Endrenyi L, Taback N, Tothfalusi L
University of Toronto, Department of Pharmacology, Toronto, Ontario, Canada.
Stat Med. 2000 Oct 30;19(20):2867-78. doi: 10.1002/1097-0258(20001030)19:20<2867::aid-sim551>3.0.co;2-j.
Characteristics of the variance component for the subject-by-formulation interaction (sigma(2)(D)), estimated in simulated studies of individual bioequivalence and in three- and four-period cross-over trials reported by the FDA, were compared. sigma(2)(D) was estimated by (i) restricted maximum likelihood (REML) and (ii) the method of moments (MM). Variation of the variance component, estimated by both procedures (s(2)(D)) and for both the simulated and FDA data, increased with rising intra-individual variation. Consequently, a constant level of s(2)(D) (such as 0.0225 suggested by the FDA) may not be regarded as a basis for demonstrating substantial interactions. Features of the FDA and simulated parameters were similar. The results suggested that the FDA data were compatible with assuming sigma(D)=0.05 or perhaps 0.00. Therefore, there is no foundation for concerns about public health. Both simulations and calculations demonstrated that s(2)(D) estimated by MM was unbiased and its variance was proportional to sigma(4)(WF) when sigma(2)(D)=0.
对在个体生物等效性模拟研究以及美国食品药品监督管理局（FDA）报告的三周期和四周期交叉试验中估计的受试者与制剂相互作用方差分量（sigma(2)(D)）的特征进行了比较。sigma(2)(D)通过以下两种方法进行估计：（i）限制最大似然法（REML）和（ii）矩量法（MM）。通过这两种程序（s(2)(D)）对模拟数据和FDA数据估计的方差分量的变化，均随着个体内变异的增加而增加。因此，不能将s(2)(D)的恒定水平（如FDA建议的0.0225）视为证明存在实质性相互作用的依据。FDA数据和模拟参数的特征相似。结果表明，FDA数据与假设sigma(D)=0.05或可能为0.00相符。因此，不存在对公共卫生问题担忧的依据。模拟和计算均表明，当sigma(2)(D)=0时，通过MM估计的s(2)(D)无偏，其方差与sigma(4)(WF)成比例。
