Bioequivalence and Bioavailability Forum

Dear Joy!

❝ Would you know if US FDA recommends deletion of outliers?

OK. Let's talk about outlying subjects (not 'inadequate profiles' / 'pharmacokinetic outliers').

FDA (like all other regulatory authorities) strongly discourages deletion of outliers based solely on statistics.

You should include a procedure in your protocol (subjects may be excluded prior to statistical analysis if e.g., vomiting or diarrhea was observed). http://www.fda.gov/cder/guidance/5356fnl.pdf FDA states:

'We recommend that data from subjects who experience emesis during the course of a BE study for IR products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of MR products, the data from subjects who experience emesis any time during the labeled dosing interval can be deleted.'

If you find an outlying subject based on product failure of the reference in a replicate design on only one occasion, the outlier http://www.fda.gov/cder/guidance/3616fnl.pdf may be deleted, but '[...] the retest character of these designs should indicate whether to delete an outlier value or not. Sponsors or applicants with these types of data sets may wish to review how to handle outliers with appropriate review staff.'

Aside from rumours spreading at numerous BA/BE conferences about retesting of outlying subjects (a small study including the outlier and 20% of subjects who showed 'normal' values in the main study), I don't know of an official guideline issued by the FDA covering this topic. One warning: if you decide for retesting, statistics will be very tricky - nothing for M$-Excel

Maybe these proceedings from the Canadian HFPB may give you further insights:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-com/bio/sacbb_rop_ccsbb_crd_2001-11-15_e.html
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/sci-com/bio/sacbb_rop_ccsbb_crd_2004-06-03_e.html

If you don't have rules specified in the protocol a-priori, your chances of acceptance are low - it may look like 'data dredging', although the ICH Guideline Statistical Principles for Clinical Trials suggests presenting the full data set (including the outlier), and the reduced data set (outlier excluded), and discussing the implications.

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Edit: Links corrected for FDA’s new site. [Helmut]