Bioequivalence and Bioavailability Forum

Hi Martin,

❝ Body weight stratum 1: x mg for T1, T2 and R for subjects < z kg

❝ Body weight stratum 2: y mg for T1, T2 and R for subjects > z kg

❝ Study design: Williams’ design (3-treatment, 3-period, 6-sequence) with stratified randomization according to body weight stratum (<z kg and > z kg) to ensure balance regarding this strata.

Modifying this code:

Randomization table          created: 2018-06-08 11:06:57
(seed: 8503789 blocksize: 6 )

 subject stratum seqno sequence period 1 period 2 period 3
       1  low BW     1  T2-T1-R       T2       T1        R
       2  low BW     5  R-T2-T1        R       T2       T1
       3 high BW     3  T1-T2-R       T1       T2        R
       4 high BW     2  T2-R-T1       T2        R       T1
       5  low BW     6  R-T1-T2        R       T1       T2
       6  low BW     4  T1-R-T2       T1        R       T2
       7  low BW     3  T1-T2-R       T1       T2        R
       8 high BW     6  R-T1-T2        R       T1       T2
       9  low BW     2  T2-R-T1       T2        R       T1
      10 high BW     5  R-T2-T1        R       T2       T1
      11 high BW     4  T1-R-T2       T1        R       T2
      12 high BW     1  T2-T1-R       T2       T1        R
      13  low BW     1  T2-T1-R       T2       T1        R
      14  low BW     6  R-T1-T2        R       T1       T2
      15  low BW     4  T1-R-T2       T1        R       T2
      16 high BW     2  T2-R-T1       T2        R       T1
      17 high BW     3  T1-T2-R       T1       T2        R
      18  low BW     5  R-T2-T1        R       T2       T1
      19 high BW     5  R-T2-T1        R       T2       T1
      20  low BW     3  T1-T2-R       T1       T2        R
      21 high BW     1  T2-T1-R       T2       T1        R
      22 high BW     4  T1-R-T2       T1        R       T2
      23 high BW     6  R-T1-T2        R       T1       T2
      24  low BW     2  T2-R-T1       T2        R       T1


Summary of randomisation

24 subjects randomized into 6 sequence groups.
Number of subjects in sequence groups:
R-T1-T2 R-T2-T1 T1-R-T2 T1-T2-R T2-R-T1 T2-T1-R
      4       4       4       4       4       4
Runs test of randomness: p.value=0.4038

R-T1-T2,     low BW: 2
R-T1-T2,    high BW: 2
R-T2-T1,     low BW: 2
R-T2-T1,    high BW: 2
T1-R-T2,     low BW: 2
T1-R-T2,    high BW: 2
T1-T2-R,     low BW: 2
T1-T2-R,    high BW: 2
T2-R-T1,     low BW: 2
T2-R-T1,    high BW: 2
T2-T1-R,     low BW: 2
T2-T1-R,    high BW: 2

Trivial: Your sample size has to be a multiple of 12.

❝ 1) Can the BE assessment be based on all data combined or does this require a separate analysis per body weight stratum

Strictly speaking BE is a comparison of at the same molar dose. Hence, separate?

❝ 2) If a combined assessment is the way to go how should the model look like

❝ a) Ignoring body weight strata and use classical model (FDA): fixed effects for period, sequence, treatment and random effect for subject nested in sequence.

❝ b) Including body weight strata as mentioned in ICH E9 (i.e. factors on which randomization has been stratified should be accounted for later in the analysis): fixed effects for period, sequence, treatment, body weight strata and random effect for subject nested in sequence.

If you go with a) what is the purpose of the stratification?
In b) the stratum is a between-group term anyhow and I guess that the residual error will be the same as in a).