# Replicated studies for EMEA...

**URL:** <https://forum.certara.com/t/replicated-studies-for-emea/2687>\
**Category:** Phoenix WNL basics\
**Created:** [February 1, 2014, 2:59pm UTC](https://forum.certara.com/t/replicated-studies-for-emea/2687 "2014-02-01T14:59:14Z")\
**Posts on this page:** 3\
**Page:** 1

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**Author:** ![tushar](https://avatars.discourse-cdn.com/v4/letter/t/5fc32e/32.png) [@tushar](https://forum.certara.com/u/tushar)\
**Post date:** [February 1, 2014, 2:59pm UTC](https://forum.certara.com/t/replicated-studies-for-emea/2687/1 "2014-02-01T14:59:14Z")

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Dear All, Few months before I attended webinar concerning replicated designs using Phoenix WNL. Must say amazing piece of work it is. In Webinar, Box plot method was suggested based on Studentized intra-subject residuals for EMEA to prove higher CV is not caused by outlier. Is that method suggested by EMEA than any other method like Cooks distance and hotelling T[sup]2[/sup] applicable for this? I wanted to go with replicated study aproach for EMEA submission. but confused regarding Outlier method since I dont have SOP on this method? Is it Ok if I mentioned this box plot method on protocol only? Thanks in Advance. Regards, Tushar

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**Author:** ![ana.henry](https://sea1.discourse-cdn.com/certara/user_avatar/forum.certara.com/ana.henry/32/2578_2.png) [@ana.henry](https://forum.certara.com/u/ana.henry)\
**Post date:** [February 4, 2014, 4:11am UTC](https://forum.certara.com/t/replicated-studies-for-emea/2687/2 "2014-02-04T04:11:23Z")

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Dear Tushar, The EMEA Guidelines do not mention any specific method but just says that outliers should be reviewed: " The applicant should justify that the calculated intra-subject variability is a reliable estimate and that it is not the result of outliers ". The proposed intra-subject studentized residuals box plots is one way of determining outliers but not the only one. This method is described on: Page 224 in the second edition of Chow/Liu book – Design and Analysis of BA and BE studies, equation 8.2.9. Hope this helps, Ana

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**Author:** ![Helmut\_Schuetz](https://avatars.discourse-cdn.com/v4/letter/h/eb8c5e/32.png) [@Helmut\_Schuetz](https://forum.certara.com/u/Helmut_Schuetz)\
**Post date:** [February 4, 2014, 4:25pm UTC](https://forum.certara.com/t/replicated-studies-for-emea/2687/3 "2014-02-04T16:25:48Z")

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Hi Tushar, I asked EMA’s panelists at the joint EGA/EMA-workshop (London, June 2010) which one of the many statistical outlier tests they would prefer. The answer was clear: “We don’t want statistical tests.” So – as a joke – I replied “What do you expect instead. Box plots?” I aimed it as a joke because box plots are essentially nonparametric – a topic which in the past gave EMA the creeps. Remember that EMA removed the comparison of t[sub]max[/sub] from the GL just to avoid nonparametrics? To my great surprise they said “Yes, box plots are a great idea.” Stupid, but see the quote from the [Q&A-document](http://www.egagenerics.com/doc/EGA_BEQ_Q&A_WEB_QA_1_32.pdf) (page 21) published after the workshop: On a case by case basis, a study could be acceptable if the bioequivalence requirements are met both including the outlier subject (using the scaled average bioequivalence approach and the within-subject CV with this subject) and after exclusion of the outlier (using the within-subject CV without this subject). An outlier test is not an expectation of the medicines agencies but outliers could be shown by a box plot. This would allow the medicines agencies to compare the data between them.