BEBAC   Ing. Helmut Schütz

Highly Variable Drugs


In the meeting on 06 October 2006 the Advisory Committee for Pharmaceutical Sciences (ACPS) was asked two questions by the FDA, namely:

  1. Does the committee agree with the use of a point estimate constraint, when applying scaled bioequivalence? If yes, is the 80 – 125% limit on the point estimate appropriate?
  2. We propose a minimum sample size of 36 subjects when evaluating the BE of highly variable drugs, does the committee concur?

The committee supported the use of GMR constraints when using Scaled Average Bioequivalence (SABE) for Highly Variable Drugs (HVDs).
No consensus was reached about the limits for such a constraint.

The majority of the committee’s members supported a minimum sample size, but were not convinced by FDA’s proposal of n=36 (some members felt comfortable with a lower sample size of n=24).

Advisory Committee for Pharmaceutical Sciences (ACPS)
Background Information of the Meeting
Introduction Memorandum
Meeting Agenda
Slides from October 6, 2006 Meeting
BE Requirements for HVDs and HVDPs (ACPS Meeting April 14, 2004)
Slides from April 14, 2004 Meeting

A follow-up paper was published in January 2008; the proposed replicate study design involves the three sequences [TRR-RTR-RRT] and a minimum sample size of 24 subjects. The point estimate is restricted within [0.80, 1.25]:
S.H. Haidar, B. Davit, M.-L. Chen, D. Conner, L.M. Lee, Q.H. Li, R. Lionberger, F. Makhlouf, D. Patel, D.J. Schuirmann, and L.X. Yu
Bioequivalence Approaches for Highly Variable Drugs and Drug Products
Pharmaceutical Research 25/1, 237-241 (2008, DOI: 10.1007/s11095-007-9434-x)
free online resource


The first drafted product-specific guideline was published for Lansoprazole in October 2008. The document refers to the paper by Haidar et al. (2008). Both from the wording and also from the pesentation Bioequivalence Testing in the U.S. for Generic Drug Products by P. Chandaroy and K. Dhariwal (Division of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, April 16, 2008) it seems that scaling is acceptable to the FDA both for Cmax and AUC.
Other candidates for scaling are Lovastatin/Niacin (December 2008) and Alendronate Sodium (April 2009).