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Find video protocols related to scientific articles indexed in Pubmed.
Statistical Considerations in Setting Product Specifications.
J Biopharm Stat
PUBLISHED: 10-31-2014
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ABSTRACT According to ICH Q6A (1999), a specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. For drug products, specifications usually consist of test methods and acceptance criteria for Assay, Impurities, pH, Dissolution, Moisture, and Microbial Limits, etc., depending on the dosage forms. They are usually proposed by the manufacturers, and subject to the regulatory approval for use. When the acceptance criteria in product specifications cannot be pre-defined based on prior knowledge, the conventional approach is to use data from a limited number of clinical batches during the clinical development phases. Often in time, such acceptance criteria is set as an interval bounded by the sample mean plus and minus two to four standard deviations. This interval may be revised with the accumulated data collected from released batches after drug approval. In this paper, we describe and discuss statistical issues of commonly used approaches in setting or revising specifications (usually tighten the limits), including reference interval, (Min, Max) method, tolerance interval, and confidence limit of percentiles. We also compare their performance in terms of interval width and the intended coverage. Based on our study results and review experiences, we make some recommendations on how to select appropriate statistical methods in setting product specifications to better ensure the product quality.
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Quality Assurance Test of Delivered Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products*
J Biopharm Stat
PUBLISHED: 10-31-2014
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Abstract The delivered dose uniformity is one of the most critical requirements for dry powder inhaler and metered dose inhaler products. In 1999, Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34). This sampling acceptance plan is also applied to Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium (IPAC), FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals for small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in Journal of Biopharmaceutical Statistics (Tsong et al, 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the two one-sided tolerance intervals procedure to single tier procedure with any number of canisters.
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Statistical evaluation of several methods for cut point determination of immunogenicity screening assay.
J Biopharm Stat
PUBLISHED: 10-31-2014
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ABSTRACT Cut point of the immunogenicity screening assay is the level of response of the immunogenicity screening assay at or above which a sample is defined to be positive and below which it is defined to be negative. Food and Drug Administration Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutic recommends the cut point to be an upper 95 percentile of the negative control patients. In this article, we assume that the assay data is a random sample from a normal distribution. The sample normal percentile is a point estimate with variability that decreases with the increase of sample size. Therefore the sample percentile does not assure at least 5% false positive rate with high confidence level (e.g., 90%) when the sample size is not sufficiently enough. With this concern, we propose to use a lower confidence limit for a percentile as the cut point instead. We have conducted an extensive literature review on the estimation of the statistical cut point and compare several selected methods for the immunogenicity screening assay cut point determination in terms of bias, the coverage probability, and false positive rate. The selected methods evaluated for the immunogenicity screening assay cut point determination are sample normal percentile, the exact lower confidence limit of a normal percentile (Charkraborti and Li, 2007), and the approximate lower confidence limit of a normal percentile. It is shown that the actual coverage probability for the lower confidence limit of a normal percentile using approximate normal method is much larger than required confidence level with a small number of assays conducted in practice. We recommend using the exact lower confidence limit of a normal percentile for cut point determination.
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Using Tolerance Intervals for Assessment of Pharmaceutical Quality.
J Biopharm Stat
PUBLISHED: 10-31-2014
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ABSTRACT In quality control of drug products, tolerance intervals are commonly used methods to assure a certain proportion of the products covered within a pre-specified acceptance interval. Depending on the nature of the quality attributes, the corresponding acceptance interval could be one-sided or two-sided. Thus, the tolerance intervals can also be one-sided or two-sided. To better utilize tolerance intervals for quality assurance, we reviewed the computation method and studied their statistical properties in terms of batch acceptance probability in this paper. We also illustrate the application of one-sided and two-sided tolerance, as well as two one-sided test through the examples of dose content uniformity test, delivered dose uniformity test, and dissolution test.
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Sample size determination for a three-arm equivalence trial of normally distributed responses.
J Biopharm Stat
PUBLISHED: 08-08-2014
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The equivalence assessment is often conducted through a three-arm clinical trial (namely, test, reference, and placebo) and it usually consists of three tests. The first two tests are to demonstrate the superiority of the test and the reference treatment to the placebo, and they are followed by an equivalence test between the test treatment and the reference treatment. When the response variable is continuous, equivalence is commonly defined in terms of mean difference, mean ratio, or ratio of mean differences, that is, the mean difference of the test and the placebo to the mean difference of the reference and the placebo. These equivalence tests can be performed with both a hypothesis-testing approach and a confidence-interval approach. The advantage of applying the equivalence test by ratio of mean differences is that it can test both superiority of the test treatment over placebo and equivalence between the test and the reference simultaneously through a single hypothesis. In this article, we derive the test statistics and the power function for the ratio of mean differences hypothesis and solve the required sample size for a three-arm clinical trial. Examples of required sample size are given in this article, and are compared with the required sample size by the traditional mean difference equivalence test. After a careful examination, we suggest increasing the power of the ratio of mean differences approach by appropriately adjusting the lower limit of the equivalence interval.
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Equivalence tests for interchangeability based on two one-sided probabilities.
J Biopharm Stat
PUBLISHED: 07-18-2014
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A test treatment is considered to be interchangeable with its reference treatment if they are equivalent and expected to produce the same clinical result in any given patient. To assess interchangeability, FDA Draft Guidance (1999) and Guidance for Industry (2001, 2003) recommend using individual bioequivalence (IBE) and population bioequivalence (PBE) procedures. Chow (1999) and Chow and Liu (1999) gave a discussion on the limitation of the aggregate criteria of the IBE and PBE proposed therein. They mentioned that it is not clear whether IBE or PBE can imply average bioequivalence. Alternative approaches have been proposed to address the weakness of IBE and PBE. Dong et al. (2014) discuss the tolerance interval method and an approximate test for interchangeability defined by a two-sided probability. These tests may not be able to test for the two one-sided tests (TOST) with asymmetric margins around the true mean difference. In addition, the tests of two-sided probability provide no direction when failing the equivalence in interchangeability. Thus, we reexamine the statistical properties of the two one-sided tolerance interval approaches proposed by Tsong and Shen (2007, 2008). In this project, we extend their approach for parallel arms trials and paired/crossover data without the assumption of equal sample sizes and variances. We also develop the exact power function and assess the type I error rate of our proposed approach. In addition, we study the sample size determination based on the interchangeability testing utilizing the tolerance interval method.
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Equivalence assessment for interchangeability based on two-sided tests.
J Biopharm Stat
PUBLISHED: 07-18-2014
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Interchangeability was originally developed in order to assess drug bioequivalence beyond average bioequivalence. In 2003, the Food and Drug Administration (FDA) published a Guidance documenting the procedures on using in vivo bioequivalence crossover trial to assess interchangeability between test and reference products. In general, this FDA Guidance describes interchangeability in terms of population and individual bioequivalence. The Guidance procedures were criticized for their lack of sampling distribution of the test statistics. As a result, the critical points were generated from simulation studies without adjusting for sample size. Further more, they lack consistency with average bioequivalence required in the 1992 FDA Guidance. Alternative interchangeability or interchangeability procedures were proposed to measure the probability of individual response difference under two treatments within prespecified lower and upper limits. Interchangeability is claimed if this probability is greater than a prespecified threshold. Tse et al. (2006) proposed an approximate distribution of the estimated probability based on the second-order Taylor expansion. For the same interchangeability probability hypothesis, Liu and Chow (1997) and Tsong and Shen (2007) also proposed a tolerance interval-based approach that can be extended to clinical trials with parallel arm design under the normality assumption. In this article, we first generalized the two-sided tolerance interval based interchangeability without equal sample size and variance assumption. We also derived a power function for the proposed method, and performed simulation studies to compare the type I error rate, power, and sample size between the Tse approximated test and the generalized tolerance interval approach for interchangeability assessment.
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Sample size determination for equivalence assessment with multiple endpoints.
J Biopharm Stat
PUBLISHED: 07-18-2014
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Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.
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Ba2B10O17: a new centrosymmetric alkaline-earth metal borate with a deep-UV cut-off edge.
Dalton Trans
PUBLISHED: 05-08-2014
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A new centrosymmetric alkaline-earth metal borate, Ba2B10O17, has been successfully synthesized through high-temperature solid-state reactions. The single-crystal X-ray structural analysis shows that Ba2B10O17 crystallizes in the triclinic space group P1[combining macron]. The parameters of the triclinic unit cell are a = 6.7128(3) Å, b = 9.8698(4) Å, c = 9.9998(4) Å, ? = 76.860(3)°, ? = 83.200(3)°, ? = 73.332(3)°, and Z = 2. The title compound features a [B10O17]? three-dimensional anionic framework with infinite channels in which the Ba(2+) cations are located. Ba2B10O17 possesses a large experimental band gap of 6.29 eV and a short cut-off edge lower than 180 nm proved by the transmission spectrum on a single crystal sample 0.5 mm in thickness. The calculated band structures and the density of states of Ba2B10O17 suggest that its indirect energy gap is 5.97 eV which agrees with the experimental result. The thermal behavior and the IR spectrum of Ba2B10O17 are also reported in this work.
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Effects of pulsed electromagnetic fields on the expression of NFATc1 and CAII in mouse osteoclast-like cells.
Aging Clin Exp Res
PUBLISHED: 05-06-2014
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Pulsed electromagnetic fields (PEMF) have proven to be an effective noninvasive method in the prevention and treatment of osteoporosis. This study evaluated the effects of PEMF on the expression of the NFATc1, CAII and RANK genes in mouse osteoclast-like cells.
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Special ?¹[OPb2] chains and ?¹[O2Pb3] ribbons based on OPb4 anion-centered tetrahedra in Pb2(O4Pb8)(BO3)3Br3 and Pb2(O8Pb12)(BO3)2Br6.
Inorg Chem
PUBLISHED: 09-19-2013
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The structures of two new lead-containing oxyborate bromines, Pb2(O4Pb8)(BO3)3Br3 (1) and Pb2(O8Pb12)(BO3)2Br6 (2), are determined by single-crystal X-ray diffraction for the first time. Both of them crystallize in the space group C2/c of the monoclinic crystal system. Although the two compounds have the same type of fundmental building units (FBUs), the OPb4 anion-centered tetrahedra and BO3 triangles, they exhibit different connection modes. Compound 1 consists of single ?(1)[OPb2] chains, while compound 2 possesses ?(1)[O2Pb3] ribbons. Interestingly, large Br atoms profoundly influence the conformation of polyions based on the OPb4 anion-centered tetrahedra, resulting in single ?(1)[OPb2] chains linked up by finite zweier chains with four OPb4 tetrahedra via the opposite edges in compound 1 and ?(1)[O2Pb3] ribbons with sequential condensation of OPb2 chains in compound 2. A detailed description of the effect of large Br atoms on the conformation of polyions is discussed. IR spectroscopy, UV-vis-NIR diffuse reflectance spectroscopy, and thermal analysis are also performed on the reported materials.
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Executive dysfunction and gray matter atrophy in amnestic mild cognitive impairment.
Neurobiol. Aging
PUBLISHED: 03-23-2013
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Recent studies have shown that impairment in executive function (EF) is common in patients with amnestic mild cognitive impairment (aMCI). However, the neuroanatomic basis of executive impairment in patients with aMCI remains unclear. In this study, multiple regression voxel-based morphometry analyses were used to examine the relationship between regional gray matter volumes and EF performance in 50 patients with aMCI and 48 healthy age-matched controls. The core EF components (response inhibition, working memory and task switching, based on the EF model of Miyake et al) were accessed with computerized tasks. Atrophic brain areas related to decreases in the three EF components in patients with aMCI were located in the frontal and temporal cortices. Within the frontal cortex, the brain region related to response inhibition was identified in the right inferior frontal gyrus. Brain regions related to working memory were located in the left anterior cingulate gyrus, left premotor cortex, and right inferior frontal gyrus, and brain regions related to task shifting were distributed in the bilateral frontal cortex. Atrophy in the right inferior frontal gyrus was most closely associated with a decrease in all three EF components in patients with aMCI. Our data, from the perspective of brain morphology, contribute to a better understanding of the role of these brain areas in the neural network of EF.
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Na11B21O36X2 (X = Cl, Br): halogen sodium borates with a new graphene-like borate double layer.
Chemistry
PUBLISHED: 03-08-2013
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Borate not graphene: The [B6O12]?(6-) single borate layer is a graphene-like layer (see figure). The weak Na(+)-Br(Cl)(-) ionic connection between the layers leads to the layer cleavage, and difficulty of the block crystal growth.
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Comparing the response rates for superiority, noninferiority and equivalence testing with multiple-to-one matched binary data.
J Biopharm Stat
PUBLISHED: 01-22-2013
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Paired and multiple-to-one matched data have often been collected in clinical trials and epidemiological safety studies. When the response is binary, the sample size and power are determined by the discordant pairs or matched sets. Fixed sample size determination in assessing response rate difference of superiority, noninferiority, and equivalence tests of paired binary data has been discussed by Lu and Bean (1995)Nam (1997), and Liu et al. (2002). We extend the results of Lu and Bean (1995)Nam (1997), and Liu et al. (2002) to more general cases of multiple-to-one matched binary data. We further examine two issues regarding such tests. First, we examine the issue of simultaneous test and two-stage test for both superiority and noninferiority/equivalence hypotheses. Although, as discussed in Nam (1997) and Liu et al. (2002), the standard errors restricted to null hypothesis are different between superiority and noninferiority test, the monotonic property of the two tests makes the simultaneous testing and switching between the hypotheses valid. Second, in practice, the joint distribution of matched responses is often unknown, and thus determining the sample size using only the background information of the control group could be inefficient. Furthermore, for noninferiority or equivalence tests, the sample sizes are often determined using the unrealistic alternative hypothesis that the response rates of both treatments are identical. We propose to use a two-stage adaptive design strategy for sample size reestimation that uses the interim information to improve the efficiency.
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Bayesian approach to assay sensitivity analysis of thorough QT trials.
J Biopharm Stat
PUBLISHED: 01-22-2013
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One of the analyses recommended in ICH E14 Guidance (International Conference on Harmonisation, 2005) after the test drug is shown to be negative in QT interval prolongation after subjects treated with the test drug is an assay sensitivity analysis of a positive control drug with known effect on QT prolongation. The assay sensitivity is validated if the response profile is shown to be expected and the QT interval after administration of the positive control drug is shown to be at least 5 ms more than placebo. The negative result of the test treatment is validated if the prolongation of the positive control is verified among the study subjects. One of the most frequently used positive control drugs in thorough QT (TQT) trials is moxifloxacin. In order to improve the efficiency of the study and to reduce the number of subjects exposed to moxifloxacin, we explore the potential sample size reduction with a Bayesian approach to the assay sensitivity utilizing the data of historical TQT trials. We derived the distribution of moxifloxacin-induced QT prolongation based on 14 crossover trials and six parallel trials. The estimated distribution is used as a prior distribution to assess the posterior probability that the moxifloxacin-induced QT prolongation is larger than 5 ms. Sample size based on such Bayesian approach will be compared with the conventional frequentist approach for efficiency assessment.
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Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNFalpha-mediated vascular smooth muscle cell proliferation via suppressing ERK activation.
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-17-2009
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Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNFalpha)-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNFalpha-induced activation of ERK and DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNFalpha hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.
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An emerging role of deubiquitinating enzyme cylindromatosis (CYLD) in the tubulointerstitial inflammation of IgA nephropathy.
Biochem. Biophys. Res. Commun.
PUBLISHED: 09-21-2009
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Immunoglobulin A (IgA) nephropathy is an important cause of end-stage kidney disease (ESKD). Tubulointerstitial inflammation and subsequent fibrosis appear to be a major contributor of the disease progression to ESKD; however, the underlying mechanism is poorly understood. Herein, we report that a unique feature of CYLD expression in kidneys of patients with IgA nephropathy and a CYLD-mediated negative regulation of inflammatory responses in human tubular epithelial cells. Immunochemical staining revealed that CYLD was predominantly expressed in renal tubular epithelial cells in 81% of the patients (37 cases) with proteinuric IgA nephropathy. Patients with positive CYLD had significantly less tubulointerstitial lesions and higher estimated glomerular filtration rate (eGFR) levels when compared with those negative. Logistic regression analysis indicated that eGFR was a predictor for the CYLD expression. In cultured human tubular epithelial HK-2 cells, tumor necrosis factor-alpha (TNFalpha) up-regulated CYLD expression. Adenoviral knockdown of CYLD did not affect albumin-, hydrogen peroxide (H(2)O(2))-, tunicamycin- or thapsigargin-induced cell death; however, it enhanced TNFalpha-induced expression of intracellular adhesion molecule (ICAM)-1 as well as activation of c-Jun N-terminal kinase (JNK). Moreover, monocyte adhesion to the TNFalpha-inflamed HK-2 cells was significantly increased by the CYLD shRNA approach. Taken together, our results suggest that CYLD negatively regulates tubulointertitial inflammatory responses via suppressing activation of JNK in tubular epithelial cells, putatively attenuating the progressive tubulointerstitial lesions in IgA nephropathy.
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The overall impairment of core executive function components in patients with amnestic mild cognitive impairment: a cross-sectional study.
BMC Neurol
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It remains unclear how executive function (EF) is affected in the stage of amnestic mild cognitive impairment (aMCI). Previous studies using different methods to assess EF in patients with aMCI have reached inconsistent conclusions. The aim of the study was to explore the characteristics of EF impairments in patients with aMCI.
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Na3Cd3B(PO4)4: a new noncentrosymmetric borophosphate with zero-dimensional anion units.
Inorg Chem
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A new noncentrosymmetric borophosphate, Na(3)Cd(3)B(PO(4))(4), has been successfully synthesized by conventional solid state reaction for the first time. It crystallizes in the orthorhombic space group Pmc2(1) with unit cell parameters of a = 13.6854(3) Å, b = 5.3346(11) Å, c = 18.2169(4) Å, and Z = 4. Na(3)Cd(3)B(PO(4))(4) features zero-dimensional [B(PO(4))(4)](9-) anion units with Cd(2+) and Na(+)/Cd(2+) cations located around them, in which the BO(4) tetrahedron is surrounded by four PO(4) tetrahedra by sharing the vertexes of O atoms. Second harmonic generation (SHG) measurements show that Na(3)Cd(3)B(PO(4))(4) exhibits a SHG response 1.1 times larger than that of KH(2)PO(4) (KDP) and is phase matchable.
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Design and analysis issues of multiregional clinical trials with different regional primary endpoints.
J Biopharm Stat
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One of the challenges of multiregional drug development program is to design and analyze a multiple regional clinical trial with the objective being to satisfy different regional requirements on primary endpoints. Considered in this article is a multiregional clinical trial (MRCT) designed to test for two primary endpoints. Data of a regular fixed-size well-controlled parallel arm trial are used to test for two null hypotheses in terms of two distinct yet correlated endpoints. The two hypotheses may be tested sequentially or simultaneously. Depending on the structure of the hypotheses to be tested and the understanding of type I error rate control, various scenarios of type I error rate adjustments may be applied. Furthermore, for the objective of getting approval from regional authorities for different primary endpoints, various sample size and power determinations may be applied. In this article, comparisons of different approaches are discussed systematically.
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Assessment of regional treatment effect in a multiregional clinical trial.
J Biopharm Stat
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The 11th question-and-answer document (Q&A) for ICH E5 (1998) was published in 2006. This Q&A describes points to consider for evaluating the possibility of bridging among regions by a multiregional trial. The primary objective of a multiregional bridging trial is to show the overall efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region. To apply the overall results to a specific region, it suggested that the results in that region should be consistent with the overall results. The Japanese Ministry of Health, Labor, and Welfare (MHLW) published the "Basic Principles on Global Clinical Trials" guidance document (2007) and proposed two methods to support the bridging claims. Due to the limited sample sizes allocated to the region, the regular interaction test for treatment by region is not practical. On the other hand, the sample size requirement for the Japanese region as described in Uyama et al. (2005) and Uesaka (2009) is to satisfy an 80% or greater power for the Japanese region, conditioning on the effect of the overall global trial. Quan et al. (2010) further extended the results to trials with various endpoints. Ko, Tsou, Liu and Hsiao (2010) focused on a specific region and established statistical criteria for consistency between the region of interest and overall results. The proposed method was based on the assumption that true effect size is uniform across regions. In this article, we propose to analyze a completed multiregional trial for any specific regional effect by controlling the type I error rate adjusted for the regional sample size and the planned power of the global trial. Accordingly, in order to attain the approval for a specific region, we propose to determine the sample size requirement for the specific regions using the overall power planned and a regional acceptable type I error rate.
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A note on two approaches of testing bridging evidence to a new region.
J Biopharm Stat
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Bridging studies are performed in a new region for medicines already approved in the original region. In order to borrow the strength of the original trial to establish the treatment effect in the bridging region, Lan et al. (2005) proposed to use a weighted z-test approach to combine the test statistics of the same hypothesis for both the original and bridging regions for bridging study. Based on a similar concept, Tsou et al. (2012) proposed instead to test a hypothesis of the weighted treatment effects of the original and bridging regions. In this article, we explore the differences of the concept in hypothesis testing and perform a simulation study to examine the type I error rate and power of the two approaches.
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Weighted evidence approach of bridging study.
J Biopharm Stat
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The ICH E5 Guidance facilitates the registration of medicine among ICH regions by recommending a framework for evaluating the impact of ethnic factors upon a medicines effect. It further describes the use of bridging studies, when necessary, to allow extrapolation of foreign clinical data to a new region. Bridging studies are performed in a new region for medicines already approved in the original region. The conventional noninferiority criterion requires the treatment effect (adjusted for placebo) attained in the new region preserves a prespecified proportion of the treatment effect attained in the original region. Such a bridging criterion, however, is often impractical. Hsiao et al. (2007) proposed a Bayesian approach that borrows the strength of the original trial to establish the treatment effect in the bridging region through using a weighted prior distribution. The weight, however, is often difficult to prespecify. In this presentation, we consider the overall treatment effect by combining the weighted effects attained in the original and bridging regions. The maximum weight allowed to be placed on the estimate of bridging region in order to show a significant overall treatment effect represents the strength of the treatment effect in the bridging region. Regional approval will be evaluated either by comparing the weight estimate with the prespecified limit or by benefit-risk evaluation of the medicine. Sample size requirements for the approaches are derived. The simulation results of type I error rate and power for the proposed methods are given. An example illustrates the application of the proposed procedures.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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