1. BE Issues of HVD & HVDP Kamal K. Midha, Maureen Rawson Gordon McKay & John W. Hubbard PharmaLytics Inc. A Non-Profit Institute of the University of Saskatchewan Saskatoon, SK, Canada, S7N 3R2 Advisory Committee for Pharmaceutical Sciences, Nov 29 2001

2. Highly Variable Drugs (HVD and HVDP) A drug with an ANOVA-CV  30% has been defined as an HVD A highly variable drug product is a formulation with an ANOVA-CV  30% and has been termed HVDP With an HVD/P, a very large number of subjects is required in a traditional ABE study, even when two samples from the same lot of the same ref formulation are compared

3. HVDs Chlorpromazine (CPZ) is an example of an HVD which has an ANOVA-CV of 34% on AUC and 43% on Cmax. The following slide shows results of a 3- period ABE study on CPZ with 37 subjects The test product was given once and the ref product was given twice (two samples from the same lot of the ref product)

4. CPZ 3-way ABE Study (n=37) Test vs 2 administrations of Ref 1991 CV% Test vs Ref Ref vs Ref GMR 90% CI GMR 90% CI AUC*34% 108 95 - 123 102 90 - 116 Cmax*43% 106 90 - 126 115** 98 - 136 *Based on log transformed data **Probability of passing (36 subjects 2-period study, GMR 115%) is ca 15% only

5. Comments It is clear that 2 samples from the same lot of the reference product were not found BE with each other because the ANOVA-CV was 43% and GMR 115% These (and other) data showed that the reference formulation was a good quality product (HVD not an HVDP)

6. Comments Under the new recommendations of the Oct 2000 Guidance, when stated a priori and after due consultation with the agency, scaled IBE based on a replicate design may be allowed for an HVD, HVDP. This is a reasonable proposal for HVD/Ps which should be maintained at least for a trial period of two years so as to foster the gathering of data to be acquired in BE studies with a reasonable number of subjects.

7. Comments The use of scaling for HVD/Ps permits the the assessment of BE to be performed with a reasonable number of subjects without compromising either the consumer risk and/or the producer risk.

8. Comments An additional advantage of IBE is that the study provides an assessment of the quality of the dosage forms under investigation The constraint that the GMR must fall within 80-125% for scaled IBE is reasonable, and should be maintained

9. Comments Increasing the constraint on GMR in IBE to <125% (e.g. 115%) would take us back a decade! Our plea is that we should not modify the recommendation in the Guidance until scientific evaluations of the scaled metrics are completed.