Statistical Analysis

The following sections provide recommendations on statistical methodology for assessment of average, population, and individual BE.

Logarithmic Transformation General Procedures

This guidance recommends that BE measures (e.g., AUC and Cmax) be log transformed using either common logarithms to the base 10 or natural logarithms. The choice of common or natural logs should be consistent and should be stated in the study report. The limited sample size in a typical BE study precludes a reliable determination of the distribution of the dataset. Sponsors and/or applicants are not encouraged to test for normality of error distribution after log transformation, nor should they use normality of error distribution as a reason for carrying out the statistical analysis on the original scale. Justification should be provided if sponsors or applicants believe that their BE study data should be statistically analyzed on the original rather than on the log scale.

Clinical Rationale

The FDA Generic Drugs Advisory Committee recommended in 1991 that the primary comparison of interest in a BE study is the ratio, rather than the difference, between average parameter data from the T and R formulations. Using logarithmic transformation, the general linear statistical model employed in the analysis of BE data allows inferences about the difference between the two means on the log scale, which can then be retransformed into inferences about the ratio of the two averages (means or medians) on the original scale. Logarithmic transformation thus achieves a general comparison based on the ratio rather than the differences.

PK Rationale

Westlake observed that a multiplicative model is postulated for PK measures in BA/BE studies (i.e., AUC and Cmax, but not Tmax). Assuming that elimination of the drug is first order and only occurs from the central compartment, the following equation holds after an extravascular route of administration:

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