Individual Bioequivalence: Background and Concepts

1. Advisory Committee for Pharmaceutical Science Individual Bioequivalence:Background and Concepts Mei-Ling Chen, Ph.D.Associate Director Office of Pharmaceutical Science November 28-29, 2001 Rockville, MD

2. Individual BioequivalenceAdvantages • Compares both population means and variances • Considers subject-by-formulation interaction • Establishes goalposts based on the reference variability for highly variable drug products • Creates incentive for both innovators and generic sponsors to manufacture less variable products • Encourages use of heterogeneous subjects that are more representative of the general population

3. Individual Bioequivalence AssessmentDistance Concept • Individual Difference Ratio (IDR) Difference between T and R • IDR = ------------------------------------- Difference between R and R’ • Both T and R are administered to the same individual • Goal: IDR not substantially greater than 1

4. Individual Bioequivalence (Average Difference)2 + Variance Terms • ------------------------------------------------------ BE LimitReference Variance (mT - mR)2 + sD2 + (sWT2 - sWR2) • ------------------------------------------- qIsWR2 • Variance Terms- Subject-by-formulation interaction (sD2) - Within-subject variances (sWT2, sWR2)

5. Subject-by-Formulation Interaction • The S x F interaction is a measure of the extent to which the individual mean differences, mTj - mRj, between the T and R products are likely to differ. • sD2 = variance of (µTj - µRj) = (sBT - sBR)2 + 2 (1- ) sBTsBR • µTj, µRj : individual-specific means • sBT, sBR: between-subject standard deviations •  : correlation coefficient between µTj & µRj • sD2 : S x F interaction variance component

6. Sources of S x F Interaction sD2 = var (µTj - µRj) = (sBT - sBR)2 + 2 (1- ) sBTsBR • Changes in between-subject variability for T and R formulation • Lack of congruence in individual means between T and R formulation

7. Verapamil Immediate ReleaseAge-based SxF Interaction *SxF interaction occurred to Generic 1, but not Generic 2. Reference: Carter BL et al., Pharmacotherapy, 13, 1993

8. Calcium Channel Blocker Gender-based S x F Interaction

9. Interpretation of S x F Interaction • Approach 1Percentage of individuals whose average T/R ratios lie outside the range of 80-125% • Approach 2Presence of a subgroup(s) with a different average T/R ratio(s) from the remaining subjects of the population

10. Proportion of Individuals With T/R Ratio Outside 80-125% (Assuming T/R mean ratio is 1.0) Approach 1 60 50 40 % 30 20 10 0 0.1 0.15 0.2 0.25 0.3 0.35 0.4 Sigma D Value

11. Approach 2 S x F Interaction Due to Subgroups

12. Individual Bioequivalence Criterion (mT - mR)2 + sD2 + (sWT2 - sWR2) ------------------------------------------- qIsWR2 • Reference Scaling • Away from the “one-size-fits-all” approach • Goalposts adjusted for highly variable drug products

13. Mixed-Scaling Approach • Reference-Scaled (if sWR > sW0 )(mT - mR)2 + sD2 + (sWT2 - sWR2) ------------------------------------------- qIsWR2 • Constant-Scaled (if sWRsW0 ) (mT - mR)2 + sD2 + (sWT2 - sWR2) ------------------------------------------- qIsW02

14. Constraint on Mean Difference (mT - mR)2 + sD2 + (sWT2 - sWR2) ------------------------------------------- qIsWR2 • Incentives for manufacturing less variable formulations • Mean-variance tradeoff • Possibility of a large mean difference • Guidance recommendation - Further constraint on the point estimate of geometric T/R mean ratio to be within 80-125%

15. Advisory Committee for Pharmaceutical Science Replicate Design Studies:NDA’s and FDA Database Mei-Ling Chen, Ph.D.Associate Director Office of Pharmaceutical Science November 28-29, 2001 Rockville, MD

16. Replicate Design Data NDAs and ANDAs

17. Old Database

18. New Data N= 17- 93

19. Modified Release Products - NDAs

20. Immediate Release Products - NDAs

21. IR - Data Set #2 Subject #9

22. FDA Contract Studies • Replicated-Crossover Design • Conducted at the University of Tennessee • Ranitidine • Metoprolol • Methylphenidate

23. Interplay of Drugs and Excipients Drugs R Ranitidine Metoprolol (Low P) (High P) Excipient 1SorbitolLow permeability Osmotic pressureGI transit time Excipient 2 SucroseHigh permeability Bioavailability? SxF Interaction?

24. Excipient EffectHypothesis • The bioavailability of a low permeability drug (e.g., ranitidine) is more likely to be affected by an excipient such as sorbitol that reduces the gastrointestinal transit time. • Subject-by-formulation interactions may occur when two syrup formulations contain different sweetening agents, e.g., sorbitol versus sucrose.

25. Ranitidine Levels Failed ABE and IBE AUCinf, T/R = 0.56 Cmax, T/R = 0.49 (reference) (test)

26. Metoprolol Levels AUCinf, T/R = 0.93 Cmax, T/R = 0.77 AUCinf Passed ABE & IBE Cmax Failed Both (reference) (test)

27. Ranitidine in Sucrose vs. Sorbitol Solution Subject-by-Formulation Interaction Reduction of between-subject variability from sucrose to sorbitol resulted in an SxF interaction (sD = 0.15) sBR= 0.24 sBT= 0.13

28. Methylphenidate