An Assessment of the 4-6-20 Rule for Acceptance of Analytical Runs in Bioavailability,Bioequivalence, and Pharmacokinetic Studies

A recent conference report described a decision rule, hereafter referred to as the 4-6-20 rule, for acceptance/rejection of analytical runs in bioavailability, bioequivalence, and pharmacokinetic studies. This procedure requires that quality control specimens at three concentrations (low, medium, and high) be assayed in duplicate in each run. For run acceptance, at least four of the six assay values must be within ±20% of their respective nominal concentrations, and at least one of the two values at each concentration must be within these limits. An inherent flaw in this decision rule is that the risk of rejecting runs, when the assay performance has in fact not deteriorated, varies for each assay and is neither known nor controlled. In this paper simulation methods are used to evaluate the operating characteristics of the 4-6-20 rule in comparison to those of classical statistical quality control procedures.