Bioequivalence and Bioavailability Forum

Dear Vijay,

❝ 1. What is the default multiple pairwise comparison adjustment used in PROC MIXED when we specify “LSMEANS TRT/pdiff cl” where we have more than 2 treatments? The SAS manual says that there is a default adjustment of all pairwise differences, but does not state what it is. [...]

The entry in the SAS manual is totally misleading here . Proc MIXED uses the same default as Proc GLM namely ADJUST=T, which is an oxymoron because this option does not apply any multiplicity adjustment but merely calculates each pairwise confidence intervals using the appropriate quantiles of the student's t-distribution with unadjusted alpha.

Because the ESTIMATE ... statement handles only one contrast at a time, the confidence intervals are also based on t-distribution without any multiplicity adjustment.

❝ 2. Is it redundant to use the ESTIMATE statement with contrasts, “ESTIMATE ‘t-r’ -1 1/cl alpha=0.1’ and ‘LSMEANS TRT/pdiff cl alpha=0.1’ in the same model. [...]

From the above said it is redundant (or better one of both is enough) unless you specify any adjustment for multiplicity. In that case it is also superfluous to use ESTIMATE ... and LSMEANS ... together because then you are interested in the multiplicity adjusted results and not in the pairwise unadjusted.

For your example statements it is always redundant, because for studies with 2 treatments any adjustment method degenerates to the case without adjustment.

❝ 3. I am frequently getting almost similar estimates for the standard errors of the point estimates in both the ESTIMATE and LSMEANS output.

If not, your SAS installation is in error .
Provided your ESTIMATE ... statement defines the same contrast as the LSMEANS difference.

Point 4. I will leave over for others. It is another pair of shoes.
But SEARCH! There are some threads in this Forum dealing with dose / potency correction.

Dear Vijay!

❝ 4. Finally, I may be totally naïve in asking this question but I still need to clarify . Does one use the actual AUC and Cmax parameters or the dose normalized AUC and Cmax parameters while assessing bioequivalence.

The former.

❝ Is there any difference?

The definition of bioequivalence (for different wordings see the Guidelines) includes the same molar dose giving the same rate and extent of bioavailability.

❝ If we consider a scenario where a lesser dose of a new formulation (say 7.5 mg) is being tested against an old formulation (say 10mg), then we do not need to dose normalize on the presumption that the new formulation is designed to perform as good as theold formulation but with a lesser dose due to better bioavailability.

Wonderful, that’s an improvement! The technical term is “Suprabioavailability” (see the EMEA’s NfG Section 5.5). If you succeed, most likely you have to run additionally a (small) clinical study to show safety/efficacy as well. IIRC, an example was glibenclamide, where a formulation of 3.5 mg with micronized particles gave a similar BA as the conventional formulation with 5 mg.