Bioequivalence and Bioavailability Forum • Three Formulation

K2K
★

India,
2013-10-18 12:05
(4226 d 05:35 ago)

Posting: # 11691
Views: 8,389

Three Formulation - Partial Replicate [RSABE / ABEL]

Dear All,

As Per the FDA Draft Guideline (Additional Comments: Applicants may consider using a reference-scaled average bioequivalence approach. Please refer to Progesterone Capsules Guidance for information regarding statistical analysis method using the reference scaled average bioequivalence approach)

We Plan to conduct the pilot Study with 2 test formulation.

So Pls suggest me which design is suitable.

Design 1: Williams’ design with T1 = test 1, T2 = test 2, R =reference
(6 sequence, 3 treatment and 3 period)

or

Design 2: Partial replicate design (T1, T2 and R (2 times)) with Four Sequence, Four Period, Three treatment. (Crossover design for four medications (Williams’ design))

1  R  T2 R  T1

2  T1 R  R  T2

3  R  T1 T2 R

4  T2 R  R  T1

Whether its possible to do Partial Replicate design like this.

Pls suggest me which design is suitable.

Thanks and Regards
k2k

Edit: Category changed. [Helmut]

vinayshed ☆ 2013-10-28 09:42 (4216 d 06:57 ago) @ K2K Posting: # 11788 Views: 7,013	Three Formulation - Partial Replicate Post reply
	Since you want reference scaled study and have two formulations, you can to use R R T1 T2 for your pilot study. Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Dr_Dan] Please see the Forum’s Policy.

Helmut ★★★ Vienna, Austria, 2013-10-28 13:11 (4216 d 03:28 ago) @ vinayshed Posting: # 11792 Views: 7,026	Randomization? Post reply
	Dear Vinay, ❝ Since you want reference scaled study and have two formulations, you can to use R R T1 T2 for your pilot study. Are you serious? — 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

vinayshed ☆ 2013-10-28 15:47 (4216 d 00:53 ago) @ Helmut Posting: # 11795 Views: 6,986	Randomization? Post reply
	Does he/she have any other option?

Helmut
★★★

Vienna, Austria,
2013-10-28 16:09
(4216 d 00:30 ago)

@ vinayshed
Posting: # 11797
Views: 6,979

Randomization?

Post reply

Dear Vinay,

❝ Does he/she have any other option?

Your design is not randomized and therefore, period effects are not accounted for. Maybe somebody else can come up with a suitable design.

PS: Please follow the Forum’s Policy as Dr. Dan already suggested. If you prefer laconic statements, consider joining Twitter instead.

—
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

K2K ★ India, 2013-10-29 11:10 (4215 d 05:30 ago) @ Helmut Posting: # 11802 Views: 6,980	Randomization? Post reply
	Dear Helmut, ❝ Your design is not randomized and therefore, period effects are not accounted for. How its not accounted for period effects? As per the Link http://forum.bebac.at/mix_entry.php?id=10358 Mr. d_labes suggested sequence for the same but sequence as changed little bit. Shall i consider this sequence or not. Thanks and Regards K2k

Helmut
★★★

Vienna, Austria,
2013-10-29 14:14
(4215 d 02:25 ago)

@ K2K
Posting: # 11803
Views: 6,960

not randomized!

Post reply

Hi K2k,

❝ How its not accounted for period effects?

Again: Vinay’s infamous RRT₁T₂ is not randomized!
Imagine you have period effects of ±0, +20, +15, –10% and ‘true’ bioequivalence of both formulations, i.e., T₁=T₂=R=1. Responses in the four periods are expected to be P₁=1+0=1, P₂=1+1×20%=1.20, P₃=1+1×15%=1.15, and P₄=1–1×10%=0.90. Estimated treatment effects will be R=(P₁+P₂)/2=(1+1.20)/2=1.10, T₁=P₃=1.15, and T₂=P₄=0.90. GMRs will be T₁/R=1.15/1.10=104.55% and T₂/R=0.90/1.10=81.82%. That’s not the 100% we expect (biased due to lacking randomization).
Any cross-over design which is not randomized & balanced for treatments within periods cannot give unbiased treatment effects.

❝ As per the Link http://forum.bebac.at/mix_entry.php?id=10358 Mr. d_labes suggested sequence for the same but sequence as changed little bit.

If you have read the entire thread (and the linked references) you would have noticed that it is not that easy.

❝ Shall i consider this sequence or not.

Never apply anything you don’t completely comprehend.

PS: To quote Detlew:

“I myself would not go with such a design due to the uncertainties involved.”

PPS: What if both tests have similar GMRs? With which one would you perform the pivotal study? Would be nice to get some information about the products’ variances. Maybe we can work in the spirit of Balaam’s design?

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

Don’t ask me how to evaluate that.
Though I have some ideas…
_{Homework/exercise: Is the design balanced for period effects? And for carry-over?}

Why don’t you simply run two separate fully replicated three period studies – and tell us afterwards how much CV_WR differed between the two?

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

—
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

K2K ★ India, 2013-10-31 11:08 (4213 d 05:31 ago) @ Helmut Posting: # 11835 Views: 6,772	not randomized! Post reply
	Dear Helmut, ❝ Why don’t you simply run two separate fully replicated three period studies – and tell us afterwards how much CV_WR differed between the two? ❝ `T1 R T1 T2 R T2` ❝ `R T1 R R T2 R` After Completion of Study I will Share the CV_WR. Thanks for your valuable suggestions. Thanks and Regards K2k

Helmut
★★★

Vienna, Austria,
2013-10-31 17:25
(4212 d 23:14 ago)

@ K2K
Posting: # 11845
Views: 6,789

CVwr

Post reply

Hi K2k,

❝ After Completion of Study I will Share the CV_WR.

Even if you tell us the drug / reference formulation I have limited interest in that. Would only be nice to compare the CV_WR from two different studies (same site / design / sample size).

—
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