Bioequivalence and Bioavailability Forum

Jay ☆ India, 2015-11-02 11:47 (3465 d 12:42 ago) Posting: # 15597 Views: 9,127	Sample size with CV more than 100% [Power / Sample Size] Post reply
	Dear all, In pilot study results of a modified release molecule, the CV obtained for AUC5-t is 114% and the T/R is around 88%. Can one use CV for more than 100% i.e. 114% in above case for the calculation of pivotal sample size. Regards, Jay

d_labes
★★★

Berlin, Germany,
2015-11-02 12:08
(3465 d 12:21 ago)

@ Jay
Posting: # 15598
Views: 7,470

Why not?

Post reply

Dear Jay,

❝ In pilot study results of a modified release molecule, the CV obtained for AUC5-t is 114% and the T/R is around 88%.

❝ Can one use CV for more than 100% i.e. 114% in above case for the calculation of pivotal sample size.

If you believe in that CV's, i.e. all was OK with the study conduct:
Why not?

There is not theoretical bound in the CV, beside it has to be > zero.

—
Regards,

Detlew

Jay ☆ India, 2015-11-02 12:29 (3465 d 11:59 ago) @ d_labes Posting: # 15599 Views: 7,449	Why not? Post reply
	Dear d_labes, Thanks for the response. If CV of one parameter such as AUC5-t is observed more than 100% while for other parameter such as Cmax, Auc0-5 or AUCinf is within 20-30%. So should one go for full replicate design and sample size estimation based on highest CV observed as 114%. Regard, Jay

d_labes
★★★

Berlin, Germany,
2015-11-02 14:06
(3465 d 10:23 ago)

@ Jay
Posting: # 15600
Views: 7,520

Sample size for HVD's

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Dear Jay,

❝ If CV of one parameter such as AUC5-t is observed more than 100% while for other parameter such as Cmax, Auc0-5 or AUCinf is within 20-30%. So should one go for full replicate design and sample size estimation based on highest CV observed as 114%.

If you have to show bioequivalence also for the partial AUC's your sample size is clearly driven by the CV of that PK metric.

To go with a full replicate design has only advantages if you aim to show bioequivalence via scaled average bioequivalence. Sample size for the FDA recommended method for HVD's (target power 80%):

library(PowerTOST)

sampleN.RSABE(CV=1.14, theta0=0.9, design="2x2x4")



++++++++ Reference scaled ABE crit. +++++++++

           Sample size estimation

---------------------------------------------

Study design:  2x2x4 (full replicate) 

log-transformed data (multiplicative model)

1e+05 studies for each step simulated.



alpha  = 0.05, target power = 0.8

CVw(T) = 1.14; CVw(R) = 1.14

Null (true) ratio = 0.9

ABE limits / PE constraints = 0.8 ... 1.25 

Regulatory settings: FDA 

- CVswitch =  0.3 

- Regulatory constant = 0.8925742 



Sample size search

 n     power

44   0.79442 

46   0.80099

But that's in Europe a no go for AUC values. Here scaled ABE (via widened acceptance limits, ABEL) is only allowed for Cmax, which in your study came out as not highly variable.
Thus you have to stuck with conventional ABE.

sampleN.TOST(CV=1.14, theta0=0.9, 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 = 0.9,  CV = 1.14



Sample size (total)

 n     power

372   0.800404

See also this recent thread for a more extreme example.

—
Regards,

Detlew

Helmut
★★★

Vienna, Austria,
2015-11-02 15:35
(3465 d 08:54 ago)

@ d_labes
Posting: # 15602
Views: 7,536

EMA: MR – ABEL for partial AUCs

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Dear Detlew and Jay,

❝ ❝ If CV of one parameter such as AUC5-t is observed more than 100% while for other parameter such as Cmax, Auc0-5 or AUCinf is within 20-30%. So should one go for full replicate design and sample size estimation based on highest CV observed as 114%.

IMHO it is rather unusual for MR-products that the late partial AUC is more variable than the early one. Was this behavior due to an “outlying” subject? If yes, which CV do you get after exclusion? I would be cautious to draw premature conclusions.

❝ But that's in Europe a no go for AUC values. Here scaled ABE (via widened acceptance limits, ABEL) is only allowed for Cmax, […]

Disagree. The MR-GL (Section 6.8.2.2.) allows ABEL for partial AUCs. Hence,

library(PowerTOST) sampleN.scABEL(CV=1.14, theta0=0.9, design="2x2x4") +++++++++++ scaled (widened) ABEL +++++++++++ Sample size estimation --------------------------------------------- Study design: 2x2x4 (full replicate) log-transformed data (multiplicative model) 1e+05 studies for each step simulated. alpha = 0.05, target power = 0.8 CVw(T) = 1.14; CVw(R) = 1.14 Null (true) ratio = 0.9 ABE limits / PE constraints = 0.8 ... 1.25 Regulatory settings: EMA - CVswitch = 0.3, cap on scABEL if CVw(R) > 0.5 - Regulatory constant = 0.76 Sample size search n power 80 0.7954 82 0.8049

—
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Helmut Schütz

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d_labes ★★★ Berlin, Germany, 2015-11-02 15:48 (3465 d 08:41 ago) @ Helmut Posting: # 15604 Views: 7,432	EMA: MR – ABEL for partial AUCs Post reply
	Dear Helmut, ❝ Disagree. The MR-GL (Section 6.8.2.2.) allows ABEL for partial AUCs. Thanks for teaching me, I'm obviously not up to date . — Regards, Detlew

Sample size with CV more than 100% [Power / Sample Size]

Why not?

Why not?

Sample size for HVD's

EMA: MR – ABEL for partial AUCs

EMA: MR – ABEL for partial AUCs