Handling missing values in bioequivalence studies?

Phoenix Certara Forums Modelling and Simulation
1

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

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.at/mix_entry.php?id=16182#top16182

Simon

3

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