Bioequivalence and Bioavailability Forum

Dear all,

since at least the Danish Authority requires a narrower acceptance range for some drugs in the following you may find a table giving sample sizes for the acceptance range of 0.90-1.11 (cave: the upper limit is 1/0.9=1.1111..., except for Canada, where the upper limit is set to 1.12).

Sample sizes were calculated for an expected deviation of -5% from the reference (80% and 90% power) according to approximations (which can easily implemented e.g. in a speadsheet for any combination of power and deviation) given in
[1] Hauschke D, Steinijans VW, Diletti E and M Burke
    Sample Size Determination for Bioequivalence Assessment Using a Multiplicative Model
    J Pharmacokin Biopharm 20/5, 557-561, 1992
and
[2] S-C Chow and H Wang
    On Sample Size Calculation in Bioequivalence Trials
    J Pharmacokin Pharmacodyn 28/2, 155-169, 2001
    Errata: J Pharmacokin Pharmacodyn 29/2, 101-102, 2002

Approximate sample sizes differ slightly from exact values given by
[3] Diletti E, Hauschke D and VW Steinijans
    Sample size determination: Extended tables for the multiplicative model
    and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43
    Int J Clin Pharm Ther Toxicol 30/Suppl.1, S59-62, 1992 and
[4] B Oloffson
    StudySize2.01
    CreoStat HB, 2006
       +-----------+-----------+-----------+-----------+
       |    [1]    |     [2]   |     [3]   |     [4]   |
+------+-----------+-----------+-----------+-----------+
|  CV% |  80%  90% |  80%  90% |  80%  90% |  80%  90% |
+------+-----------+-----------+-----------+-----------+
|  5.0 |  12    16 |  12    16 |  14    18 |  14    18 |
|  6.0 |  18    24 |  18    22 |   .     . |  18    24 |
|  7.0 |  22    30 |  22    30 |   .     . |  24    32 |
|  7.5 |  26    36 |  26    34 |  26    36 |  26    36 |
|  8.0 |  30    40 |  28    40 |   .     . |  30    40 |
|  9.0 |  36    50 |  36    50 |   .     . |  36    50 |
| 10.0 |  44    60 |  44    60 |  44    60 |  44    60 |
| 11.0 |  54    74 |  52    72 |   .     . |  54    72 |
| 12.0 |  62    86 |  62    86 |   .     . |  62    86 |
| 12.5 |  68    94 |  68    94 |  68    94 |  68    94 |
| 13.0 |  74   102 |  74   100 |   .     . |  74   100 |
| 14.0 |  84   116 |  84   116 |   .     . |  84   116 |
| 15.0 |  98   134 |  96   134 |  96   132 |  96   132 |
| 17.5 | 132   182 | 132   182 | 130   180 | 130   180 |
| 20.0 | 172   236 | 170   236 | 168   232 | 168   232 |
| 22.5 | 216   298 | 216   298 |   .     . | 212   292 |
| 25.0 | 266   368 | 266   368 |   .     . | 258   358 |
+------+-----------+-----------+-----------+-----------+

If using approximations you should allow for a safety margin; sample sizes are sometimes a little larger (overlined) than exact ones, except for small CVs (underlined) where the sample size is underestimated.

Hopefully your narrow therapeutic index drug shows low variability - which is often the case; otherwise it will be very difficult to demonstrate BE in a conventional 2x2 cross-over study...