Expected loss in power [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2015-10-15 15:45 (3412 d 04:04 ago) – Posting: # 15565
Views: 6,891

Hi Compliance,

❝ Expiry of reference product is only one year and we are planning to conduct 3-WSABE study due to high variability. Due to this we could not keep long wash out period.


OK, since you are limited by the shelf life of the reference I assume that the FDA would still expect you to plan the wash­outs as long as possible.

❝ however we are taking chance that if pre dose >5 % would be higher then it would not been considered for the BE.


Nitpicking: 5%, not >5%. State conditions for exclusion unambiguously in the protocol.

You shouldn’t worry about loosing power due to excluded subjects. Example for GMR 0.9 (con­ser­va­tive, since highly vari­able!), CV 60%, target power 90%, minimum power 80%, partial re­pli­cate design, FDA’s RSABE:

library(PowerTOST)
pa.scABE(CV=0.6, theta=0.9, targetpower=0.9, minpower=0.8,
  design="2x3x3", regulator="FDA")


gives

Sample size plan scABE (FDA/RSABE)
 Design alpha CVwT CVwR theta0 theta1 theta2 Sample size Achieved power Target power
  2x3x3  0.05  0.6  0.6    0.9    0.8   1.25          57        0.90445          0.9

Power analysis
CV, theta0 and number of subjects which lead to min. acceptable power of at least 0.8:
 CV= 0.9993, theta0= 0.8633
 N = 31 (power= 0.8008)


If you perform the study in 57 subjects, you may loose (dropouts) and/or exclude (predose ≥5% Cmax) 26 (45%!) and still achieve 80% power.

❝ We performed one pilot study […] In which we got total 13 subject out of 48 with positive pre dose. Out of 13, 09 subject has shown > 5% pre dose concentration.


OK, that’s ~20%. Following ElMaestro’s question: Did you see any differences between T and R – especially in λz? For such a formulation λz represents absorption… Or the other way ’round: Was there a substantial diffe­rence in the PEs of AUCt and AUC? If yes, you should consider to sample longer.

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