Sample size requirement in analytical studies for similarity assessment

ABSTRACT

For the assessment of biosimilar products, the FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biologic product. The stepwise approach starts with analytical studies for assessing similarity in critical quality attributes (CQAs), which are relevant to clinical outcomes at various stages of the manufacturing process. For CQAs that are the most relevant to clinical outcomes, the FDA requires an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC) that is obtained using a single test value of some selected reference lots. In practice, we often have extremely imbalanced numbers of reference and test lots available for the establishment of EAC. In this case, to assist the sponsors, the FDA proposed an idea for determining the number of reference lots and the number of test lots required in order not to have imbalanced sample sizes when establishing EAC for the equivalence test based on extensive simulation studies. Along this line, this article not only provides statistical justification of Dong, Tsong, and Weng’s proposal, but also proposes an alternative method for sample size requirement for the Tier 1 equivalence test.     

The Evaluation of Proof-of-Concept Trial Design for Compound Selection

ABSTRACT

Traditionally, clinical proof-of-concept (POC) trials were designed as mini-phase III trials with a lower power and/or an intermediate endpoint. And go/no-go decisions were made based on a specification of the Type I error. This article considers a POC trial a tool to select the compound with a desired efficacy profile and introduces the approach to compute the distribution of the treatment effect given a go decision. The methodology is then applied to three POC design options that range from a direct comparison to indirect comparisons utilizing historical data. Using the tools proposed, we are able to compare the performance of the designs and impact of sample sizes with respect to the probability of meeting the target product profile given a go decision or no-go decision. Furthermore, for given a design we highlight the trade-off for the go/no-go decision and propose an approach to search for the optimal decision criterion that maximizes a utility defined by an economic scale. We illustrate the approach and results with an example for the development of a treatment for rheumatoid arthritis.     

云南新型农村合作医疗评价指标体系及标准研究

介绍了新型农村合作医疗评价指标体系及标准的产生过程、研究采用的方法 ,指标体系包括可行性评价和效果评价两个部分。     

Bayesian estimation of a random effects heteroscedastic probit model

Summary Bayesian analysis is given of a random effects binary probit model that allows for heteroscedasticity. Real and simulated examples illustrate the approach and show that ignoring heteroscedasticity when it exists may lead to biased estimates and poor prediction. The computation is carried out by an efficient Markov chain Monte Carlo sampling scheme that generates the parameters in blocks. We use the Bayes factor, cross‐validation of the predictive density, the deviance information criterion and Receiver Operating Characteristic (ROC) curves for model comparison.     

Working‐correlation‐structure identification in generalized estimating equations

Selecting an appropriate working correlation structure is pertinent to clustered data analysis using generalized estimating equations (GEE) because an inappropriate choice will lead to inefficient parameter estimation. We investigate the well‐known criterion of QIC for selecting a working correlation structure, and have found that performance of the QIC is deteriorated by a term that is theoretically independent of the correlation structures but has to be estimated with an error. This leads us to propose a correlation information criterion (CIC) that substantially improves the QIC performance. Extensive simulation studies indicate that the CIC has remarkable improvement in selecting the correct correlation structures. We also illustrate our findings using a data set from the Madras Longitudinal Schizophrenia Study. Copyright © 2008 John Wiley & Sons, Ltd.     

A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients. We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed-sample design. Our results suggest that the three methods have the expected statistical properties for size and power; they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.     

染料木素对维甲酸模型大鼠血生化指标和骨密度的作用

目的 :探讨染料木素对维甲酸所致骨质疏松模型大鼠的影响 .方法 :取SD雄性大鼠 2 5 6只 ,随机分为正常对照组、模型组、骨疏康组 (5g·kg-1)、染料木素大、中、小剂量组(18,9,4 .5mg·kg-1) .给予维甲酸 70mg·kg-1·d-1灌胃 2wk(正常对照组除外 ) ,分别于不同时间从各组取 8只大鼠对体质量、血生化指标和骨密度等进行测定 .结果 :染料木素①可增加维甲酸模型大鼠的左股骨质量、左胫骨质量 (P <0 .0 5或P <0 .0 1) ;②使模型大鼠的血清Ca ,P ,Mg,CT水平明显降低 ,BGP ,ALP水平升高 ,与模型组有显著差异 (P <0 .0 5或P <0 .0 1) ;③在 4 .5mg·kg-1,9mg·kg-1时可明显增强模型大鼠的股骨、胫骨和腰椎L2 -4的骨密度 (P <0 .0 5或P <0 .0 1) .结论 :染料木素可明显改善维甲酸模型大鼠的骨密度和血生化指标 ,对骨质疏松有较好的疗效     

深圳地区QCT骨密度正常值调查与临床诊断标准的探讨

目的　通过对深圳地区正常人群腰椎骨密度测量 ,获得本地区QCT骨密度正常参考值。方法　采用CT扫描机 ,羟磷灰石固体体模和QCT骨密度测量软件 ,选择了无骨质疏松疾病的正常人 1 0 2 8例 ,扫描第 3、第 4腰椎中层横断面 ,做QCT骨密度测量。对测量结果进行统计处理 ,得到男女人群骨峰值和年龄组均值。通过对年龄组数据进行不同标准的统计处理 ,探讨较为合理的诊断标准。通过不同的测量方法 (单纯松质和包括皮质 )的对比 ,探讨QCT与其他方法的差异。结果　根据 2 1～ 35岁年龄段统计出的骨峰值男性第 3腰椎为 1 65 85± 30 1 7,第 4腰椎为 1 70 95± 31 81。女性第 3腰椎为 1 75 33± 2 6 95 ,第 4腰椎为 1 81 97± 2 7 63。采用 4种不同的骨峰值降低标准统计骨质疏松症检出率 ,发现M 2 5 %组检出率偏高 ,M 30 %与M 2S较接近。包括皮质骨的测量降低敏感性。结论　进行深圳地区骨密度正常值调查 ,获得了男女人群骨峰值和年龄组均值 ,临床诊断建议采用骨峰值 30 %作为QCT测量诊断骨质疏松症的基本界限     

Comparison between the more recent techniques for smoothing and derivative assessment in biomechanics

When analysising and evaluating human motion, two strictly interconnected problems arise: the data smoothing and the determination of velocities and accelerations from displacement data. Differentiating procedures magnify the noise superimposed on the useful kinematic data. A smoothing procedure is thus required to reduce the measurement noise before the differentiation can be carried out. In the paper two techniques for derivative assessment are presented, tested and compared. One of these is the procedure known as one of the best automatic smoothing and differentiating techniques: generalised cross validatory spline smoothing and differentiation (GCVC). The other, which has recently been presented, features an automatic model-based bandwidth-selection procedure (LAMBDA). The procedures have been tested with signals presented by other authors and available in the literature, by test signals acquired using the ELITE motion analyser and by synthetic data. The results show better or similar performance of LAMBDA compared with GCVC. In the cases in which the natural conditions at the signal boundaries are not met GCVC gives bad results (especially on the third derivative) whereas LAMBDA is not affected at all. Moreover, analysis time is dramatically lower for LAMBDA.