- On 12 Jan 2005 at 15:50:14, "Hansson Henrik" (Henrik.Hansson.aaa.mpa.se) sent the message

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Dear David,

I have a question regarding the subject effect (nested within

sequence) in ANOVA. When can this effect be of importance in a

bioequivalence study to say that the study is not valid given that the

formulations are bioequivalent? - On 12 Jan 2005 at 11:47:06, Navdeep Randhawa (Navdeep.Randhawa.-a-.biovail.com) sent the message

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The following message was posted to: PharmPK

Dear Hansson,

The importance of subject effect nested within sequence is such that you

must use the subject(sequence) term as the error term when testing for

sequence effects. For a standard 2X2 crossover design, the sequence

effect

is confounded with the carryover effect and the formulation-by-period

interaction. Therefore, a statistically significant sequence effect

could

indicate that a) there is a true sequence effect b) there is a true

carryover effect c) true formulation by period interaction or, d) there

is a

failure of randomization (Chow and Liu, 2000). Due to this confounding,

the

guidance suggests that a test for the sequence effect be performed at

the

10% level of significance. Chow and Liu also recommend using a

higher-order

crossover design for comparing two formulations (advantage being that

formulation, carryover and sequence effects are not confounded with one

another). I don't believe that the test for significance of

subject(sequence) effect has any bearing on the study results, rather

it is

used as the error term to test the sequence effect.

I hope that helps.

Nav

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