• Journal of Pharmaceutical Investigation
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• v.17 no.3
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• pp.143-157
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• 1987

• Communications for Statistical Applications and Methods
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• v.29 no.4
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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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• v.25 no.2
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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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• v.18 no.5
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• pp.581-594
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• 2011

The traditional method of 3+3 standard design and model-based Bayesian continual reassessment method (CRM) are commonly used in Phase I clinical trials to identify the maximal tolerated dose(MTD) of a new drug. In this paper we review clinical examples of Phase I trials that were carried out in patients with refractory or relapsed leukemia and myelodysplastic syndrome. The recently proposed 3+1+1 design and rolling-6 design can shorten the trial duration, when a very slow accrual of patients with a simple 3+3 standard design may result in the untimely termination of trials. Too conservative approaches in determining the dose levels in Phase I clinical trials can leave clinical investigators unable to accurately determine the MTD. When determining future patient doses, the designs that use a time-to-event CRM can cooperate late toxicities by accounting for the proportion of the observation period of each enrolled patient. With the CRM design, simulations under different scenarios during the trial are important in detecting the under- or over-estimation of the initial estimate of the dose-limiting toxicity rate for each dose level. We present the advantages and drawbacks of the designs used in Phase I clinical trials for leukemia patients.

• Asian-Australasian Journal of Animal Sciences
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• v.14 no.10
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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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• v.15 no.2
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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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• v.26 no.4
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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.

• The Korean Journal of Applied Statistics
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• v.35 no.2
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• pp.251-263
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• 2022

Phase I clinical trial is called 'Dose finding study'. It is first step of experimenting on humans with new drugs developed through animal experiments or vitro experiments. The important area of interest in designing Phase I clinical trial is determining the dose that acceptable level to the patients and provides the greatest efficacy. In this paper, we explain about methods to determine the maximum tolerated dose using various stopping rules. The SM3, NM, Rim, J3, BSM methods are compared through simulation. And we consider how the methods might be reformed. As a result of the simulation, BSM estimated the MTD closest to the target toxicity probability. J3 method required the least number of subjects. These results are due to the feature of the stopping rules of both methods. The BSM adds 2 or 1 subject at the same dose level when there is a toxic reaction. In addition, the J3 method has a smaller number of subjects than the other methods. If the methods are improved by combining these features, MTD can be estimated more efficiently. If the total number of subjects can be reduced while using the stopping rule of the BSM, accurate estimation is possible for a small number of subjects.

• Proceedings of the KSMRM Conference
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• 2005.09a
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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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• v.26 no.2
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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.