Bioequivalence and Bioavailability Forum

Hi everyone,

Thanks for noticing this post The reason I came across this is because about a year ago, a number of people asked me how to run the stats for scaled BE (FDA), and I wrote the FDA to ask them how they did it. Yesterday, the FDA called me to notify me of the progesterone recommendations.

I'm by no means a statistician, but I will try to address some of the questions as I understand them.

D. Labes:
BTW: What is missing is explicit code for ABE evaluation for the partial replicate design in case of sWR < 0.294 (CV = 30%): "The two one-sided test procedure must be used for PK parameters with sWR < 0.294."

The explicit code for this is on the last page (page 9) of the progesterone guidance. It's just the unscaled approach. You can use that method for both 4-period and 3-period designs.

BTW2: It is not clear why they recommend Proc MIXED in case of fully replicate design and Proc GLM in case of partial replicate. In both cases the call to these procedures have only sequence as fixed effect. They only serve as means to get the sequence "stratified" means of the corresponding inter-subject contrasts. Or is this meant with respect to the unscaled ABE evaluation?


I don't know why they go back and forth on this. Up until this point I have only ever seen MIXED used in any replicate design, and to be perfectly honest this nuance along with the contrasts is completely above my head. When one method crashed when I was in CRO land, we would use the other and write a protocol deviation for the statistical analysis.


ElMaestro:
Bonus questions: Pass - I have no idea.

KR: I had this concern myself, since the FDA design 3-period replicate only repeats the test formulation. I emailed my sample size guru and oracle, Stephen Julious, back in February to confirm. Stephen said,

"It would not effect the sample size but I would push back on the sequences they recommend as you are not replicating the test treatment (I assume T and R mean Test and Reference) only the Reference which we are least interested in. The “standard” design is TRR RTT"

I had a sort of logical overload thinking about this problem because the TRR/RRT trial will have the same number of direct T-R and R-T comparisons as a 2-way. Picture smoke coming out of my ears from over-heating. In the end, I just put it away when I received Stephen's reply. After all, there has to be some advantage in sample size if you run another period.

Helmut:
In general, I would always take the guidance literally, instead of scientifically. For instance, when the EMEA general BA/BE guidance said:
"The interval must be prospectively defined e.g. 0.75-1.33" I never took the reciprocal of 0.75 to give 1.33 repeating, even though in theory that would make the most sense. This is for the sole reason that you never know when you are going to hit THAT regulator - the type A that doesn't care what makes scientific sense and takes every digit literally. So when the new guidance says 0.760, even though you and I both know that it doesn't back-calculate to a perfect 30.0% CV, guess what I would recommend using?

This problem pops up again and again. Look at the older Canadian guidelines for narrow therapeutics:

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/bio/critical_dose_critique-eng.pdf

The requirements are 90.0-112.0%, not 90.0-111.11 repeating. They didn't even round down, they rounded UP. So I became a to-the-letter kind of guy, despite my academic side crying "unfair! unfair!". I learned to suppress those little hairs standing up at the back of my neck.

One thing I was happy about with the FDA progesterone recommendations was that the FDA specified 0.294 for sig_wr, because a few of their previous publications recommended using 0.25, which didn't map close to the 30% intraCV cutoff. I can drop the extra decimals (0.293560379) and still sleep ok. I presented this discrepancy in a talk at Washington State University, and it's almost worth flying back to Pullman to tell them the end of the story. Well, almost. There were 3 stop overs to that trip, and it took almost 12 hours to get there!!!! Maybe I'll just email.

Glad to hear from you guys,
-Dave