2013-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/669762摘要：生技製藥產品精密度及學名藥與原廠藥生物對等性之評估指標均是常態分佈二次動差的函數。在評估學名藥與原廠藥個體生物對等性時，在重複交叉設計下，美國食品藥物管理局的評估指標為學名藥與原廠藥平均數差之平方、處理與個體交互作用變異數及學名藥與原廠藥個體內變異數差之和。在評估體外檢驗試劑之精密度時，美國臨床實驗標準研究所的EP5-A2準則所公告評估體外檢驗試劑精密度之指標為天數、實驗與重複三個變異成分之和。美國食品藥物管理局的「鼻用噴霧器及氣膠器」的準則中所公告評估學名藥體外生物對等性的指標包括學名藥與原廠藥平均數差的平方以及學名藥與原廠藥在批次、樣本及生命週期變異成分差的和。目前已有修正大樣本方法與廣義樞紐量等檢定方法對上述二次動差的評估標準進行推論，但目前二次動差推論的樣本數估算的文獻甚少，所以本專題研究計畫為二年期計畫將發展個體生物對等性、體外檢驗試劑精密度評估及體外生物對等性的總樣本數估算方法。本專題研究計畫並將研究不同變異成份樣本數最佳配置方法與探討個變異成分大小及成本對樣本數之影響，我們亦將執行模擬試驗來評估所提出方法的表現。我們亦將以實際數例介紹提出方法之應用。<br> Abstract: Statistical criteria for evaluation of the precision of biopharmaceutical products or between the generic and innovative products often involve functions of the second moments of the normal distribution. Under replicated cross-over designs, the criteria for individual bioequivalence (IBE) proposed by the guidance of the US Food and Drug Administration (FDA) contain the squared mean difference, variance of treatment-by-subject interaction, and the difference in within-subject variances between the generic and innovative products. Under the design recommended by the approved guideline EP5-A2 of Clinical Laboratory Standard Institute (CLSI), the criterion for evaluation of the with-in precision for in vitro diagnostic devices (IVD) is the sum of the variance components due to day, run, and replicates. The criterion for the in vitro bioequivalence (BE) proposed by the draft guidance of the US FDA consists of the squared mean difference, the sum of the differences in variance components due to batch, sample, and life stage. Various testing procedures have been proposed for the inference with respect to these criteria. These procedures include modified large-sample (MLS) method and the approaches by the generalized pivotal quantities (GPQ). However, scarce literature exists for the sample size determination for the inference based on the second moments. As a result, this two-year project, we will develop the methods on sample size determination with respect to IBE, the within-device precision of IVD, and in vitro bioequivalence. In addition to the total sample size, we will try to develop the methods for the optimal allocation of the sample sizes to different sources of variation such as day, run, and replicate for the within-device IVD; batch, sample, and life cycle for the in vitro BE. Impacts of the magnitudes of variance components and cost on the sample sizes will be also explored. Simulation studies will be conducted to evaluate the adequacy of the proposed methods. In addition, the proposed methods will be illustrated with real data.個體生體對等性試劑內精密度體外生體對等性樣本數估計Individual BioequivalenceWithin-device precisionIn Vitro BioequivalenceSample Size Determination