yjlee168
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Kaohsiung, Taiwan,
2008-11-17 08:52

Posting: # 2679
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 90% CIs for BE? [R for BE/BA]

dear all, this thread was inspired by last replied message by DLabes when we talked about 90% CIs he calculated with SAS. Usually, we talk about 90% CIs in data analysis of a BE study, but we do not mention what 90% CIs we calculate. since we're now considering to add various 90% confidence interval (CI) calculations into bear for R. My questions are: (1) is it necessary to do so? regulatory or statistical basis? and (2) if yes, what 90% CIs will you recommend (Anderson-Hauck's, Westlake's, Locke' exact CI, Fixed Fieller's, Mandallaz-Mau's, etc.)? Thanks.

All the best,
---Yung-jin Lee
bear v2.8.4:- created by Hsin-ya Lee & Yung-jin Lee
Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear
Download link (updated) -> here
ElMaestro
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Denmark,
2008-11-17 09:46
(edited by ElMaestro on 2008-11-17 11:32)

@ yjlee168
Posting: # 2682
Views: 8,627
 

 90% CIs for BE?

» My questions are: (1) is it necessary to do so? regulatory or statistical basis? and (2) if yes, what 90% CIs will you recommend (Anderson-Huack's, Westlake's, Locke' exact CI, Fixed Fieller's, Mandallaz-Mau's, etc.)? Thanks.

Hi,
In a sense, the basis is empirical. It seems to work well, that's pretty much the present reason behind it. The standard way is the classic (shortest) CI. Look it up in Chow & Liu's book (Ch. 4.2.1 in the 2000 version).
When regulators have 5 minutes to assess a BE dossier then the CI is the primary thing they look at (very often 5 minutes is a reality, for reasons that go beyond the scope of this question). The anova test for treatment effect is neglected; obviously it is not problematic per se if two formulations are different. It is only problematic if they are different in a clinically significant way, and that is what the CI empirically addresses.

So I think the answer to (1) is yes, a CI is necessary, and (2) shortest.

EM.
d_labes
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Berlin, Germany,
2008-11-17 13:07

@ yjlee168
Posting: # 2687
Views: 8,674
 

 90% CIs for BE?

Dear Yung-yin

» [...] Usually, we talk about 90% CIs in data analysis of a BE study, but we do not mention what 90% CIs we calculate.

This is partly due to the fact that we implicitly assume that we talk about classical confidence intervals and therefore there is no need to mention the sort of variation by their name.

» to add various 90% confidence interval (CI) calculations into bear for R.
» My questions are: (1) is it necessary to do so? regulatory or statistical basis? and (2) if yes, what 90% CIs will you recommend (Anderson-Hauck's, Westlake's, Locke' exact CI, Fixed Fieller's, Mandallaz-Mau's, etc.)?

As always it depends. On the purpose which bear shall be used for.

Is it a tool for evaluation of ABE studies which have to be submitted to regulatory authorities?
Then my recommendation is:
(1) It is not necessary to implement some sort of other CI's.
To borrow a sentence of Helmut (I hope with his permission): There can only be one!

Imagine some variants of other CIs implemented and all used and submitted by "naive" users (and, without bothering someone personally, there are such out there, too on this forum ;-) ).
  Method1 -> bioequivalent
  Method2 -> not bioequivalent
  Method3 -> bioequivalent

and so on. What do you think about regulator's view of that?
Especially if they take five minutes as ElMaestro mentioned. Although I think the right time span is in mathematically notation < 5 min :-D .

Since the standard method is the classical CI, leave it as is.
If mentioned at all guidelines recommend this approach.

There is one exception: If you are not willing to assume a log-normal distribution for a specific pharmacokinetic target but rather a normal distribution (and this can be a reasonable strategy for such metrics as HVD, Swing, PTF or others), but need the CI for the ratio, the Locke/Fieller CI for the untransformed values may be helpful.
But I have not seen many cases where such PK metrics are used as primary targets with the need of calculating a CI as BE test.

But if bear is a tool for academic interest, implement other CIs for educational purposes. Most of your mentioned variants under (2) of your question are historical milestones in BE testing and certainly have interest in education. Which to implement you, as university staff, know better then I.

Regards,

Detlew
Helmut
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Vienna, Austria,
2008-11-17 17:12

@ d_labes
Posting: # 2696
Views: 8,893
 

 There can be only one!

Dear Dlabes!

» To borrow a sentence of Helmut (I hope with his permission): There can only be one!

Oh, I'm just recycling this sentence myself from the movíe 'Highlander' (1986 written by Gregory Widen, Peter Bellwood, and Larry Ferguson). :cool:

Cheers,
Helmut Schütz
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Helmut
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Vienna, Austria,
2008-11-17 13:30

@ yjlee168
Posting: # 2688
Views: 8,705
 

 90% CIs for BE?

Dear Yung-jin,

I agree with ElMaestro. BTW, Westlake’s CI should never be used and thrown into the statistical garbage collection because it obscures information about the location of the difference (I have not the slightest idea why it’s still used in WinNonlin).
Example from a study with low variability (CVintra 8.63%, n=12):

Shortest CI:   100.54% – 113.52% (PE 106.84%)
Westlake’s CI:  88.06% – 111.94%

According to the original paper of Westlake* the CI would be stated as ±11.94%:not really: You have no clue that the BA of the test formulation is statistically significant (though not clinically relevant) higher than the reference’s.


  • Westlake WJ. Symmetrical Confidence Intervals for Bioequivalence Trials. Biometrics. 1976;32(4):741–4. doi:10.2307/2529259.

Cheers,
Helmut Schütz
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ElMaestro
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Denmark,
2008-11-17 13:51

@ Helmut
Posting: # 2690
Views: 8,517
 

 90% CIs for BE?

» BTW, Westlake’s CI should never be used and thrown into the statistical garbage collection...
....where I hope it will land on top of individual bioequivalence and breaks its spine.

EM.
d_labes
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Berlin, Germany,
2008-11-17 13:56

@ ElMaestro
Posting: # 2691
Views: 8,563
 

 90% CIs for BE?

» ....where I hope it will land on top of individual bioequivalence and breaks its spine.

Tssss, what an unchristian wish! ;-)

Regards,

Detlew
yjlee168
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Kaohsiung, Taiwan,
2008-11-17 18:10

@ Helmut
Posting: # 2697
Views: 8,566
 

 90% CIs for BE?

dear Helmut,

» ...information about the location of the difference (I have not the slightest idea why it’s still used in WinNonlin)...

Do you know that they still use Westlake's 90% CI in WNL v6 later?

All the best,
---Yung-jin Lee
bear v2.8.4:- created by Hsin-ya Lee & Yung-jin Lee
Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear
Download link (updated) -> here
Helmut
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Vienna, Austria,
2008-11-17 18:14

@ yjlee168
Posting: # 2698
Views: 8,604
 

 90% CIs for BE?

Dear Yung-jin!

» Do you know that they still use Westlake's 90% CI in WNL v6 later?

Yes! :crying:

Cheers,
Helmut Schütz
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yjlee168
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Kaohsiung, Taiwan,
2008-11-17 18:26

@ Helmut
Posting: # 2699
Views: 8,628
 

 90% CIs for BE?

dear Helmut,

» Yes! :crying:

That's terrible. They have a program called "...a Cooperative Research and Development Agreement (CRADA) with the Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER)..." and "... Under the terms of the CRADA, Pharsight will provide the FDA with software for the analysis, visualization, storage, reporting and review of PK/PD data. The specific Pharsight products covered by the CRADA include:

* Pharsight Knowledgebase Server™ (PKS™)
* PKS Validation Suite™
* WinNonlin®...[quoted from Pharsight CRADA website]

Does that imply that USA FDA can accept Westlake's approach? Or there is nothing to do with this?

All the best,
---Yung-jin Lee
bear v2.8.4:- created by Hsin-ya Lee & Yung-jin Lee
Kaohsiung, Taiwan http://pkpd.kmu.edu.tw/bear
Download link (updated) -> here
ElMaestro
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Denmark,
2008-11-17 19:49

@ yjlee168
Posting: # 2700
Views: 8,579
 

 90% CIs for BE?

Dear Yung-jin,

it really sounds interesting if FDA will be using Pharsight's software.
Did I really write interesting?? I of course meant horrible!

Remember the type III discussion? There is not agreement about them among statisticians but since FDA published source scripts based on SAS (which uses type III SS by default) they have somehow become a de facto standard.
I could easily imagine a similar phenomenon will reveal itself with Pharsight's software. PK analyses in the world's companies then will be a struggle to reproduce the output of WinNonlin etc rather than a scientific exercise that strives to do it properly.

EM.
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