## Misunderstanding? [Regulatives / Guidelines]

Hi ElMaestro,

❝ If we look at SAS documentation e.g. here and here, then

❝ 1. I do not understand the underlying math (just try and look into the spectral decomposition things mentioned as part of DDFM derivation; it sends my head spinning).

Wooaah!!

❝ 2. Whatever SAS does, it seems to require that we work in V through ZGZt+R in order to estimate CI's for the fixed effects.

Seems so.

❝ It would be interesting to see someone who has solid understanding of matrix theory and stats to work out the equations when the between and within-variability for T cannot be separated.

Definitely not me…

❝ However, since FDA now threw the mixed model out for semi-replicate designs, …

What on earth gives you this impression? I’m talking about ABE (Stats guidance Appendix E, Progesterone guidance page 8, ANDA guidance page 29):

The following codes are an example of the determination of unscaled average BE for LAUCT with a partially replicate 3-way BE design:

PROC MIXED   data=pk;   CLASSES SEQ SUBJ PER TRT;   MODEL LAUCT = SEQ PER TRT/ DDFM=SATTERTH;   RANDOM TRT/TYPE=FA0(2) SUB=SUBJ G;   REPEATED/GRP=TRT SUB=SUBJ;   ESTIMATE 'T vs. R' TRT 1 -1/CL ALPHA=0.1;   ods output Estimates=unsc1;   title1 'unscaled BE 90% CI - guidance version';   title2 'AUCt'; run; data unsc1;   set unsc1;   unscabe_lower=exp(lower);   unscabe_upper=exp(upper); run;

If reference-scaling is acceptable (right branch), even a spreadsheet (‼) would do.

❝ … interesting may in reality just mean academically attractive but possible not too useful at this moment.

Nope. Talk to John about his data sets which didn’t converge. Given, FA0(1) did – with a warning – but I think there is a data set posted at Certara’s forum where nothing worked. Study done, no result. THX, .

❝ But who knows - until someone does it and explores it, it is not known if there is an advantageous property hidden somewhere.

Might be.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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