• Journal of Pharmaceutical Investigation
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• 제17권3호
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• pp.143-157
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• 1987

• Communications for Statistical Applications and Methods
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• 제29권4호
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• pp.421-439
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• 2022

Phase I dose-finding trials are essential in drug development. By finding the maximum tolerated dose (MTD) of a new drug or treatment, a Phase I trial establishes the recommended doses for later-phase testing. The primary toxicity endpoint of interest is often a binary variable, which describes an event of a patient who experiences dose-limiting toxicity. However, there is a growing interest in dose-finding studies regarding non-binary outcomes, defined by either the weighted sum of rates of various toxicity grades or a continuous outcome. Although several novel methods have been proposed in the literature, accessible software is still lacking to implement these methods. This study introduces a newly developed R package, UnifiedDoseFinding, which implements three phase I dose-finding methods with non-binary outcomes (Quasi- and Robust Quasi-CRM designs by Yuan et al. (2007) and Pan et al. (2014), gBOIN design by Mu et al. (2019), and by a method by Ivanova and Kim (2009)). For each of the methods, UnifiedDoseFinding provides corresponding functions that begin with next that determines the dose for the next cohort of patients, select, which selects the MTD defined by the non-binary toxicity endpoint when the trial is completed, and get oc, which obtains the operating characteristics. Three real examples are provided to help practitioners use these methods. The R package UnifiedDoseFinding, which is accessible in R CRAN, provides a user-friendly tool to facilitate the implementation of innovative dose-finding studies with nonbinary outcomes.

• Journal of Acupuncture Research
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• 제25권2호
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• pp.227-242
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• 2008

Objectives : To compare the efficacy of local acupoint with distal acupuncture at relieving pain and improving function in knee osteoarthritis. Designs : A randomized, single-blinded, crossover clinical trial. Settings : One outpatient clinic(department of acupuncture & moxibustion) located in academic teaching hospital, South Korea. Patients : 17 patients with osteoarthritis of the knee(mean age 62.76[$SD{\pm}4.37$] years). Interventions : The trial had 4 stages : baseline(2weeks), phase I and II(each 2weeks), washout period(2weeks). Patients were randomly assigned to either group A or group B. Group A received acupuncture at local acupoints during phase I, then acupuncture at distal acupoints in phase II. Group B received the treatments in reverse order. In each phase, the patients were treated with acupuncture for 6 times. Measurements : The primary outcome was subjective pain as measured by a 100mm visual analogue scale(VAS) ranging from 0(no pain) to 10(worst pain ever). Secondary outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC) total and pain scores. Measurements were obtained at baseline, 1st day of phase I and II, and 2 days after last treatment of phase I and II. Results : The 17 participants in 2 groups were well matched for age, sex, target knees, baseline VAS score, WOMAC pain score and WOMAC score. Participants in local acupoint group experienced greater improvement than distal acupoint group at 2 days after last treatment in WOMAC total score(mean difference, -10.65[95% CI, -20.56 to -0.74] ; P=0.036) but not in VAS(mean difference, -12.41[95% CI, -29.56 to 4.73] P=0.15) and WOMAC pain score(mean difference, -1.82[95% CI, -3.98 to 0.33] ; P=0.094). Conclusions : Local acupoints are more effective than distal acupoints at relieving pain and improving function in knee osteoarthritis.

• 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.

• Asian-Australasian Journal of Animal Sciences
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• 제14권10호
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• pp.1419-1424
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• 2001

Previous research in our laboratory has demonstrated the importance of lactose in phase I and II pig starter diets. Two experiments were conducted to evaluate the use of a carbohydrate by-product (food by-products) as a replacement for lactose. In Exp. I, 120 weaned pigs ($14{\pm}2d$ and 5.65kg) were allotted in a randomized complete block design (RCBD) to 10 replications with four pigs per pen. This experiment evaluated three carbohydrate sources (lactose, carbohydrate by-product, and 50-50 blend of the carbohydrate by-product and lactose). The carbohydrate sources were added at 26% in the phase I diets and 15% in the phase II diets. Phase I diets contained 7.5% spray dried plasma protein (SDP). The phase I diets were fed from d 0 to 14 and the phase II diets from d 15 to 28. There were no significant differences between carbohydrate sources on pig performance in phase I. However, during phase II pigs fed the diet with lactose had an improved gain/feed ratio (G/F) (p=0.06) compared to pigs fed the carbohydrate by-product. For the entire 28 d trial ADG, ADFI and G/F were similar for the 50-50 blend and those fed lactose. Total replacement of lactose with the carbohydrate byproduct resulted in a reduced G/F (p=0.09). Exp. 2 used 100 weaned pigs ($17{\pm}2d$ and 4.75kg) with five replications with five pigs per pen. This experiment evaluated four carbohydrate treatments (lactose, carbohydrate by-products, 50-50 blend, and corn). All phase I diets contained 3.5% SDP with the carbohydrate sources included at 15%, and were fed d 0 to 14. The phase II diets contained 7.5% of the carbohydrate sources and were fed d 15 to 27. A common phase III diet was fed d 28 to 42. During all phases pigs fed com tended to have a lower ADG than pigs fed the other carbohydrate sources with the 50-50 blend resulting in the highest ADG. The results of both experiments suggest that this carbohydrate by-product can replace at least 50% of the lactose in phase I and phase II pig starter diets.

• 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.

• Translational and Clinical Pharmacology
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• 제26권4호
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• pp.172-176
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• 2018

Mandatory registration of clinical trials in public registry can ensure the transparency of clinical trials. Public clinical trial registry of can provide current chronological and geographical distribution of clinical trial throughout the country. We used public clinical trial registry provided by Ministry of Food and Drug Safety to analyze current status of clinical trial from 2014 to 2016 in South Korea. The number of clinical trials in antineoplastic and immunomodulating agents area was the greatest, followed by cardiovascular system and antiinfectives for systemic use as a whole. From 2014 to 2016, overall number of clinical trials decreased while the number of phase I clinical trials increased. Seoul accounted for more than half number of clinical trials in Korea. Supports for clinical trials in non-metropolitan area needs to be considered.

• 응용통계연구
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• 제35권2호
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• pp.251-263
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• 2022

제1상 임상시험은 '투약 용량 발견 시험(dose finding study)'라고도 불리는데 동물 실험 또는 시험관 실험을 통하여 개발된 신약 물질을 사람에게 시험하는 첫 단계이다. 제 1상 임상시험의 목적 중 하나는 환자에게 허용할 수 있으면서 최대의 효능을 가진 복용량인 최대허용용량(maximum tolerated dose, MTD)을 결정하는 것이다. 본 논문에서는 다양한 멈춤 규칙을 이용한 MTD 추정법들을 소개한다. 또한 모의실험을 통해 SM3, NM, Rim, J3, BSM 방법을 비교하고 효율적인 MTD 추정법에 대해 고찰한다. 모의실험 결과 BSM방법이 목표독성확률에 가장 가깝게 MTD를 추정하는 것으로 나타났다. 또한 J3방법의 피험자 수가 가장 적었다. 이러한 결과는 두 방법의 멈춤 규칙의 특성 때문이라고 판단되는데 BSM방법은 독성 반응이 있을 때 같은 용량에 피험자를 2명 또는 1명을 추가한다. 또한 J3방법은 동일한 용량에 할당되는 최대 피험자 수가 다른 방법에 비해 적다. 이러한 특성들을 결합하여 추정법을 개선한다면 더 효율적으로 MTD를 추정할 수 있을 것이다. 특히 BSM방법의 멈춤 규칙을 이용하면서 총 피험자 수를 줄일 수 있다면 적은 수의 피험자로 정확한 추정이 가능할 것이다.

• 대한자기공명의과학회:학술대회논문집
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• 대한자기공명의과학회.한국자기공명학회 2005년도 공동학술대회
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• pp.77-78
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• 2005

A specific FUS-MRI platform was designed for breast cancer treatment. phased array technologies, sideways FUS transmission, and spatio-temporal temperature control in the complete region of interest, were combined for a novel therapy approach with enhanced safety and afficacy. A phase I clinical trial will start soon.

• Communications for Statistical Applications and Methods
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• 제26권2호
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• pp.163-173
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• 2019

Simon's two-stage designs are frequently used in phase II single-arm trials for efficacy studies. A concern of safety studies is too many patients who experience an adverse event. We show that Simon's two-stage designs for efficacy studies can be similarly used to design a two-stage safety study by modifying some of the design parameters. Given the type I and II error rates and the proportion of adverse events experienced in the first stage cohort, we prescribe a procedure whether to terminate the trial or proceed with a stage 2 trial by recruiting additional patients. We study the relationship between a two-stage design with a safety endpoint and an efficacy endpoint as well as use simulation studies to ascertain their properties. We provide a real-life application and a free R package gen2stage to facilitate direct use of two-stage designs in a safety study.