Bioequivalence and Bioavailability Forum

Group effect commonly not relevant [Software]

posted by Helmut  – Vienna, Austria, 2014-06-30 18:55 (3948 d 01:17 ago) – Posting: # 13174
Views: 27,749

Hi Zan,

first I agree with what ElMaestro wrote. Two groups are no issue generally (same protocol, same site, not too large interval [months!] between groups).
Maybe you are interested in this thread and some quotes from the FDA. I don’t have Win­Nonlin any more (consider upgrading to Phoenix; release 6.4 is expected this summer). My setup in Phoenix / Win­Nonlin 6.3:

• Group model I:
  fixed:  Group+Sequence+Sequence(Group)+Period(Group)+Treatment+Treatment×Group
random: Subject(Sequence×Group)
  If the Treatment-by-Group term is not significant (p ≥0.1) this term can be dropped from the model, proceeding to Group Model II.
  If the Treatment-by-Group term is significant (p <0.1), FDA’s Division of Bioequivalence requests that equiva­lence be demonstrated in one of the groups, provided that the group meets minimum requirements for a com­plete BE study (i.e., 12).
  
• Group model II:
  fixed:  Group+Sequence+Sequence(Group)+Period(Group)+Treatment
random: Subject(Sequence×Group)
  
• Conventional model:
  fixed:  Sequence+Period+Treatment
random: Subject(Sequence)
  If all conditions stated in FDA’s letters are fulfilled (most cases), that’s the way to go.

Like any between-subject test the one for Treatment-by-Group is lacking power (therefore, testing at α 0.10). However, you could expect then a false-positive rate in 10% of studies!

❝ I am working on a 2x2 crossover BE study with large N (N=54). Due to limited clinical capacity the site separated subjects into two dosing groups (N=27 each).

IMHO, a 1:1 split is not optimal. Let’s assume the worst, i.e., for any wacky reasons FDA insist on model I and there is a significant Treatment-by-Group Interaction. No pooling; go with one of the groups. In your design both have a size of 27. Let’s assume a T/R of 0.95, CV 30.5%, and target power 90%. You end up with 54 subjects (power 90.38%). BTW, your 1:1 split results in imbalanced sequences in both groups. Let’s further assume that in both groups the T/R-ratio and CV come out exactly as planned and you have no drop-outs. Power will be just 60.97% in both. If both groups are equally sized the questions also arises on which one you will base the assessment of BE. The nicer one? 
I would suggest to split subjects in such a way that one of the groups is the maximum capacity of the clinical site. Which power can we expect in the groups?
G1  % power  G2  % power
────────────────────────
27   60.97   27   60.97 
28   63.13   26   58.63 
30   66.92   24   53.92
32   70.27   22   48.33 
34   73.25   20   41.98 
36   75.89   18   34.91 
────────────────────────

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

• Phoenix WNL to handle 2x2 crossover study with multip group zan 2014-06-27 23:29 
  • Phoenix WNL to handle 2x2 crossover study with multip group ElMaestro 2014-06-28 23:23
  • Group effect commonly not relevantHelmut 2014-06-30 16:55
    • Group effect in 2x2 BE study zan 2014-06-30 19:18
      • Group effect in 2x2 BE study ElMaestro 2014-06-30 20:36
      • To pool or not to pool Helmut 2014-06-30 20:51
        • To pool or not to pool zan 2014-06-30 21:02
          • To pool or not to pool Helmut 2014-06-30 21:38
            • To pool or not to pool zan 2014-06-30 21:46
              • To pool or not to pool Helmut 2014-06-30 22:22
                • To pool or not to pool zan 2014-07-01 01:15
                  • Partial vs. sequential tests in WNL Helmut 2014-07-01 12:26
                    • Partial vs. sequential tests in WNL zan 2014-07-01 18:03
                      • Loosing patience Helmut 2014-07-01 18:23
            • To pool or not to pool ElMaestro 2014-06-30 22:11
              • To pool or not to pool zan 2014-07-01 01:18
              • To pool or not to pool zan 2014-07-02 19:56
                • To pool or not to pool ElMaestro 2014-07-03 00:17
                  • To pool or not to pool zan 2014-07-03 00:36
                • sequence- / period effect #666 Helmut 2014-07-03 10:05
    • Group effect commonly not relevant AngusMcLean 2014-07-06 16:19
      • Group effect commonly not relevant Helmut 2014-07-06 20:32
        • Group effect commonly not relevant AngusMcLean 2014-07-06 22:52
          • Group effect commonly not relevant Helmut 2014-07-06 23:57
            • PHX: Parameter mapping AngusMcLean 2014-07-07 15:04
              • PHX: Parameter mapping Helmut 2014-07-07 15:45
                • PHX: Parameter mapping Shuanghe 2014-07-07 17:35
                  • Great hint! Helmut 2014-07-07 17:54
                  • PHX: Parameter mapping AngusMcLean 2014-07-07 20:49
                • PHX: Parameter mapping AngusMcLean 2014-07-07 18:46