AB
☆    

India,
2012-02-08 09:21
(4432 d 10:45 ago)

Posting: # 8069
Views: 21,335
 

 ISCV and CI [RSABE / ABEL]

Dear All,

Is there any possibility to get the CI within 80-125 limits if the ISCV of reference & also the ISCV obtained form both test & Ref are approximately 47% in a full replicate ref scale approach (for EMA)?

Thanks,
AB


Edit: Category changed. [Helmut]

Regards,
AB
drgunasakaran1
★★  
avatar

2012-02-08 09:44
(4432 d 10:23 ago)

@ AB
Posting: # 8070
Views: 19,943
 

 ISCV and CI

Very very less chance to have that possibility.

You can widen the lower limit around 72.15% and upper limit to 138.59% if the ISCV% is around 45% for EMA submission in case of Replicate design.

Dr S Gunasakaran MBBS MD
Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same.
d_labes
★★★

Berlin, Germany,
2012-02-08 10:47
(4432 d 09:20 ago)

@ AB
Posting: # 8071
Views: 19,904
 

 Sample size feasible

Dear AB,

if your point estimator is ok (i.e. in the range 0.95 ... 1.0526) a sample size estimation with your ISCV and a full replicate design (2-sequence-4-period) gives (using R with package PowerTOST)
library(PowerTOST)
sampleN.TOST(CV=0.47, design="2x2x4")

+++++++++++ Equivalence test - TOST +++++++++++
            Sample size estimation
-----------------------------------------------
Study design:  2x2x4 replicate crossover
log-transformed data (multiplicative model)

alpha = 0.05, target power = 0.8
BE margins        = 0.8 ... 1.25
Null (true) ratio = 0.95,  CV = 0.47

Sample size (total)
 n     power
44   0.806110


Thus the chance with a feasible sample size is greater then anticipated by my previous speaker above :cool:.

But the question remains: Why do you resist in using the 80-125% acceptance range also the EMA allows you a widening :confused:. Or is your ISCV from AUC?

Regards,

Detlew
AB
☆    

India,
2012-02-08 12:40
(4432 d 07:27 ago)

@ d_labes
Posting: # 8075
Views: 19,896
 

 Sample size feasible

Dear d_labes & drgunasakaran

Thanks for Quick response.

The data provided is of Cmax from the study.
PE is 100 and the number of subjects completed in the study were 70, the resulting CI was well within 80-125 with ISCV of 47%.
could i suspect something wrong went in analysis?
on the other hand if every thing was correct why do we need widening of CI?

Regards,
AB
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-02-08 14:37
(4432 d 05:29 ago)

@ AB
Posting: # 8077
Views: 19,974
 

 No worries!

Dear AB!

❝ PE is 100 and the number of subjects completed in the study were 70, the resulting CI was well within 80-125 with ISCV of 47%.

❝ could i suspect something wrong went in analysis?


I’m not a friend of post-hoc power calculations, but your result is not surprising:

library(PowerTOST)
power.TOST(theta0=1.00, CV=0.47, n=70, design="2x2x4")
[1] 0.9872979


According to Endrényi & Tóthfalusi, Table A2 (see there), you would have needed only 25 subjects (50% CV, PE 1.00) to show BE with 90% power.

❝ on the other hand if every thing was correct why do we need widening of CI?


You should follow the protocol. See the GL Section 4.1.10:

The request for widened interval must be prospectively specified in the protocol.

  • If you did not intend to scale: The acceptance range remains at 80.00–125.00% and since your 90% CI is within ⇒ BE.
  • If you intended to scale the widened AR is:
    library(PowerTOST)
    exp(-0.76*CV2se(0.47)); exp(+0.76*CV2se(0.47))
    [1] 0.7121033
    [1] 1.404291

    Since your 90% CI is within 71.21–140.43% and the PE is within 80.00–125.00% ⇒ BE.
No worries; you wasted only money.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Berlin, Germany,
2012-02-08 15:18
(4432 d 04:49 ago)

@ AB
Posting: # 8079
Views: 19,943
 

 Sample size down!

Dear AB

❝ The data provided is of Cmax from the study.

❝ PE is 100 and the number of subjects completed in the study were 70, the resulting CI was well within 80-125 with ISCV of 47%.

❝ could i suspect something wrong went in analysis?


See this post for a (simple) formula to use for the 90% CI in case of a fully replicate design.
The standard error s in this post is obtained via s=sqrt(log(CV*CV+1)), CV as ratio, not percent.

Your givings thus should result in
CI = 91.56 ... 109.22%
If the exact result you have is reasonable near this result (within the accuracy of the givings) you don't have to be afraid. All went right in your analysis :cool:.

❝ on the other hand if every thing was correct why do we need widening of CI?


You have obtained your result with an extraordinary high number of subjects. At least extraordinary high within the context of BE studies, especially considering the replicate design :yes:. I had seldom seen such a high number of subjects in BE studies during my over 30 years career :no:.

The widening of the acceptance range in case of ISCV >30% (of reference) has the purpose of avoiding such a high numbers of subjects under study.
See this recent thread for sample size tables for scaled average bioequivalence, including the EMA and the FDA analysis methods.

These tables give you a necessary sample size of N=20 for the EMA evaluation, assuming target power = 80%, GMR=1 and an ISCV=50% (Table A2 of the paper). Even if you follow the recommendation of the two Laszlo's and assume a GMR=0.90 the sample size necessary is N=28.
Thus you could have saved your sponsor quite a lot of money. But on the other hand your company did earn lesser money :-D.
Moreover you could had prevented your volunteers from a lot of blood losses (Someone may call your study unethically). But on the other hand they were of course poorer of the volunteer fee :-D.
One's owl is another one's nightingale.


Sorry. Seen just now after submitting that some points were doubled with Helmut.

Regards,

Detlew
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-02-08 15:31
(4432 d 04:35 ago)

@ d_labes
Posting: # 8080
Views: 20,166
 

 World record?

Dear Detlew!

❝ I had seldom seen such a high number of subjects in BE studies during my over 30 years career :no:.


See Boehringer’s world record (?): 180 subjects, full replicate. :-D

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Berlin, Germany,
2012-02-08 17:16
(4432 d 02:50 ago)

@ Helmut
Posting: # 8081
Views: 19,806
 

 Wow!

Dear Helmut!

❝ See Boehringer’s world record (?): 180 subjects, full replicate. :-D


It must be a drug from which the survival of mankind is dependent! Or highly profitable?

Regards,

Detlew
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2012-02-08 17:24
(4432 d 02:43 ago)

@ d_labes
Posting: # 8082
Views: 19,882
 

 Wow!

Dear Detlew!

❝ It must be a drug from which the survival of mankind is dependent! Or highly profitable?


Dabigatran? Guess!

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2012-02-08 17:48
(4432 d 02:19 ago)

@ Helmut
Posting: # 8083
Views: 19,860
 

 Wow!

Dear Detlew and Helmut,
Many thanks for making it very clear.

Regards,
AB
jag009
★★★

NJ,
2015-09-23 22:43
(3108 d 22:24 ago)

@ Helmut
Posting: # 15462
Views: 17,422
 

 World record?

Hi Helmut,

world record (?): 180 subjects, full replicate. :-D

What would the sample size be if it was run as a 2-way study :-D:-D:-D

John
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2015-09-23 23:57
(3108 d 21:09 ago)

@ jag009
Posting: # 15463
Views: 17,433
 

 Nope

Hi John,

world record (?): 180 subjects, full replicate. :-D


❝ What would the sample size be if it was run as a 2-way study :-D:-D:-D


IIRC what the guy planning the study told me, B-I expected a high GMR. Don’t forget that the study was designed for FDA’s RSABE. For a GMR of 1.2, CV 0.55, and 85% power that would transfer into 172 subjects. Add an expected droput-rate of 5% and you end up with 180 dosed.
No scaling in a 2×2×2 study. Therefore, 2,282 subjects… To fulfill the FDA’s new requirements (4-period full replicate, assuming CVT=CVR) according to Detlew’s new function sampleN.HVNTID() in the pre-release PowerTOST 1.3-01 1,146 subjects. Forget it.
If dabigatran would be classified by the EMA as an NTID, 90.00–111.11% would be required. Sample size estimation not possible for a PE of 1.2.
Anyhow, the PEs in the “world record” study were >1.25. Not even n=∞ would have helped – regardless which fancy method ever one would apply.

This one on mesalamine was a 2×2×4 in 238 subjects. AFAIK, the current world record is held by another innovator, Pfizer (two fully replicated 4-period studies in hundreds [sic] of subjects; personal communication Scott Patterson). No idea which Wonder-Pill economically justified such studies.

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,636 registered users;
85 visitors (0 registered, 85 guests [including 8 identified bots]).
Forum time: 20:07 CET (Europe/Vienna)

Nothing shows a lack of mathematical education more
than an overly precise calculation.    Carl Friedrich Gauß

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5