Bioequivalence and Bioavailability Forum

Hi Mahmoud,

❝ in the following SAS code

where does this code come from? It’s not the standard one recommended by the FDA here and there.

❝ model AUCT=sequence period treat/DDFM=kr;

I would suggest to use DDFM=SATTER (as the FDA recommends). The default of DDFM=KR uses the observed information matrix (SCORING=0) as does jmp. You may run into troubles if your study is re-evaluated in other software which uses the expected information matrix (e.g., Stata, R-package replicateBE). In SAS you can get the expected information matrix by setting SCORING=1.

❝ random treat/type=CSH subject=subject G;

❝

❝ In the Random statement TYPE=CSH could possibly be replaced by TYPE=FA(1)

Acc. to the FDA’s guidance, Appendix E:

In the Random statement, TYPE=FA0(2) could possibly be replaced by TYPE=CSH.

So why compound symmetry in the first place?

❝ FA(1) is not the same as FA0(2)

Of course. FA(q) = factor analytic and FA0(q) = no diagonal factor analytic.
If this is a full replicate design, I would follow the FDA’s recommendation and use FA0(2).
However, in the stupid partial replicate designs (TRR|RTR|RRT or TRR|RTR) the optimizer may fail to converge since the model is over-specified (T not repeated). Then you’ve performed a study and don’t get a result cause SAS shows you the finger.* I suggest to specify FA0(1) instead. State that already in the SAP.

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• If you are lucky SAS throws only a warning.
  Convergence criteria met but final hessian is not positive definite.
  But if Murphy’s law hits:
  WARNING: Did not converge.
WARNING: Output 'Estimates' was not created.