Bioequivalence and Bioavailability Forum • crossover design when use RSABE with two test products

Darborn
☆

Japan,
2023-08-22 04:24
(36 d 02:36 ago)

Posting: # 23704
Views: 591

crossover design when use RSABE with two test products [Design Issues]

Dear all,

Normally we use 2x3x3 or 2x2x4 replicated design for RSABE, but it needs only one test drug.
When design a crossover trial with two test drug (or one ODT given with/without water), I run into confusion about how to give a balanced design for the trial.
Furthermore, which make things even worse, I always get confused by "variance-balanced" and "carryover-balance" design.

I came out with the following design, but I'm not sure if it is suitable to use when analyzed with FDA RSABE approach.

T1 R T2 R R T1 R T2 T2 R T1 R R T2 R T1

Thank you!
Darborn

Edit: Tabulators changed to spaces and BBcoded; see also this post #6. [Helmut]

Helmut
★★★

Vienna, Austria,
2023-08-23 12:01
(34 d 18:59 ago)

@ Darborn
Posting: # 23705
Views: 476

RSABE with two test products

Post reply

Hi Darborn,

❝ When design a crossover trial with two test drug (or one ODT given with/without water), I run into confusion about how to give a balanced design for the trial.

If the design is not reference-replicated, easy. See this article.

❝ Furthermore, which make things even worse, I always get confused by "variance-balanced" and "carryover-balance" design.

True unequal carryover will bias the treatment effect. It cannot be “corrected” statistically. It can only be avoided by sufficiently long washouts. See this article. Carryover is not included in the current models for BE. Since sample sizes for a conventional Latin Squares and (variance-balanced) Williams’ designs are similar,* you can use any of them.

❝ I came out with the following design, but I'm not sure if it is suitable to use when analyzed with FDA RSABE approach.

❝ T1 R T2 R

❝ R T1 R T2

❝ T2 R T1 R

❝ R T2 R T1

First of all you have to receive a positive statement from the FDA in a “Controlled Correspondence” because this is not one of the recommended designs for RSABE.
According to ICH M13A you have to exclude treatments (T1 or T2) and perform two separate analyses on the respective others (T1 vs R and T2 vs R). Your design will lead to two partial replicate designs with missing observations (denoted with • below):

T1 R • R R T1 R • • R T1 R R • R T1
• R T2 R R • R T2 T2 R • R R T2 R •

So far I’ve done that only in pilot studies (deciding which of two candidate formulations should be used in a pivotal study). Drawback: You have to assume CV_wT = CV_wR because in partial replicate designs CV_wT is unknown. If CV_wT < CV_wR (quite often), your study will be overpowered and economically questionable. If CV_wT > CV_wR your study will be underpowered (higher risk of failure). Both cases are ethically questionable.

For 4-treatments the sample size is equal in Latin Squares and one of the six possible Williams’ designs.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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Darborn
☆

Japan,
2023-08-23 13:13
(34 d 17:46 ago)

@ Helmut
Posting: # 23706
Views: 458

RSABE with two test products

Post reply

Thank your reply Helmut!

❝ According to ICH M13A you have to exclude treatments (T1 or T2) and perform two separate analyses on the respective others (T1 vs R and T2 vs R). Your design will lead to two partial replicate designs with missing observations (denoted with • below):

❝ 1.

❝ T1 R • R

❝ R T1 R •

❝ • R T1 R

❝ R • R T1

❝

❝ 2.

❝ • R T2 R

❝ R • R T2

❝ T2 R • R

❝ R T2 R •

I tried to read your article about replicate crossover, and now I know it is so called "incomplete block design" (am I right?). However, the true nightmare comes, how can I estimate the sample size required for a power of 80%. :confused:

I guess that using the design of 2x3x3 or 2x2x4 in powerTOST is a big NO… :no:

Helmut
★★★

Vienna, Austria,
2023-08-23 13:51
(34 d 17:08 ago)

@ Darborn
Posting: # 23707
Views: 450

RSABE with two test products: Sample size?

Post reply

Hi Darborn,

❝ I tried to read your article about replicate crossover, and now I know it is so called "incomplete block design" (am I right?).

You are. Specifically it is the result of excluding treatments.

❝ However, the true nightmare comes, how can I estimate the sample size required for a power of 80%. :confused:

❝ I guess that using the design of 2x3x3 or 2x2x4 in powerTOST is a big NO… :no:

You would need the function sampleN.RSABE(), but the argument design = "2x4x4" is not implemented. Sorry.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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

Darborn ☆ Japan, 2023-08-30 10:07 (27 d 20:52 ago) @ Helmut Posting: # 23709 Views: 315	RSABE with two test products: Sample size? Post reply
	Thank you Helmut for answering the question