- On 13 Mar 1998 at 09:55:08, "Tony Lee" (p2149z.aaa.hotmail.com) sent the message

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Dear All:

I would like to know your feedback

about the explanations to the ANOVA

output of bioequivalence analysis.

For a bioequivalence study using two-period,

two-sequence crossover design, if one of

the effects shows significant difference

after the ANOVA analysis, my thought is:

Sequence: two groups of subjects were

not from a population;

Subject(seq): ?

Period: carry-over effect;

Formulation: two formulations were not

bioequivalent.

Your comments on the explanations

are much aprreciated.

Tony Lee - On 21 Apr 1998 at 11:43:52, "Dr. W. Webster" (webstew.aaa.mail.firn.edu) sent the message

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>The FDA has a GUIDANCE paper "STATISTICAL PROCEDURES FOR BIOEQUIVALENCE

STUDIES USING A STANDARD TWO-TREATMENT CROSSOVER DESIGN Was printed in

July 1992. Mostly based on work by Schuirmann DJ. I have also run into the

problem of non equivalence by ANOVA but practically there was no difference.

Essentially you reverse the null hypothesis from there is no difference to

the difference lies within an a priori determined range which is acceptable

and the alternate is the difference is greater than this range, and if not

proven different, then accepted as equivalent. The FDA generally agrees

that the range should be between 80 & 125% for the ratio of the products.

This is a gross generalization and the paper was developed specifically for

solid oral dosage form. However, in my experience the principles outlined

have been adopted/adapted by all groups.

The guidance paper has the SAS model outlined to accomplish the analysis.

The parameters of interest need to be selected for analysis with some

rational scientific thought.

WW - On 23 Apr 1998 at 10:31:40, "Dr. W. Webster" (webstew.-a-.mail.firn.edu) sent the message

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For those wanting more information:

Chow S and Liu J. Recent Statistical Developments in Bioequivalence

Trials -- A Review of the FDA Guidance. Drug Information Journal, Vol. 28,

pp 851-864, 1994

This refers to the original document which I have scanned and am sending as

an attached file (Needs a little more cleaning up but the section on SAS

procedure seems intact)

[db - not attached]

The underlying thought is that, traditionally the researcher sought to

compensate for bias by trying to prove the opposite of what their belief was

and if not successful, then the researcher accepted the alternate. In

bioequivalence testing, the researcher has a bias in favor of equivalence

and this is not considered in standard null hypothesis approaches. As I

have stated previously, the null hypothesis is "reversed" by trying to prove

there is a difference, that is non-equivalence, and if not successful, then

the alternate of equivalence is accepted. This somewhat negates the

researchers bias but more practically, reduces the 'n' needed for power.

If you are talking to the FDA & they refer to 90% confidence intervals, this

is where they are coming from even if it doesn't pertain to solid oral

dosage forms. Note also: WinNonlin's new PRO package has this methodology

built in (I don't have any relationship with WinNonlin & prefer to do my own

laundry if possible -- but the windows 95 environment with cut&paste makes

me love some of the features of the program -- convince wins in the end).

Thought provoking question of the day:

Is the 95% confidence interval more or less restrictive than the 90% CI ?

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