Darborn
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Japan,
2023-08-22 04:24
(191 d 20:31 ago)

Posting: # 23704
Views: 1,609
 

 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
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Vienna, Austria,
2023-08-23 12:01
(190 d 12:54 ago)

@ Darborn
Posting: # 23705
Views: 1,328
 

 RSABE with two test products

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):

  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   •
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 CVwT = CVwR because in partial replicate designs CVwT is unknown. If CVwT < CVwR (quite often), your study will be overpowered and economically questionable. If CVwT > CVwR 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.

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Darborn
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Japan,
2023-08-23 13:13
(190 d 11:42 ago)

@ Helmut
Posting: # 23706
Views: 1,355
 

 RSABE with two test products

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
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2023-08-23 13:51
(190 d 11:04 ago)

@ Darborn
Posting: # 23707
Views: 1,306
 

 RSABE with two test products: Sample size?

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.

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Darborn
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Japan,
2023-08-30 10:07
(183 d 14:48 ago)

@ Helmut
Posting: # 23709
Views: 1,184
 

 RSABE with two test products: Sample size?

Thank you Helmut for answering the question ;-)
fethiye
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Colchester,
2024-02-23 08:14
(6 d 15:41 ago)

@ Helmut
Posting: # 23875
Views: 239
 

 RSABE with two test products

Thanks for information :-)
BEQool
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2024-02-22 10:15
(7 d 13:41 ago)

@ Darborn
Posting: # 23870
Views: 288
 

 crossover design when use ABEL with two test products

Hello,
so the most appropriate design for 2 test treatments and replicated reference is a below one?

T1  R   T2   R

R   T1  R   T2

T2  R   T1  R

R   T2  R   T1


Do you think EMA regulators would have any objections if this is was pivotal study (of course bearing Bonferroni adjustment in mind)?

Probably following designs would be worse?:

a) EMA suggested replicate design with additional test treatment
TRR|T2
RTR|T2
RRT|T2


b) 3x6x3 Williams design with additional reference treatment
ABC|C
ACB|C
BAC|C
BCA|C
CAB|C
CBA|C


Best regards
BEQool
Helmut
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2024-02-23 10:25
(6 d 13:30 ago)

@ BEQool
Posting: # 23876
Views: 220
 

 crossover design when use ABEL with two test products

Hi BEQool,

❝ so the most appropriate design for 2 test treatments and replicated reference is a below one?

❝ ❝ T1  R   T2   R

❝ ❝ R   T1  R   T2

❝ ❝ T2  R   T1  R

❝ ❝ R   T2  R   T1

I think so. I performed such studies but only as pilots. The pivotals were full replicates with the most promising candidate.1

❝ Do you think EMA regulators would have any objections if this is was pivotal study (of course bearing Bonferroni adjustment in mind)?

No idea.

❝ Probably following designs would be worse?:

Yes (see below why).

❝ a) EMA suggested replicate design with additional test treatment

TRR|T2

RTR|T2

RRT|T2

❝ b) 3x6x3 Williams design with additional reference treatment

ABC|C

ACB|C

BAC|C

BCA|C

CAB|C

CBA|C


That’s the same idea as in the so-called ‘extra-reference design’2 (a two-sequence partial replicate TRR|RTR). This design – like both of yours – is biased in the presence of true period effects.


  1. Evaluate two IBDs by excluding either T1 or T2. Select the candidate with a T/R-ratio closer to 1. If similar, select the one with lower CVw.
  2. Chow, SC, Shao J, Wang H. Individual bioequivalence testing under 2×3 designs. Stat Med. 2002; 21(5): 629–48. doi:10.1002/sim.1056.

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BEQool
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2024-02-25 10:59
(4 d 12:56 ago)

@ Helmut
Posting: # 23881
Views: 146
 

 crossover design when use ABEL with two test products

Dear Helmut,
thank you for your explanations. Useful as always :-)

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