Bioequivalence Example

Bioequivalence Example

Sample Size for TOST for means-crossover

What sample size is required for a 2×2 crossover study to have 90% power for establishment of equivalence between the 32 hour AUC of two different dosage forms of a drug? Bioequivalence limits will be established for the ratio of the means and the data are expected to have a reasonably normal distribution in the original scale, so the Sasabuchi two one-sided t-tests procedure (TOST) will be used for analysis.

To illustrate how to use pilot information from prior studies, our example is based on data from Table 3.6.1 in Chow SC, Liu JP (1992) Design and Analysis of Bioavailability and Bioequivalence Studies, Marcel Dekker, Inc. The mean for the standard was about 82, the intra-subject MSE was 167.25, which yields an intra-subject CV of 12.9/82 = .158, and the inter-subject MSE was 736.89, so that 2σ_s² is estimated as

736.89-167.25, and the between-subject CV as 16.88/82 = .206. How many subjects will be required for a crossover design to establish that the ratio of means is in the interval (.90, 1.111)?

nQuery Advisor® can provide sample size and power for two-group or crossover bioequivalence trials where the difference in means or the ratio of means is the equivalence parameter.

• Select File … New, and in the Study Goal and Design Box, select Means, Two Groups, and Equivalence.
• Select TOST for ratio of means for crossover design (original scale).
• Fill in the desired significance level for each test, the required lower (0.90) and upper (1.11) equivalence limits for the ratio of means, and the expected ratio of means (typically 1.0).
• Enter the Coefficient of variation terms, 0.206 between subjects and 0.158 within subjects.
• Enter the requested power (90%) and nQuery Advisor® will solve for the required sample size for each of the two sequence groups. Here n = 26 per group, so a total of 52 subjects is required.

You may then try out other possible scenarios, and request a plot of power versus sample size, a sample size justification statement, and a printout of the sample size table. The table, plots, and statements can be saved or copied to a spreadsheet or word processing program for pasting into your manuscript or protocol.