- On 16 Aug 2002 at 14:05:09, Jaime Ilha (ilha.-a-.lexxa.com.br) sent the message

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Dear all

I would appreciate any help regarding the consequences of finding a

sequence effect in the ANOVA tests (subject within sequence term)

when performing a bioequivalence study (conventional single dose, 2

treatment, 2 period, 2 sequence cross-over, balanced design with 24

subjects for Captopril).

My impression is that the conclusion of bioequivalence can not be

ruled out, provided one gets the 90%CIs within the proposed limits

(in fact I got ratios like 100.7% (CI 90.7-111.8%) for Cmax and

101.2% (CI 93.9-109.1) for AUC.)

Just as an additional information, figures are almost the same when

taking the mean ratio and 90%CIs of Period 2 against Period 1.

Sequence t-r against sequence r-t shows, however, a ratio around 80%.

ANOVA

Effect SS df MS f Probability

Ln(Cmax) Seq 0.632 1 0.631992 14.33 0.0010

Ln(Cmax) Subject(Seq) 2.537 22 0.115321 2.62 0.0143

Ln(Cmax) Period 0.0097 1 0.009699 0.22 0.6437

Ln(Cmax) FormName 0.0006 1 0.000634 0.01 0.9056

Ln(Cmax) Error 0.9701 22 0.044100

Ln(AUC) Seq 0.3116 1 0.311565 13.67 0.0013

Ln(AUC) Subject(Seq) 2.2398 22 0.101809 4.47 0.0004

Ln(AUC) Period 0.0017 1 0.001677 0.07 0.7887

Ln(AUC) FormName 0.0018 1 0.001789 0.08 0.7819

Ln(AUC) Error 0.5015 22 0.022700

Thanks in advance

Jaime Ilha

Cartesius Analytical Unit

ilha.at.lexxa.com.br - On 18 Aug 2002 at 12:31:32, Dan Weiner (DWeiner.at.Pharsight.com) sent the message

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Dear Jaime;

In a situation such as yours, where there are sequence effects but no

associated period effects (and the CIs are acceptable), it generally is okay

to claim bioequivalence. Sequence effects by themselves are usually not

worrisome in that they reflect subject to subject variation. I'm assuming

the sequence groups had no designed differences (such as male vs female,

etc.). On the other hand, if you experience significant sequence effects in

conjunction with significant period effects, that is suggestive of a

treatment by period interaction which is more problematic.

Dan

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