joyjac
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Philippines,
2006-05-09 07:45

Posting: # 120
Views: 7,245
 

 Parent Drug and Active Metabolite [Regulatives / Guidelines]

FDA CDER Guidance states that if the parent drug can be measured, the confidence interval should be applied to the parent drug but data of the active metabolite must be submitted to provide evidence of comparable therapeutic outcome. Does this mean we need to calculate also the 90% CI for the active metabolite? What if the 90% CI for the parent drug falls within the BE limit but Not for the active metabolite? Highly appreciate your insight on this BE issue. Thanks.
Helmut
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Vienna, Austria,
2006-05-09 11:34

@ joyjac
Posting: # 121
Views: 5,786
 

 Parent Drug and Active Metabolite (FDA)

» FDA CDER Guidance states that if the parent drug can be measured, the confidence interval should be applied to the parent drug but data of the active metabolite must be submitted to provide evidence of comparable therapeutic outcome.

[image]Hi Joy,

to the right you see my personal interpretation of the guidance.
Green arrows stand for 'yes' decisions, red arrows for 'no'.

Only if exception (2) from the recommended general approach (assessment of parent drug only) applies:
Presystemic metabolism (e.g., gut wall) and the metabolite contributes meaningfully to safety and/or efficacy.

» Does this mean we need to calculate also the 90% CI for the active metabolite?

No - otherwise we would run into statistical problems of multiplicity.
Just present the metabolite descriptively (individual data, mean, standard deviation, linear and semilogarithmic plots, etc).

» What if the 90% CI for the parent drug falls within the BE limit but Not for the active metabolite?

This should not happen (see above). BTW, if you calculate the CI, it's very likely that the game goes just the other way 'round: metabolite is BE whereas the parent drug is not (because generally the variability of the parent drug is higher than the variability of the metabolite).

Cheers,
Helmut Schütz
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joyjac
★    

Philippines,
2006-05-10 05:44

@ Helmut
Posting: # 122
Views: 5,641
 

 Parent Drug and Active Metabolite (FDA)

Dear HS,

Just to clarify in case of (2): 90% CI will be applied to the parent drug and present the metabolite data descriptively - would this mean that ANOVA on the metabolite data is not necessary?

Thanks for sharing your expertise.
Joy
Helmut
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Vienna, Austria,
2006-05-10 08:22

@ joyjac
Posting: # 123
Views: 5,749
 

 Parent Drug and Active Metabolite (FDA)

» […] would this mean that ANOVA on the metabolite data is not necessary?

Hi Joy,

yes, IMHO no confidence interval of the metabolite; you should present just means, standard deviations, etc. If you opt to present a confidence interval make clear in the protocol, that there's no acceptance range for it.

The wonderful thing about FDA is that you have to present the study protocol to them anyhow; if they don't like it, they will tell you ;-)

Cheers,
Helmut Schütz
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