Mean difference vs. variability reduction: tradeoffs in aggregate measures for individual bioequivalence. FDA Individual Bioequivalence Working Group.
Aggregate criteria for individual bioequivalence allow a tradeoff between difference in average bioavailability and reduction in within-subject variability. That is, a large difference in the average bioavailability between a test and a reference formulation can be offset by a sufficient reduction in variability of the test formulation. This offset could allow the test formulation to pass many individual bioequivalence criteria. We have identified 4 possible approaches for dealing with this tradeoff issue: say "No problem," since a reduction in variability is desirable; use disaggregate criteria; use general weighted forms of the individual bioequivalence criteria that weight the variance terms; and change the acceptable upper limits to reduce the impact of scaling to the reference formulation's within-subject variability. A dataset with a 14% increase in average bioavailability and a 48% reduction in within-subject standard deviation is used as an example of these issues.
Hauck
W W
WW
Biostatistics Section, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Chen
M L
ML
Hyslop
T
T
Patnaik
R
R
Schuirmann
D
D
Williams
R
R
D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006801:Humans; D010599:Pharmacokinetics; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration