Bioequivalence and Bioavailability Forum

Hi MGR,

like ElMaestro I’m not a SASian and my knowledge is limited.

❝ […] I am not able to calculate the inter-subject variabilities for test and reference treatments. Please help me with this calculation.

With the EMA’s example ‘Data set I’ (download CSV) you should get sumfink like:

        Covariance Parameter Estimates
Cov Parm     Subject    Group    Estimate
FA(1,1)      SUBJ                0.8530
FA(2,1)      SUBJ                0.8284
FA(2,2)      SUBJ                8.339e-07
Residual     SUBJ       TRT R    0.2021
Residual     SUBJ       TRT T    0.1174

In Phoenix/WinNonlin slightly different terms.

Final variance parameter estimates:
           lambda(1,1)_11  0.852995
           lambda(1,2)_11  0.828407
           lambda(2,2)_11  8.33919e-007
Var(PER*TRT*SUBJ)_21       0.202118
Var(PER*TRT*SUBJ)_22       0.117394

The first two lines give $\small{\widehat{s_\textrm{bR}^2}}$ and $\small{\widehat{s_\textrm{bT}^2}}$ and the last two $\small{\widehat{s_\textrm{wR}^2}}$ and $\small{\widehat{s_\textrm{wT}^2}}$. Ignore the third, which is the Subject-by-Formulation Interaction. Then as usual $\small{100\sqrt{\exp \left ( \widehat{s_{\ldots}^2} \right )-1}}$.
Here $\small{CV_\textrm{bR}=116.0\%,\;CV_\textrm{bT}=113.6\%,\;CV_\textrm{wR}=47.3\%,\;CV_\textrm{wT}=35.3\%}$.

As ElMaestro wrote, you can get the estimated between-subject variances also from Col1 of the estimated G matrix, where the 1^st Row is for R and 2^nd for T.

❝ But when I use the proc varcomp procedure in SAS, I am able to generate the Variabilities (Inter and Intra) for test and reference treatments.

Out of curiosity: Do they are agree with the results of Proc Mixed as outlined above?

❝ My doubt is that whether it is acceptable by FDA regulatory?

The between-subject variabilities are not required for RSABE (in the FDA’s Summary Table 3B you have to give only the within-subject variance and standard deviation of the reference).



For ABE (Table 3A) variances are not required at all.

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