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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?
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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.
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