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ABSTRACT: There was no existing scale in Mandarin Chinese to specifically measure QOL in old age. We aimed to validate a Chinese Taiwan version of the CASP-19 (control, autonomy, self-realization, pleasure), a QOL questionnaire, in Taiwan. The existing CASP-19 Cantonese version was modified into Chinese Taiwan version and pilot tested. Data were then gathered from 699 older people. Score distribution, exploratory and confirmatory factor structure, reliability and clinical validity of the CASP-19 and its shortened version, the CASP-12, were examined. The mean age of the participants was 75.5 (standard deviation (SD) 6.5), and half (49.5%) were female. The mean CASP-19 score was 38.2 (range 11-56; SD 7.1), lower than that of Western countries. Exploratory factor analysis revealed an additional factor, 'participation' (CASPP-19). There was satisfactory internal consistency (Cronbach's α 0.63-0.85) for the subscales, except for the control domain. For the 19-item scale, the first order five-domain model (CASPP-19) yielded the best fit. For the CASP-12, first and second order original CASP-12 models performed equally well. There was an inverse relationship between the CASP total scores and frailty, chronic diseases, depressive disorders, living alone and fall events in the past 12months, supporting good clinical validity for all versions of the CASP scale (CASP-19, CASPP-19, original and new CASP-12). The original CASP-12 may be presently the best choice for use in China, Taiwan or other Mandarin-speaking populations due to its conciseness and model parsimony.
Archives of gerontology and geriatrics 04/2013; · 1.36 Impact Factor
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ABSTRACT: For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures. Copyright © 2013 John Wiley & Sons, Ltd.
Pharmaceutical Statistics 04/2013; · 2.07 Impact Factor
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ABSTRACT: In 1998, the International Conference on Harmonization (ICH) published a guidance to facilitate the registration of medicines among ICH regions including the European Union, the United States, and Japan by recommending a framework for evaluating the impact of ethnic factors on a medicine's effect, such as its efficacy and safety at a particular dosage and dose regimen (ICH E5, 1998). The purpose of ICH E5 is not only to evaluate the ethnic factor influence on safety, efficacy, dosage, and dose regimen, but also more importantly to minimize duplication of clinical data and allow extrapolation of foreign clinical data to a new region. In this article, statistical methods for evaluation of bridging studies based on the concepts of consistency (Shih, 2001 ), reproducibility/generalizability (Shao and Chow, 2002 ), the weighted Z-tests for the design of bridging studies (Lan et al., 2005 ), and similarity between the new and original region based in terms of positive treatment effect (Hsiao et al., 2007 ) are studied. The relative merits and disadvantages of these methods are compared by several examples.
Journal of Biopharmaceutical Statistics 09/2012; 22(5):903-15. · 1.34 Impact Factor
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ABSTRACT: Biological drug products are therapeutic moieties manufactured by a living system or organisms. These are important life-saving drug products for patients with unmet medical needs. Because of expensive cost, only a few patients have access to life-saving biological products. Most of the early biological products will lose their patent in the next few years. This provides the opportunity for generic versions of the biological products, referred to as biosimilar drug products. The US Biologic Price Competition and Innovation Act passed in 2009 and the draft guidance issued in 2012 provide an approval pathway for biological products shown to be biosimilar to, or interchangeable with, a Food and Drug Administration-licensed reference biological product. Hence, cost reduction and affordability of the biosimilar products to the average patients may become possible. However, the complexity and heterogeneity of the molecular structures, complicated manufacturing processes, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence between the biosimilar products and their corresponding reference product a great challenge for statisticians and regulatory agencies. To accommodate the stepwise approach and totality of evidence, we propose to apply a parallel assay to evaluate the extrapolation of the similarity in product characteristics such as doses or pharmacokinetic responses to the similarity in binary efficacy endpoints. We also report the results of simulation studies to evaluate the performance, in terms of size and power, of our proposed methods. We present numerical examples to illustrate the suggested procedures. Copyright © 2012 John Wiley & Sons, Ltd.
Statistics in Medicine 08/2012; · 1.88 Impact Factor
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Pharmaceutical Statistics 05/2012; 11(4):343-5. · 2.07 Impact Factor
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ABSTRACT: The evidence for a relationship between dietary patterns and uric acid concentrations is scanty. Here, we used a validated food frequency questionnaire for an ethnic Chinese population in Taiwan to investigate the relationship between dietary patterns and uric acid concentrations. A cross-sectional study on 266 adults, who were interviewed with a 38-item food frequency questionnaire, was conducted and serum uric acid levels were measured. Three dietary patterns were derived from the questionnaire by exploratory factor analysis. Participants in the higher vegetable and fruit pattern quartiles were more likely to have a lower uric acid concentration (6.5 for the first, 5.7 for the second, 6.0 for the third, and 6.0 mg/dL for the fourth quartile, p = 0.030). For uric acid-prone patterns, as the quartiles increased, the adjusted mean uric acid concentrations increased significantly (5.88, 5.93, 5.99 and 6.38 mg/dL for each quartile, respectively, p = 0.04). However, the significance level was attenuated after adjusting for additional confounding factors. In conclusion, three dietary patterns were identified for ethnic Chinese in Taiwan, and the relationship between these dietary patterns and uric acid was not significant after adjustment.
Asia Pacific Journal of Clinical Nutrition 01/2012; 21(2):263-70. · 1.13 Impact Factor
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ABSTRACT: Recently, global drug developments have attracted much attention from sponsors as well as regulatory authorities. The ICH E5 guideline defines a bridging study as a supplementary study conducted in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen to allow extrapolation of the foreign clinical data to the population of the new region. On the other hand, a multi-regional trial may incorporate subjects from many regions around the world under the same protocol so that after showing the overall efficacy of a drug in all global regions, we can simultaneously evaluate the possibility of applying the overall trial results to each region and consequently support drug registration in each region. In this paper, we develop a consistency approach for assessment of similarity between a bridging study conducted in a new region and studies conducted in the original region. A statistical criterion is also established to assess the consistency between the region of interest and overall results in a multi-regional trial. The method for sample size determination for the bridging study is also proposed. Numerical examples illustrate applications of the proposed approaches in different scenarios.
Statistics in Medicine 05/2011; 30(17):2171-86. · 1.88 Impact Factor
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ABSTRACT: Dissolution is one of the tests that is required and specified by the United States Pharmacopeia and National Formulary (USP/NF) to ensure that the drug products meet the standards of the identity, strength, quality, purity, and stability. The sponsors also establish the in-house specifications for the mean and standard deviation of the dissolution rates to guarantee a high probability of passing the USP/NF dissolution test. However, the USP/NF dissolution test is a complicated three-stage sampling plan that involves both the sample mean dissolution rate of all units and the dissolution rate of individual units. It turns out that the true probability of passing the USP/NF dissolution is formidable to compute analytically even when the population mean and variance of dissolution rates are known. It is not clear that previously proposed methods are the estimators of the true probability for passing the USP dissolution test. Therefore, we propose to employ a parametric bootstrap method in conjunction with the Monte Carlo simulation to obtain the sampling distribution of the estimated probabilities of passing the USP/NF dissolution test and hence the confidence interval for the passing probability. In addition, a procedure is proposed to test whether the true probability of passing the USP/NF dissolution test is greater than some specified value. A numerical example illustrates the proposed method. Copyright © 2011 John Wiley & Sons, Ltd.
Pharmaceutical Statistics 04/2011; 11(1):32-8. · 2.07 Impact Factor
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ABSTRACT: For locally acting drug products such as nasal aerosols and nasal sprays, the 2003 US Food and Drug Administration (FDA) draft guidance suggests that bioequivalence between generic and brand-name products be established through in vitro tests. In addition, for non-profile analyses based on spray content uniformity, droplet size distribution, spray pattern, priming, and re-priming, the draft US FDA guidance recommends that the population bioequivalence (PBE) between generic and innovator's products be demonstrated. However, the linearized criterion recommended in the draft FDA guidance does not take into consideration the variations due to batches, samples, and life stages. Hence, under a two-stage nested random effects model, we apply the methods of modified large-sample (MLS) and generalized pivotal quantities (GPQs) to construct the upper 95% confidence limit for in vitro PBE criterion with consideration of variance components as the statistical testing procedures for establishing the in vitro BE. A simulation study was conducted to compare empirical size and empirical power among the three methods. A numerical example illustrates the proposed methods. Copyright © 2010 John Wiley & Sons, Ltd.
Journal of Chemometrics 09/2010; 24(10):617 - 625. · 1.95 Impact Factor
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ABSTRACT: Recently, geotherapeutics have attracted much attention from sponsors as well as regulatory authorities. A bridging study defined by the International Conference on Harmonisation (ICH) E5 is usually conducted in the new region after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. However, extensive duplication of clinical evaluation in the new region not only requires valuable development resources but also delays availability of the test product to the needed patients in the new regions. To shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world may be desirable. On September 28, 2007, the Ministry of Health, Labour and Welfare (MHLW) in Japan published the "Basic Principles on Global Clinical Trials" guidance related to the planning and implementation of global clinical studies. The 11th question and answer for the ICH E5 guideline also discuss the concept of a multiregional trial. Both guidelines have established a framework on how to demonstrate the efficacy of a drug in all participating regions while also evaluating the possibility of applying the overall trial results to each region by conducting a multiregional trial. In this paper, we focus on a specific region and establish statistical criteria for consistency between the region of interest and overall results. More specifically, four criteria are considered. Two criteria are to assess whether the treatment effect in the region of interest is as large as that of the other regions or of the regions overall, while the other two criteria are to assess the consistency of the treatment effect of the specific region with other regions or the regions overall. Sample size required for the region of interest can also be evaluated based on these four criteria.
Journal of Biopharmaceutical Statistics 07/2010; 20(4):870-85. · 1.34 Impact Factor
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ABSTRACT: In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and to shorten approval time, the design of multi-regional trials incorporates subjects from many countries around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. Recently, the trend for simultaneous clinical development in Asian countries being undertaken simultaneously with clinical trials conducted in Europe and the United States has been rapidly rising. In this paper, proposals of statistical consideration to multi-regional trials are provided. More specifically, three aspects are addressed: the definition of the 'Asian region,' the consistency criterion between the 'Asian region' and the overall regions, and the sample size determination for the multi-regional trial.
Pharmaceutical Statistics 07/2010; 9(3):201-6. · 2.07 Impact Factor
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ABSTRACT: The success rate of drug development has been declined dramatically in recent years and the current paradigm of drug development is no longer functioning. It requires a major undertaking on breakthrough strategies and methodology for designs to minimize sample sizes and to shorten duration of the development. We propose an alternative phase II/III design based on continuous efficacy endpoints, which consists of two stages: a selection stage and a confirmation stage. For the selection stage, a randomized parallel design with several doses with a placebo group is employed for selection of doses. After the best dose is chosen, the patients of the selected dose group and placebo group continue to enter the confirmation stage. New patients will also be recruited and randomized to receive the selected dose or placebo group. The final analysis is performed with the cumulative data of patients from both stages. With the pre-specified probabilities of rejecting the drug at each stage, sample sizes and critical values for both stages can be determined. As it is a single trial with controlling overall type I and II error rates, the proposed phase II/III adaptive design may not only reduce the sample size but also improve the success rate. An example illustrates the applications of the proposed phase II/III adaptive design.
Pharmaceutical Statistics 02/2010; 10(2):105-14. · 2.07 Impact Factor
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Journal of Biopharmaceutical Statistics 01/2010; 20(1):1-2. · 1.34 Impact Factor
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ABSTRACT: Biological products or medicines are therapeutic agents that are produced using a living system or organism. Access to these life-saving biological products is limited because of their expensive costs. Patents on the early biological products will soon expire in the next few years. This allows other biopharmaceutical/biotech companies to manufacture the generic versions of the biological products, which are referred to as follow-on biological products by the U.S. Food and Drug Administration (FDA) or as biosimilar medicinal products by the European Medicine Agency (EMEA) of the European Union (EU). Competition of cost-effective follow-on biological products with equivalent efficacy and safety can cut down the costs and hence increase patients' access to the much-needed biological pharmaceuticals. Unlike for the conventional pharmaceuticals of small molecules, the complexity and heterogeneity of the molecular structure, complicated manufacturing process, different analytical methods, and possibility of severe immunogenicity reactions make evaluation of equivalence (similarity) between the biosimilar products and their corresponding innovator product a great challenge for both the scientific community and regulatory agencies. In this paper, we provide an overview of the current regulatory requirements for approval of biosimilar products. A review of current criteria for evaluation of bioequivalence for the traditional chemical generic products is provided. A detailed description of the differences between the biosimilar and chemical generic products is given with respect to size and structure, immunogenicity, product quality attributed, and manufacturing processes. In addition, statistical considerations including design criteria, fundamental biosimilar assumptions, and statistical methods are proposed. The possibility of using genomic data in evaluation of biosimilar products is also explored.
Journal of Biopharmaceutical Statistics 01/2010; 20(1):10-30. · 1.34 Impact Factor
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ABSTRACT: As more biologic products are going off patent protection, the development of follow-on biologics products has received much attention from both biotechnology industry and the regulatory agencies. Unlike small-molecule drug products, the development of biologic products is very different and variable via the manufacture process and environment. Thus, Chow et al. (2010) suggested that the assessment of biosimilarity between biologic products focus on variability rather than average biosimilarity. In addition, it is also suggested that a probability-based criterion, which is more sensitive to variability, should be employed. In this article, we propose a probability-based asymptotic statistical testing procedure to evaluate biosimilarity in variability of two biologic products. A numerical study is conducted to investigate the relationship between the probability-based criterion in variability and various study parameters. Simulation studies were also conducted to empirically investigate the performance of the proposed probability-based asymptotic statistical testing procedure in term of empirical sizes and powers. A numerical example is provided to illustrate the proposed methods.
Journal of Biopharmaceutical Statistics 01/2010; 20(1):75-89. · 1.34 Impact Factor
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ABSTRACT: Intermediate precision is one of the most important characteristics for evaluation of precision in assay validation. The current methods for evaluation of within-device precision recommended by the Clinical Laboratory Standard Institute (CLSI) guideline EP5-A2 are based on the point estimator. On the other hand, in addition to point estimators, confidence intervals can provide a range for the within-device precision with a probability statement. Therefore, we suggest a confidence interval approach for assessment of the within-device precision. Furthermore, under the two-stage nested random-effects model recommended by the approved CLSI guideline EP5-A2, in addition to the current Satterthwaite's approximation and the modified large sample (MLS) methods, we apply the technique of generalized pivotal quantities (GPQ) to derive the confidence interval for the within-device precision. The data from the approved CLSI guideline EP5-A2 illustrate the applications of the confidence interval approach and comparison of results between the three methods. Results of a simulation study on the coverage probability and expected length of the three methods are reported. The proposed method of the GPQ-based confidence intervals is also extended to consider the between-laboratories variation for precision assessment.
Journal of Biopharmaceutical Statistics 09/2009; 19(5):763-78. · 1.34 Impact Factor
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ABSTRACT: Linearity and linear range are the key evaluations of the accuracy in assay validation. The average deviation from linearity (ADL) and the sum of squares of deviations from linearity (SSDL) have been proposed for assessment of the linearity. However, both ADL and SSDL do no consider the variability of the assay for evaluation of linearity. Therefore, we proposed the coefficient of variation of deviations from linearity (CVDL) as an alternative measure for the linearity assessment. For the inference of evaluation of linearity, we proposed testing procedures based on generalized pivotal quantities (GPQ) of ADL and CVDL for evaluation of linearity. The simulation studies were conducted to empirically investigate the size and power between the three methods. The simulation results show that all three methods adequately control size. However, the ADL method is uniformly more powerful than the other two methods. A numeric example illustrates the proposed methods. Copyright © 2009 John Wiley & Sons, Ltd.
Journal of Chemometrics 05/2009; 23(9):487 - 494. · 1.95 Impact Factor
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ABSTRACT: After completion of a human genome project, the disease targets at molecular level can be identified. As a result, treatment modality for molecular targets can be developed. In practice, targeted clinical trials are usually conducted for evaluation of the possibility and feasibility of the individualized treatment of patients. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Therefore, some of the patients enrolled in targeted clinical trials with a positive result by the diagnostic device might not have the specific molecular targets and hence the treatment effects of the targeted drugs estimated from targeted clinical trials could be biased for the patient population truly with the molecular targets. Under an enrichment design for targeted clinical trials, we propose to use the EM algorithm and bootstrap method for obtaining the inference of the treatment effects of the targeted drugs in the patient population truly with molecular targets. A simulation study was conducted to empirically investigate the bias and variability of the proposed estimator and the size and power of the proposed testing method. Simulation results demonstrate that the proposed estimator is unbiased with adequate precision and the confidence interval can provide satisfactory coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. A practical example illustrates the utility of the proposed method.
Pharmaceutical Statistics 01/2009; 8(4):356-70. · 2.07 Impact Factor
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ABSTRACT: To compare the effect of equivalent doses in two different volumes of botulinum toxin type A (Dysport) on gastrocnemius spasticity.
Single-blind, randomized, controlled trial.
Hospital rehabilitation department.
Twenty-two children with spastic diplegic or quadriplegic cerebral palsy.
High (500 U/5 mL) and low (500 U/1 mL)-volume preparations of Dysport were injected into the gastrocnemius muscles, each child randomly receiving one preparation in the right and the other in the left leg.
Dynamic ankle joint range of motion (ROM), passive ROM of the ankle joint, modified Ashworth Scale scores, and the areas of the compound muscle action potential assessed before treatment and at four and eight weeks post treatment.
Both legs improved significantly. The mean (SD) improvements between baseline and the end of follow-up were 19.7 (10.83) degrees for dynamic ROM, 8.4 (9.19) degrees for passive ROM, -1.3 (0.6) for modified Ashworth Scale scores, and -9.4 (11.41) mV-ms for compound muscle action potential in the high-volume group; and 13.5 (10.45) degrees for dynamic ROM, 7.4 (7.88) for passive ROM, -0.9 (0.5) for modified Ashworth Scale scores, and -5.9 (7.50) mV-ms for areas of compound muscle action potential in the low-volume group. The high-volume preparation yielded significantly greater improvement in dynamic ROM (P<0.001), muscle tone (P < 0.001), and lower compound muscle action potential area (P = 0.006).
A high-volume preparation of Dysport is more effective than a low volume in reducing spasticity in the gastrocnemius muscle.
Clinical Rehabilitation 01/2009; 23(1):64-71. · 2.12 Impact Factor
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ABSTRACT: One of the most important characteristics for evaluation of the accuracy in assay validation is the linearity. Kroll, et al. 1 proposed a method based on the average deviation from linearity (ADL) to evaluate the linearity. Hsieh and Liu 2 suggested that hypothesis for proving the linearity be formulated as the alternative hypothesis and proposed the corrected Kroll's method. However, the issue concerning the variability in estimation of the non-centrality parameter is still unresolved. Consequently, the type I error rates may still be inflated for the corrected Kroll's method. To overcome this issue, we propose the sum of squares of deviations from linearity (SSDL) as an alternative metric for evaluation of linearity. Based on SSDL, we applied the method of generalized pivotal quantities (GPQ) for the inference of evaluation of linearity. The simulation studies were conducted to empirically investigate the size and power between current and proposed methods. The simulation results show that the proposed GPQ method not only adequately control size but also provide sufficient power than other methods. A numeric example illustrates the proposed methods. Copyright © 2008 John Wiley & Sons, Ltd.
Journal of Chemometrics 12/2008; 23(1):56 - 63. · 1.95 Impact Factor
