Bioequivalence and Bioavailability Forum

Update: S×F variance test [Regulatives / Guidelines]

posted by AngusMcLean – USA, 2014-12-08 19:18 (3424 d 19:28 ago) – Posting: # 14020
Views: 12,257

I have a recent email from Ana over at Pharsight: Please see below and let me know your thoughts. Evidently there has been confusion in the past and I am wondering whether it has been resolve (below).

"Some additional discussion about the questions that you asked about BE has taken place within Pharsight. I just wanted to give you an update.

1. We entered an enhancement on our tracking system “Provide additional output in Pop/Indiv Bioequivalence - sigmaD, sigmaWT (for subject by formulation interaction variance)”. WinNonlin is calculating this but not providing it in the output.
2. For certain designs the documentation has some information that might be useful to you:

For an RTRT/TRTR study, if the default model for replicated crossovers is used, which has a random model using type FA0(2), look at the Parameter and the Group_Level columns on the Parameter Key output workbook to determine which variance parameter is for the reference formulation and which is for the test formulation. In the following equations, it is assumed that the first output parameter is for the test formulation.

The within-subject variance of the test, sig_WT^2, and the within-subject variance of the reference, sig_WR^2, are in the output as:
sig_WT^2 = Var(Period*Formulation*Subject)_21
sig_WR^2 = Var(Period*Formulation*Subject)_22

The intra-subject CV's can be computed as:
IntraCV_T = 100%*sqrt(exp(sig_WT^2)-1)
IntraCV_R = 100%*sqrt(exp(sig_WR^2)-1)

The between-subject variance of test, sig_BT^2, the between-subject variance of reference, sig_BR^2, and the G matrix for the random model, can be computed as follows. This still assumes that the test formulation precedes the reference. The '_11' notation on the lambda parameters (which indicates that they are for the first random model and first group) has been dropped to improve readability:

G(1,1) = sig_BT^2 = lambda(1,1)^2
G(2,2) = sig_BR^2 = lambda(2,1)^2+lambda(2,2)^2
G(1,2) = rho*sig_BT*sig_BR = lambda(1,1)*lambda(2,1) (= between subject covariance for test and reference)

The subject-by-formulation interaction variance in general is sig_D^2 = sig_BT^2 + sig_BR^2 - rho*sig_BT*sig_BR, and can be computed from the above equations as:
sig_D^2=G(1,1)+G(2,2)-2*G(1,2)

The inter-subject CV's can be computed as:
InterCV_T = 100%*sqrt(exp(sig_BT^2)-1)
InterCV_R = 100%*sqrt(exp(sig_BR^2)-1)

If the CSH variance structure is used instead of FA0(2), the following equations change. This still assumes the first output parameter is for test and the second for reference.

G(1,1) = sig_BT^2 = cshSD(1)^2
G(2,2) = sig_BR^2 = cshSD(2)^2
G(1,2) = cshCorr * cshSD(1) * cshSD(2)"

The parameter name or units is not in the file I have: it is from the FDA template, it is the same file for EMEA.

Here is the output from Phoenix. Now one has to look at Ana's email

Dependent Units Parameter Estimate
Data lambda(1,1)_11 0.85299471
Data lambda(1,2)_11 0.82840678
Data lambda(2,2)_11 8.34E-07
Data Var(Period*Formulation*Subject)_21 0.20211811
Data Var(Period*Formulation*Subject)_22 0.11739421

Herr is my paramater key and the REFERENCE IS first. My file is RTRT

Dependent Units Parameter Source Type Bands Subject_Term Group_Term Group_Level
Data lambda(1,1)_11 Random No-Diag Factor Analytic 2 Subject
Data lambda(1,2)_11 Random No-Diag Factor Analytic 2 Subject
Data lambda(2,2)_11 Random No-Diag Factor Analytic 2 Subject
Data Var(Period*Formulation*Subject)_21 Repeated Variance Components Subject Formulation Formulation_R
Data Var(Period*Formulation*Subject)_22 Repeated Variance Components Subject Formulation Formulation_T

That is why the parameters are switched from yours.

Edit: Merged with two later post. Note that you can edit your original post within 24 hours. [Helmut]

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Complete thread:

Concerta Guidance: Sub x Form interaction variance test jag009 2014-12-05 20:57 [Regulatives / Guidelines]
- Concerta Guidance: Sub x Form interaction variance test AngusMcLean 2014-12-06 01:28
  - Concerta Guidance: Sub x Form interaction variance test Helmut 2014-12-06 01:53
    - Concerta Guidance: Sub x Form interaction variance test jag009 2014-12-07 20:58
      - Concerta Guidance: S×F variance test AngusMcLean 2014-12-08 01:35
        
        Concerta Guidance: S×F variance test Helmut 2014-12-08 14:12
        
        Update: S×F variance test jag009 2014-12-08 17:40
        
        Update: S×F variance test AngusMcLean 2014-12-08 18:09
        
        EMA’s dataset I Helmut 2014-12-08 18:18
        
        EMA’s dataset I AngusMcLean 2014-12-08 19:55
        
        Update: S×F variance test jag009 2014-12-08 20:41
        
        Update: S×F variance testAngusMcLean 2014-12-08 18:18
        
        Question jag009 2014-12-10 17:01
        
        Question AngusMcLean 2014-12-10 18:34
        
        Update: S×F variance test kumarnaidu 2014-12-09 06:48
        
        Update: S×F variance test jag009 2014-12-09 15:16
        
        Update: S×F variance test AngusMcLean 2014-12-09 17:47
        
        Update: S×F variance test jag009 2014-12-09 18:01
        
        Update: S×F variance test AngusMcLean 2014-12-09 18:30
        
        Update: S×F variance test jag009 2014-12-18 15:31
        
        Update: S×F variance test AngusMcLean 2014-12-18 16:12
        
        Update: S×F variance test jag009 2014-12-22 17:28
        
        Update: S×F variance test AngusMcLean 2014-12-22 19:32
        
        Update: S×F variance test jag009 2014-12-22 20:19
        
        Update: S×F variance AngusMcLean 2014-12-22 20:45
        
        Update: S×F variance jag009 2014-12-22 20:51
        
        Update: S×F variance AngusMcLean 2014-12-22 21:10
        Update: S×F variance AngusMcLean 2014-12-22 21:36
        
        Update: S×F variance jag009 2014-12-22 22:18
        
        Update: S×F variance AngusMcLean 2014-12-22 23:26
        
        Update: S×F variance jag009 2014-12-23 04:43
        
        Update: S×F variance AngusMcLean 2014-12-23 15:24
        
        Update: S×F variance test AngusMcLean 2014-12-09 21:03
        
        Coding Helmut 2014-12-09 18:49
        
        working.... jag009 2014-12-09 22:24
- Concerta Guidance: S×F variance test ElMaestro 2014-12-06 11:12
  - Concerta Guidance: S×F variance test AngusMcLean 2014-12-07 14:32
    - Concerta Guidance: S×F variance test ElMaestro 2014-12-07 18:08
      - Concerta Guidance: S×F variance test AngusMcLean 2014-12-07 23:13
        
        Concerta Guidance: S×F variance test ElMaestro 2014-12-08 12:25
        
        Concerta Guidance: S×F variance test nobody 2014-12-08 13:44
        Concerta Guidance: S×F variance test AngusMcLean 2014-12-08 14:03
        
        Concerta Guidance:S×F variance test nobody 2014-12-08 14:32

Update: S×F vari­­ance test [Regulatives / Guidelines]

Complete thread:

Update: S×F variance test [Regulatives / Guidelines]