 환자를 대상으로 시행한 제 1상 임상시험의 연구계획을 개관하였다. 단순한 표준 3+3계획으로 환자확보 기간이 길어져 연구를 완성하지 못하고 때 이르게 중단할 수밖에 없는 실정에 반하여, 최근에 제시된 표준 3+1+1계획과 Rolling-6 계획은 연구기간을 크게 단축시킬 수 있다. 제1상 임상시험의 용량수준 선택과정에서 너무 보수적인 연구자의 태도는 최대허용용량의 정확한 추정을 불가능하게 한다. 새로운 환자에게 투여할 용량수준을 결정할 시점에서 용량제한 독성반응이 아직 나타나지 않은 환자의 관측시간 및 늦게 나타나는 환자의 독성반응 시간을 모두 감안한 연속재평가방법인 TITE-CRM계획이 유용하며, 이러한 CRM계획으로 진행되는 임상시험 시행 중 모의실험으로 각 용량수준에서 용량제한 독성반응율이 과대 또는 과소 추정되는지를 파악할 수 있음이 장점이다. 백혈병환자 대상의 임상연구에서 채택되는 제 1상 임상시험의 여러 연구계획의 장, 단점을 제시한다.