Bioequivalence of Highly Variable Drugs: Regulatory Perspectives

1. Bioequivalence of Highly Variable Drugs: Regulatory Perspectives Sam H. Haidar, R.Ph., Ph.D. Pharmacometrics Office of Generic Drugs

2. Potential Advantages • Reduction in regulatory burden • Facilitate market access for highly variable but safe and effective drugs • Make it easier to approve a generic drug product which is significantly less variable than the reference listed drug

3. Current BE* RequirementsMajor Regulatory Agencies • U.S. Food and Drug Administration (FDA) • Health Canada • Committee for Proprietary Medicinal Products (CPMP), Europe • National Institute of Health Sciences (NIHS), Japan *BE = Bioequivalence

4. Current BE Requirements FDA* • AUC: 90% Confidence Interval Limits 80-125% • Cmax: 90% Confidence Interval Limits 80-125% • Criteria applied to drugs of low and high variability *Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products- General Considerations

5. Current BE Requirements Health Canada • AUC: 90% Confidence Interval Limits 80-125% • Cmax: Mean T/R ratio (point estimate) between 80-125% • Criteria judged flexible enough to deal with highly variable drugs* *Expert Advisory Committee on Bioavailability and Bioequivalence, June 26 – 27, 2003.

6. Current BE Requirements CPMP* • AUC: 90% Confidence Interval Limits 80-125% • Cmax: 90% Confidence Interval Limits 80-125% • Cmax: “In certain cases a wider interval is acceptable (e.g., 75-133%) *Note for Guidance on the Investigation of Bioavailability and Bioequivalence, January 2002

7. Current BE Requirements NIHS (Japan)* • AUC: 90% Confidence Interval Limits 80-125% • Cmax: 90% Confidence Interval Limits 80-125% • In cases of failure, add-on studies are acceptable (provided other criteria are met) *Guideline for Bioequivalence Studies of Generic Drugs, December 22, 1997.

8. Performance of FDA Criteria • Survey of ANDA Applications (1996-2001) • Evaluated distribution of Cmax and AUC T/R mean ratios (point estimates)

13. Summary • Although criteria allows for a mean difference of ± 20%, the vast majority of submissions were within ± 10% • This was also true with regard to highly variable drugs and drug products • Additional confirmation of greater variability associated with Cmax

14. Available OptionsBioequivalence of Highly Variable Drugs • Scaling based on intra-subject variability (Cmax, AUC) • Expansion of regulatory limits

15. Scaling Approaches • Reduction in sample size • Limits are defined by degree of variability • Need for point estimate constraint?

16. Expansion of Limits • Cmax only, or Cmax and AUC • Fixed Limits (e.g., 70 – 143%) for drugs meeting high variability “criterion” • Need for point estimate constraint? • Major concern: How to classify borderline drugs and drug products

17. Expansion of LimitsStudy: Hauck et al.* • AUC: 90% Confidence Interval Limits 80-125% • Cmax: 90% Confidence Interval Limits 70-143% • Outcome: Sample size reduced by 60% • Cmax ratios of 128% could pass using the 70-143% limit *Hauck et al. Int J Clin Pharm Ther. 39 (8) pp. 350-355 (2001)

18. Conclusion • If a need to make changes in the regulations is concluded: • Either approach would result in significant reduction in sample size • Additional criterion constraining point estimates may be needed • Based on prior experience, clustering around a T/R ratio of 1 would be expected for a modified BE criteria for highly variable drugs

19. Q & A • Dale Conner, Pharm.D.