Fay Michael P, Noubary Farzad, Saul Allan
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, 6700B Rockledge Drive MSC 7609, Bethesda, Maryland 20892-7609. (email:
Stat Biopharm Res. 2009 Aug 1;1(3):291-300. doi: 10.1198/sbr.2009.0023..
In comparing test formulations of a drug product to reference formulations it is necessary to check that the test formulation has as much biologic activity as the reference within some indifference zone. A modern method for testing this relative potency is to fit a nonlinear model of the dose response curve, constrained such that the dose-response of the test is modeled with the same function as the reference except for a multiplicative parameter on the dose. This method works well as long as the nonlinear model fits the data. Although tests of this fit are mentioned in the literature, how relative potency should be measured when those tests fail has not been addressed. We study the use of the sandwich estimator of variance for this non-inferiority potency problem when the model does not fit the data. We focus on the simple linear model. Using the sandwich variance, the inferences are asymptotically valid even if the model does not hold. We discuss interpretation of the results under the misspecified linear model, and show by simulation that the method performs well in some practical cases. Finally, we give advice for designing a study that uses these methods.
在将药品的测试制剂与参比制剂进行比较时，有必要检查测试制剂在某个无差异区内是否具有与参比制剂相同的生物活性。一种用于测试这种相对效价的现代方法是拟合剂量反应曲线的非线性模型，并进行约束，使得除了剂量上的一个乘法参数外，测试制剂的剂量反应与参比制剂采用相同的函数进行建模。只要非线性模型能拟合数据，这种方法就很有效。尽管文献中提到了对这种拟合的检验，但当这些检验失败时应如何测量相对效价尚未得到解决。我们研究当模型不拟合数据时，使用方差的三明治估计量来解决这种非劣效性效价问题。我们聚焦于简单线性模型。使用三明治方差，即使模型不成立，推断也是渐近有效的。我们讨论了在错误指定的线性模型下结果的解释，并通过模拟表明该方法在一些实际情况下表现良好。最后，我们给出了使用这些方法进行研究设计的建议。
