• Communications for Statistical Applications and Methods
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• v.22 no.5
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• pp.401-413
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• 2015

In this article, we review the statistical methods and theory for dose finding in early phase clinical trials, where the primary objective is to identify an acceptable dose for further clinical investigation. The dose finding literature is initially motivated by applications in phase I clinical trials, in which dose finding is often formulated as a percentile estimation problem. We will present some important phase I methods and give an update on new theoretical developments since a recent review by Cheung (2010), with an aim to cover a broader class of dose finding problems and to illustrate how the general dose finding theory may be applied to evaluate and improve a method. Specifically, we will illustrate theoretical techniques with some numerical results in the context of a phase I/II study that uses trinary toxicity/efficacy outcomes as basis of dose finding.

• 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.

• The Korean Journal of Applied Statistics
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• v.33 no.2
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• pp.137-145
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• 2020

Phase I clinical trials (Dose Finding Studies) are the first step in administering new drugs developed through animal experiments or in vitro experiments to humans. An important area of interest in designing Phase I clinical trials is determining the dose that provides the greatest efficacy and acceptable safe dose to the patient. In this paper, we propose a method to determine the maximum tolerated dose considering efficacy and safety using Biased coin design and stopping rule. The proposed method is compared with existing methods through simulation.

• 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.

• Biomolecules & Therapeutics
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• v.11 no.3
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• pp.178-182
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• 2003

The clinical use of once daily aminoglycoside (ODA) dosing has been increased because of the potential therapeutic advantages of this dosing regimen. To evaluate the optimal sampling times of ODA dosing method in a clinical setting, the study was prospectively conducted in a total of 28 patients with UTI. All of the patients were intravenously administered gentamicin at a dose of 7 mg/kg over 60 minutes and randomly divided into two groups. Blood was collected at 0, 2, and 6 hours in Group A and at 1, 2, and 6 hours in Group B after the end of 1-hour infusion. The pharmacokinetic parameters (Ke, Vd and Cmax) obtained using the 0, 6 hour levels and 2, 6 hour levels in Group A were statistically different while those of 1, 6 hour levels and 2, 6 hour levels in Group B were similar. This finding indicated that the distributional phase of ODA is completed within 1 hour following the end of the I-hour infusion. If we are allowed to collect only two blood samples in ODA considering patients comfort and the analytical cost of drug, the first one should be drawn after 1 hour following the end of infusion to obtain adequate pharmacokinetic information.

• Clinical and Experimental Reproductive Medicine
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• v.25 no.2
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• pp.115-122
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• 1998

The maintenance of a viable pregnancy has long been viewed as an immunological paradox. The deveolping embryo and trophoblast are immunologically foreign to the maternal immune system due to their maternally inherited genes products and tissue-specific differentiation antigens (Hill & Anderson, 1988). Therefore, speculation has arisen that spontaneous abortion may be caused by impaired maternal immune tolerance to the semiallogenic conceptus (Hill, 1990). Loss of recall antigen has been reported in immunosuppressed transplant recipients and is associated with graft survival (Muluk et al., 1991; Schulik et al., 1994). Progesterone $(10^{-5}M)$ has immunosuppressive capabilities (Szekeres-Bartho et al., 1985). Previous study showed that fertile women, but not women with unexplained recurrent abortion (URA), lose their immune response to recall antigens when pregnant (Bermas & Hill, 1997). Therefore, we hypothesized that immunosuppressive doses of progesterone may affect proliferative response of lymphocytes to trophoblast antigen and alloantigen. Proliferative responses using $^3H$-thymidine ($^3H$-TdR) incorporation of peripheral blood mononuclear cells (PBMCs) to the irradiated allogeneic periperal blood mononuclear cells as alloantigen, trophoblast extract and Flu as recall antigen, and PHA as mitogen were serially checked in 9 women who had experienced unexplained recurrent miscarriage. Progesterone vaginal suppositories (100mg b.i.d; Utrogestan, Organon) beginning 3 days after ovulation were given to 9 women with unexplained RSA who had prior evidence of Th1 immunity to trophoblast. We checked proliferation responses to conception cycle before and after progesterone supplementation once a week through the first 7 weeks of pregnancy. All patients of alloantigen and PHA had a positive proliferation response that occmed in the baseline phase. But 4 out of 9 patients (44.4%) of trophoblast antigen and Flu antigen had a positive proliferative response. The suppression of proliferation response to each antigen were started after proliferative phase and during pregnancy cycles. Our data demonstrated that since in vivo progesterone treated PBMCs suppressed more T-lymphocyte activation and $^3H$-TdR incorporation compare to PBMCs, which are not influenced by progesterone. This data suggested that it might be influenced by immunosuppressive effect of progesterone. In conclusion, progesterone may play an important immunological role in regulating local immune response in the fetal-placental unit. Furthermore, in the 9 women given progesterone during a conception cycle, Only two (22%) repeat pregnancy losses occured in these 9 women despite loss of antigen responsiveness (one chemical pregnancy loss and one loss at 8 weeks of growth which was karyotyped as a Trisomy 4). These finding suggested that pregnancy loss due to fetal aneuploidy is not associated with immunological phenomena.