Response to criticisms of the US FDA parametric approach for withdrawal time estimation: rebuttal and comparison to the nonparametric method proposed by Concordet and Toutain

Abstract

The benefits and drawbacks of using nonparametric methods for estimating product withdrawal times have been debated for many years. This issue was recently revived by Concordet & Toutain (1997a, b) when they described a nonparametric method for withdrawal time estimation. The authors urged the international adoption of this approach, basing their recommendation on three fundamental concerns: (1) the lack of a consistent official procedure for determining a withdrawal time within the European Union (EU); (2) the need to identify a statistical method for improving the international harmonization of withdrawal times for new chemical entities; and (3) a lack of confidence in the robustness of the US Food and Drug Administration/Center for Veterinary Medicine (US FDA) procedure, particularly with respect to minor violations in the underlying parametric assumptions. Due to the critical nature of these issues, the US FDA considers it vital to respond to these concerns. This paper provides a description of the US FDA parametric procedure. We also examine the statistical concerns expressed by Concordet and Toutain, identifying the reasons for our confidence in the US FDA parametric approach. Finally, using their Monte Carlo simulation models, we generate additional datasets to explore the behaviour of their nonparametric procedure and evaluate its ability to support US FDA regulatory activities.

Tissue disposition and depletion of penicillin G after oral administration with milk in unweaned dairy calves

“…Muscle tissue did not have detectable concentrations of penicillin G, which was expected. 22, 33 Depletion of drug from various tissues does not always occur at a similar rate, and the terminal halflives may not be equivalent. 27,29,30 This is primarily because penicillin G does not readily penetrate muscle cells, and the interstitial fluid has approximately half of the concentration of albumin, to which penicillin is approximately 50% bound as serum.…”

Critical review on the withdrawal period calculation for injection site residues

“…Martinez et al. (2000) favour a conservative method, even if it implies a marked overestimation of the estimated withdrawal time.…”

“…Martinez et al. (2000) supported the recommended method, whereas Concordet and Toutain (1997a,b) proposed a nonparametric method, on the basis of their critical review of the FDA approach.…”

Approaches in the safety evaluations of veterinary antimicrobial agents in food to determine the effects on the human intestinal microflora

“…As a conservative measure to ensure safety, the slaughter time is adjusted (increased) to take into account the variation in target animal populations leading to the longest drug depletion of the longest depleting residue. While methodologic, statistical, and regulatory approaches vary among agencies (for example, see Concordet & Toutain, 1997a,b; EMEA CVMP, 1995; Friedlander et al ., 1999; Fisch, 2000; Martinez et al ., 2000; US FDA CVM, 1994), the goal is to ensure that the withdrawal time set for the drug, administered at maximum label dose and duration, will ensure that the residue will deplete to less than the MRL in all edible tissues among those individual animals that have the longer depletion rates for the drug.…”