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Back to the forum  Query: 2017-09-26 15:01 CEST (UTC+2h)
 
Yura
Regular

Belarus,
2017-05-01 09:34

Posting: # 17285
Views: 1,687
 

 TRT / RTR Design [RSABE / ABEL]

Dear All
Do I understand correctly that using the TRT / RTR design it will be necessary to compare the RR and TT extension interval that are built on the data of subjects of different groups (50% of study subjects are used for RR and 50% of other subjects for TT), the comparison will be for different Subjects? Or will it be necessary to compare the extension interval R-R, built on 50% of the subjects, and the confidence interval T-R, built on the data of all subjects?
The appropriate sample size must be.
Alpha correction.
Best regards
mittyri
Senior

Russia,
2017-05-02 18:38

@ Yura
Posting: # 17295
Views: 1,478
 

 TRT / RTR Design

Dear Yura,

you should use all data included in PK analysis (ie all subjects) for CI estimation.
To extent the limits you need to calculate variability of RR, that is, 50% of subjects.
A hint: even if you try to calculate variability of RR for overall dataset, the majority of software (at least SAS PHX, R) is smart enough not to include the subjects with one R.

» The appropriate sample size must be.
» Alpha correction.
what did you mean here?

Kind regards,
Mittyri
Yura
Regular

Belarus,
2017-05-02 21:19

@ mittyri
Posting: # 17296
Views: 1,458
 

 TRT / RTR Design

Dear mittyri,
The approach of reference-scaled average BE (RSABE) requires that the reference formulation be measured twice in each subject. And therefore do not understand the legality of the calculation in this design.
Best regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-02 22:04

@ Yura
Posting: # 17297
Views: 1,456
 

 TRT / RTR Design

Hi Yura,

» […] reference-scaled average BE (RSABE) requires that the reference formulation be measured twice in each subject.

Says who?

» And therefore do not understand the legality of the calculation in this design.

Keep in mind that the early work on RSABE (by the two Lászlós) was solely based on exactly this design.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Yura
Regular

Belarus,
2017-05-03 07:41
(edited by Ohlbe on 2017-05-03 10:28)

@ Helmut
Posting: # 17298
Views: 1,420
 

 TRT / RTR Design

Hi Helmut
"The approach of reference-scaled average BE (RSABE) requires that the reference formulation be measured twice in each subject."
An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence

Best regards


Edit: two posts merged (remember you can edit your post within 24 hours) and link corrected [Ohlbe]
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-03 21:49

@ Yura
Posting: # 17302
Views: 1,351
 

 TRT / RTR Design

Hi Yura,

» An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence

Oops! Incidentally I was one of the reviewers of this paper. The phrase
» "The approach of reference-scaled average BE (RSABE) requires that the reference formulation be measured twice in each subject."
… slipped through my intention. My fault. This statement is – despite the two great authors – wrong.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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ElMaestro
Hero

Denmark,
2017-05-03 22:04

@ Helmut
Posting: # 17303
Views: 1,330
 

 TRT / RTR Design

Hi Hötzi,

» » "The approach of reference-scaled average BE (RSABE) requires that the reference formulation be measured twice in each subject."
» … slipped through my intention. My fault. This statement is – despite the two great authors – wrong.

Not your fault. As a reviewer you are not and will never be responsible for anything authored by others. :ok:

But having said that I think the sentence is OK, only the meaning is a bit out of context. To calculate meaningfully the intra-subject variability for Ref we need subjects in whom it has been measured (at least) twice. That was presumably what the authors tried to remind readers.
The entire issue of rsaBE cannot be approached in the absence of such subjects, and therefore the sentence makes quite some sense.

Blumentopferde :cool:

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-06 18:33

@ ElMaestro
Posting: # 17312
Views: 1,168
 

 TRT / RTR Design

Hi ElMaestro & Yura,

» But having said that I think the sentence is OK, only the meaning is a bit out of context.

Right. It appears in the introduction about the FDA’s RSABE. Nothing like that in the next paragraph about the EMA’s ABEL. The GL states only the periods (three or four) and no specific designs/sequences. In the Q&A the RTRT|TRTR and the RRT|RTR|TRR are given as examples. In Rev. 12 of the Q&A the TRT|RTR is discussed (requiring at least 12 subject in sequence RTR).

» Blumentopferde :cool:

Love it!

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Yura
Regular

Belarus,
2017-05-09 11:35

@ Helmut
Posting: # 17332
Views: 1,101
 

 TRR / RTT Design

Hi Helmut
What if the design of the TRR / RTT obtained by Cmax
CI T-R = 0.88-1.21;
CV T-R =48%;
expansion [0.71-1.40] CV R-R=47%;
GMR T-T=0.708 not belong [0.80; 1.25];
CI T-T = 0.47-1.06;
CV T-T =77%.
Is it possible to draw a conclusion about bioequivalence?
Best regards


Edit: Subject line changed; see also this post #2. [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-09 13:06

@ Yura
Posting: # 17333
Views: 1,106
 

 TRR / RTT Design

Hi Yura,

» What if the design of the TRR / RTT obtained by Cmax
» CI T-R = 0.88-1.21;
» CV T-R =48%;
» expansion [0.71-1.40] CV R-R=47%;

Fulfills all requirements for ABEL: CVwR >30%, CI within expanded limits, and PE within 0.8000–1.2500.
Following the ‘logic’ of the EMA’s Q&A document at least 12 subjects should have finished the sequence TRR in order to get a ‘reliable’ estimate of CVwR. I guess that the sample size was 34, right?
If an assessor does not accept this design (not mentioned in the Q&A…) the study demonstrated even ABE.

» GMR T-T=0.708 not belong [0.80; 1.25];
» CI T-T = 0.47-1.06;
» CV T-T =77%.
» Is it possible to draw a conclusion about bioequivalence?

Yes. By definition BE is the (desired) outcome of a comparison of T with R.
The results of T vs. T are interesting but not relevant. BTW, how did you calculate the GMR and the CI? IMHO, if you use only the data of the sequence RTT (as for CVwT) you can evaluate it only as a paired design (e.g., arbitrarily comparing data of the second administration to the first). Such an evaluation assumes no period effects – which might be false.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Yura
Regular

Belarus,
2017-05-09 16:18

@ Helmut
Posting: # 17335
Views: 1,063
 

 TRR / RTT Design

Hi Helmut
GMR - the average difference T1-T2
CI - Student's t-test for dependent samples (for 17)
Results for T-T does not take into account?
Best regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-09 16:56

@ Yura
Posting: # 17336
Views: 1,060
 

 TRR / RTT Design

Hi Yura,

» GMR - the average difference T1-T2
» CI - Student's t-test for dependent samples (for 17)

I guess by T1 you mean T in period 2 and by T2 T in period 3.
As said above such an evaluation assumes no period effects. Only if the period effect would be exactly zero, the difference in period means would be an unbiased estimate of the treatment effect. Your comparison is not correct. I assume when you run the same test on RR you will also get ‘strange’ results.

» Results for T-T does not take into account?

Does not take what into account?

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Yura
Regular

Belarus,
2017-05-09 17:36

@ Helmut
Posting: # 17337
Views: 1,041
 

 TRR / RTT Design

Hi Helmut
I also conducted ANOVA with the factors subject and period.
The same results are obtained as in the SAS code.
For constructing CI T-T MSE from this analysis?
Best regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-05-09 17:53

@ Yura
Posting: # 17338
Views: 1,027
 

 TRR / RTT Design

Hi Yura,

» I also conducted ANOVA with the factors subject and period.
» The same results are obtained as in the SAS code.

Sure.

» For constructing CI T-T MSE from this analysis?

You are taxing my patience. Heck, it is not possible – or better: any result is nonsense! :angry:

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Yura
Regular

Belarus,
2017-05-09 18:07

@ Helmut
Posting: # 17339
Views: 1,043
 

 TRR / RTT Design

HI Dear Helmut
Got it
I'll take a break
Best regards
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