Bioequivalence and Bioavailability Forum

Merhaba BRN,

❝ I figured out how to calculate the CVintra, so nevermind the related question.

Fine.

❝ I used A, B and C letters for T1, T2 and Reference products respectively not to enter T1T2R in the sequence column.

Why not? But if you want to make the life of in­spec­tors easier, I would suggest to use the treatment’s coding. You can still enter A/B/C for convenience and then replace A → T1, B → T2, and C → R. This procedure is trans­pa­rent (do­cu­ment­ed in the “History”-tab of the work­sheet).

A convenient way is to have two worksheets. One containing the blinded concentrations with columns subject / period and the other one the randomization (subject / period / se­quence / treatment). In the workflow you can merge or join them sorting by subject / period and in­clude the other columns. Generally I per­form the NCA still blinded for treatments and link to the randomization afterwards.

❝ Then I did 2 types of analysis.

❝ 1-Run the analysis on the complete data set. Getting these results (PE, 90%CI U - L):

❝ A, Cmax, 103.92 (83.42-129.46), CVintra: 39.1%

❝ B, Cmax, 96.01 (77.07-119.61), CVintra: (Getting one CVintra for Cmax, shown above)

❝

❝ 2-Run the analysis on two different datasets. One including A and C, the other including B and C.

❝ A, Cmax, 104.24 (85.84-126.57), CVintra: 32.9%

❝ B, Cmax, 95.55 (76.54-119.29), CVintra: 38.0%

❝

❝ Which way to go?

The first analysis (full model) assumes a common variance of all treatments. This is the one you would use in pivotal studies. Examples

• Dose proportionality (different doses).
  
• Line extensions (e.g., R approved up to 40 mg but highest strength 20 mg – dose 2×20 mg, T1 4×10 mg, T2 1×40 mg).

In a pilot study I guess you would drop one of the tests and perform the pivotal with the other. For a proper sample size estimation – like you already did – run two different analyses (T1 vs. R and T2 vs. R). Use the PE and CV from these. Allow for a safety margin (both the PE and CV from the pilot study are uncertain estimates).

❝ In both cases it is a highly variable drug, widened limits and bioequivalent, Right?

A high CV from a non-replicated cross-over is just a hint (CV_intra is pooled from CV_WR and CV_WT). The limits can be only widened based on the CV of the reference in a replicated design.