2006-06-15 14:19
(6200 d 06:25 ago)

Posting: # 149
Views: 7,547

 WinNonlin 2.1 [Software]

Dear all,

I would be very grateful if anyone can help me in answering my questions:

1- in ANOVA section in winnonlin 2.1 there are three sub-sections "Contrast", "Tests" and "Least Squares Means" that I don't know what I have to put there. The Bioequivalence test runs without putting anything in there.can anybody tell me about the utility of these subsections?

2- when I run the bioequivalence test in 3x3x3 study with carryover effect
Seq + Subject(Seq) + Period + Trt  + Carryovr

the program gives me the following error:

     Bioavailability Statistics

     Dependent variable: Cmax

     Alpha=0.0500  Bioequivalence Limits: (A.H.)Lower= 0.800 (A.H.)Upper= 1.200
     Transformation = NONE  Percent of Reference to Detect = 0.20
     Reference least squares mean not estimable

     Test : B             Least squares mean not estimable

     Test : C             Least squares mean not estimable

and when I eliminate the Carryover effect form the model it goes well.

Can any body help me in soving this problem?

Thank you very much in advance,
Vienna, Austria,
2006-06-15 15:07
(6200 d 05:37 ago)

@ valen
Posting: # 150
Views: 5,733

 WinNonlin 2.1

Dear Valen!

Unfortunatelly I don't have access to v2.1 (the ANOVA module was replaced by the BE module [Linear Mixed Effects Modeling] in v3.2).

Maybe some remarks are helpful:
  • you should ln-transform your data, resulting in
    Bioequivalence Limits: (A.H.)Lower= 0.800 (A.H.)Upper= 1.250
  • in a 3×3×3 design (as well as in a conventional 2×2) carry-over is confounded with other effects; therefore carry-over generally is not included in the model (lack of carry-over is verified by taking a plasma sample prior to administration in all periods, which should show concentrations <5% Cmax).
  • for drawbacks of a 3×3×3 design have a look at this post and the followings.
The statistical test for carry-over[1] is considered obsolete.[2,3,4]

BTW, what data does your variable Carryovr contain?

  1. JE Grizzle
    The two-period changeover design and its use in clinical trials
    Biometrics 21, 467-480 (1965)
  2. PR Freeman
    The Performance of the Two-Stage Analysis of Two-Treatment, Two-Period Crossover Trials
    Statistics in Medicine 8, 1421-1432 (1989)
  3. S Senn
    Cross-over Trials in Clinical Research
    2nd Edition, Wiley, Chichester, pp 35-88/295-322 (2002)
  4. Jones B and MG Kenward
    The 2x2 cross-over trial. Consequences of preliminary testing, in:
    Design and Analysis of Cross-Over Trials

    2nd Edition, Chapman & Hall, Boca Raton, pp 44-50 (2003)

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