Reference Limits for Outlier Analyses in Randomized Clinical Trials

What is it about?

This publication explains the reasons why reference limits used in determining the incidence of outlier values for common safety laboratory analytes collected in large Phase 2-4 pharmaceutical trials should be different from those reference limits used in individual patient clinical screening, diagnosis, and management. The publication then compares several sets of reference limits, developed by alternative statistical methods, with respect to optimal performance, when used in outlier analyses in clinical trials. The set of limits that is optimal across the largest number of analytes evaluated, suggests the specific statistical method that might be the best for developing limits for use in such analyses. Other pharmaceutical companies can consider developing limits for their own use using similar statistical methods. Other companies could also consider using the limits published in this manuscript that were found to be optimal if the assay methods used by their performing laboratories were considered comparable to those be the performing laboratory that provided the assay results analyzed in this manuscript.

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Why is it important?

The information in this manuscript is important because it can assist pharmaceutical companies in selecting a "best set" of reference limits for analyses of outlier values collected in clinical trials. The manuscript makes it clear that reference limits used for this specific purpose are likely to be quitter different from those used in clinical practice and published by clinical pathology laboratories (at least for some analytes).