Bioequivalence and Bioavailability Forum

Hi John!

❝ I went with T/R ratio 90%, power 90 and came up with something like 36-40 subjects. I added a few more in case of dropouts due to the washout.

I got:
require(PowerTOST)
expsampleN.TOST(targetpower=0.9, theta0=0.9, CV=0.14, dfCV=12-2, design="2x2")
++++++++ Equivalence test - TOST ++++++++
   Sample size est. with uncertain CV
-----------------------------------------
Study design:  2x2 crossover
log-transformed data (multiplicative model)

alpha = 0.05, target power = 0.9
BE margins        = 0.8 ... 1.25
Null (true) ratio = 0.9
CV                 = 0.14 with 10 df
one-sided upper CL = 0.2247103 (level = 95%)

Sample size (ntotal)
 n    exp. power
32   0.901134

With >40 you should be on the safe side.

❝ […] I did some calculation & modeling based on the t_1/2, T_max and gave the CRO a time limit of 30 mins for the 72 hour return blood draw.

OK.

❝ That is subject will be dropped from the study if they miss the cutoff time collection for the 72 hours in period 1, or their data will not be included in the stat analysis if they complete both periods but missing 72 hour sample in period 2. If the CRO can't do that then my threshold is 1 hour.

You are aware that you may loose power according to this procedure? What if the CRO want’s to make money (they all do)¹ and tell the subjects “Don’t worry too much about the 72 hours, es­pe­ci­ally in the second period.” Maybe you see some ‘personal reasons’ for coming late of the type

• There was a traffic jam – I couldn’t make it earlier.
  
• My bike was stolen. Didn’t know that public transportation is such a nightmare in this area!²
  
• Aunt Lizzie went to hospital and I had to hush my mother on the phone.
  
• Seeing a squirrel my cat panicked and I had to fetch her from the rain pipe.

❝ One hour is acceptable since I did a comparison between AUC_0-72 and AUC_0-73 based on t_1/2 of 25-40 hours and the difference is less than 1%.

Confirmed.

❝ Their limit of 4 hour is way too long. Otherwise I will ask to have them subjects housed for 72 hours.

Supported.

❝ I don't want to mess around with a BE assessment.

Yep! Probably would need a strong stand against the FDA.

❝ […] Do you have the drinking smiley?

I added this one:
If you prefer other virtual drinks, let me know.

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1. “We are really terribly sorry that the study did not pass due to so many excluded subjects. Do you want to repeat it in a larger sample size?”
   
2. Flimsy excuse. Public transportation is a nightmare everywhere in the US, IMHO.