Class-specific reference interval

The aim of partitioning is to provide a better basis for comparison of clinicai laboratory results class-specific reference intervals (e.g., age- and gender-specific reference intervals). 

When the intended purpose of the reference interval is to detect individual changes in biochemical status, subject-based reference values may be more appropriate for interpretation than class-specific reference intervals. We shall return to this problem at the end of this chapter. 

The differences of location or variation, however, may be statistically significant and still too small to justify replacing a single total reference interval with several class-specific intervals. Alternately, statistically nonsignificant differences can lead to situations in which the proportions of each subclass above the upper or below the lower reference limits (witlrout partitioning) are much different from the desired 2.5% on each side. Harris and Boyd therefore suggested criteria based on the ratio between the subclass standard deviations, a normal deviate test of means, and calculation of critical decision values dependent on the sample size. 

According to the EMA two products are considered to be bioequivalent when they contain the same active substance and when their respective bioavailabilities (rate and extent) after administration in the same molar dose and via the same route, lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy. The design and number of studies that is to be carried out to establish bioequivalence depends on the physico-chemical and pharmacokinetic properties of the active substance. In this respect reference is made to the BCS classification of the active substance. For BCS class I active substances it may even be possible to obtain a waiver for the in vivo studies (a so-called biowaiver), whereas for the active substances showing more complex pharmacokinetic behaviour extensive studies are to be carried out. In general bioequivalence will be determined from the parameters Cmax and AUC. Two products are considered to be bioequivalent when the 90 % confidence interval of the ratio of test and reference product falls within the 85-125 % acceptance interval. However, for the required design of the bioequivalence study and statistical evaluation details for a specific active substance reference is made to the appropriate (most recent) guideline on this subject [2, 3]. 

---