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Handling missing values in bioequivalence studies?

bioequivalence

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#1 simon.hutchings

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Posted 12 April 2016 - 09:48 AM

Hi all,

 

I have been scouring the relevant EMA/FDA guidance but haven’t come across anything too useful in relation to assessing the impact of missing samples in a bioequivalence study.

 

The scenario is:

 

4 way cross BE study; test vs ref in fed and fasted states

 

N = 22 HVs

 

Tmax ~60 mins

T1/2 ~120 min

 

Sampling: 0, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 105, 120, 180, 240, 360, 480 and 720 mins

 

During one of the study periods a protocol non-compliance has resulted in the 480 min time point not being available for 2 out of 22 subjects.

 

Given where the 480 h time point lies in the profile, my instinct tells me that the missing samples should have minimal/negligible impact on the study objectives (i.e. to test for bioequivalence) and should not introduce an unacceptable amount of bias into the estimation of AUCt for the 2 subjects in question.

 

However, I would like to check if there are any guidelines/best practices etc that reinforce my ‘instinct’?

 

Any thoughts most welcome!



#2 Simon Davis

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Posted 12 April 2016 - 11:27 AM

I would tend to agree with you, if you say thalf is 2 hours as you should have enough points to interpolate OK, are all subjects quantifiable at 720 min? if not what is your typical Tlast currently?

Personally, I would gauge the experiment on how well estimated AUC is for these 2 subjects compared to the rest, if they appear to be truncated then you might have problems, you may also consider asking on the BEBAC forum, there is a wealth of experience there. http://forum.bebac.at/mix.php

 

In fact this one today explores just this sort of problem; http://forum.bebac.a...=16182#top16182

 

 Simon



#3 simon.hutchings

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Posted 12 April 2016 - 11:37 AM

Thank you for the response Simon, and for suggesting the BEBAC forum (I wasn't aware of that), much appreciated!

 

Typical Tlast is 720 min (however bioanalysis is not complete yet); fingers crossed truncation won't be an issue.

 

Thanks again,

 

Simon







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