Outline

1. Statistical Methods for Assessment of Individual/Population BioequivalenceShein-Chung Chow, Ph.D.Biostatistics and Clinical Data ManagementMillennium Pharmaceuticals, Inc.Cambridge, MA 02139Presented at ASA Boston ChapterDecember 2, 2003

2. Outline • Background • What and Why? • History • Conduct of Bioequivalence Trials • Drug Interchangeability • Population Bioequivalence • Individual Bioequivalence • Recent Development • Summary

3. What and Why? • What? • Bioavailability is defined as the rate and extent to which the active drug ingredient is absorbed and becomes available at the site of drug action • Two drug products are said to be bioequivalent if they are pharmaceutical equivalent or pharmaceutical alternatives, and if their rates and extents of absorption do not show a significant difference.

4. What and Why? • New Drugs • Drug discovery, formulation, laboratory development, animal studies, clinical development, etc. • IND, NDA, IRB, Advisory Committee • The process is lengthy & costly • Generic Drugs • ANDA • The US FDA was authorized to approve generic drugs via the evaluation of bioequivalence trials in 1984

5. What and Why? Fundamental Bioequivalence Assumption When a generic drug is claimed bioequivalent to a brand-name drug, it is assumed that they are therapeutically equivalent.

6. History • 1938-1962 • Generic copies of approved drug products could be approved by an ANDA which includes the information of formulation, manufacturing and quality control procedures, and labeling. • 1975 • Regulations were established. • 1977 • Regulations were finalized and became effective (21 CFR 320).

7. History • 1977-1980 • Several decision rules were proposed: 75/75, 80/120, and 20% rules • 1984 • The Drug Price Competition and Patent Term Restoration Act • 1986 • FDA Hearing on bioequivalence issues of solid dosage form

8. History • 1992 • FDA issued a guidance on statistical procedure • Chow and Liu published the first BA/BE book • FDA Core Committee raised the issue of switchability • 1993 • Generic Drug Advisory Committee Meeting discussed individual bioequivalence • 1994 • DIA BA/BE Symposium held in Rockville, Maryland

9. History • 1995 • Generic Drug Advisory Committee Meeting • International Workshop (Canada, US, and Germany) held in Germany • SUPAC-IR • 1996 • FDA Individual BE Working Group/PhRMA/Generic Trade Association • FIP BioInternational’96, Tokyo, Japan

10. History • 1997 • DIA Hilton Head Meeting • Draft guidance on PBE/IBE circulated for comments • 1998 • AAPS annual meeting • 1999 • Revised draft guidance on PBE/IBE issued • FDA guidance on in vitro bioequivalence testing • Chow & Liu’s BA/BE book revision

11. History • 2000 • AAPS annual meeting • FDA guidance on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (October, 2000) • FDA guidance on Statistical Approaches to Establishing Bioequivalence (January, 2001) • 2001 • FDA guidance on Statistical Approaches to Establishing Bioequivalence (January, 2001) • 2002 • FDA draft guidance on Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations (July, 2002)

12. Current Regulations • Most regulatory agencies including the U.S. Food and Drug Administration (FDA) require evidence of bioequivalence in average bioavailabilities between drug products. • This type of bioequivalence is referred to as ABE. • Based on the 2001 FDA guidance, bioequivalence may be established via population and individual bioequivalence provided that the observed ratio of geometric means is within the bioequivalence limits of 80% and 125%.

13. Current Regulation - ABE • Bioequivalence is concluded if the average bioavailability of test product is within 20% of that of the reference product with 90% assurance (raw data), or • Bioequivalence is claimed if the ratio of average bioavailabilities between test and reference products is within (80%, 125%) with 90% assurance (log-transformed data).

14. RANDOMIZ A T I ON WAS H OUT Standard Two-sequence, Two period Crossover Design PERIOD II I Test Sequence 1 Reference Subjects Test Sequence 2 Reference

15. Difference in Means 0% 5% 10% 15%20 24 52 200 24 28 62 242 28 34 74 288 32 40 86 336 36 46 100 390 40 52 114 448 CV20222426 28 30 Power80% Conduct of Bioequivalence Trials • Number of Subjects - ABE • Pivotal fasting studies: 24-36 subjects • Limited food studies: minimum of 12 subjects • Liu, J.P. and Chow, S.C. (1992). J. Pharmacokin. Biopharm., 20, 101-104.

16. Conduct of Bioequivalence Trials • Washout • 5.5 half-lives for IR products • 8.5 half-lives for CR products • Blood Sampling • More sampling around Cmax • Sampling at least three half-lives

17. Statistical Methods - ABE • Confidence Interval • The classical (shortest) confidence interval • Westlake’s symmetric • Fieller’s theorem • Chow and Shao’s confidence region • Interval Hypotheses Testing • Shuirmann’s two one-sided tests procedure

18. Current Regulations - ABE • A generic drug can be used as a substitute for the brand-name drug if it has been shown to be bioequivalent to the brand-name drug. • Current regulations do not indicate that two generic copies of the same brand-name drug can be used interchangeably, even though they are bioequivalent to the same brand-name drug. • Bioequivalence between generic copies of a brand-name drug is not required.

19. Safety Concern Generic #1 Generic #K ? Generic #5 Generic #2 Brand-name Generic #4 Generic #3

20. Safety Concern Generic Drugs They’re cheaper, but do they work as well?

21. Safety Concern • Generic and brand-name drugs do exactly the same thing and are completely interchangeable. - D. McLean Deputy Associate Commissioner for Public Affairs U.S. Food and Drug Administration • I would hesitate to substitute a generic for a brand-name drug for those patients who have been on the drug for years. However, I would not hesitate to suggest a doctor start a new patient on the generic version. - A. Di Cello Executive Director Pennsylvania Pharmacists Association

22. Drug Interchangeability • Drug Prescribability • Brand-name vs. its generic copies • Generic copies vs. generic copies • Drug Switchability • Brand-name vs. its generic copies • Generic copies vs. generic copies • Current regulation for ABE does not guarantee drug prescribability and drug switchability

23. Limitations of ABE • Focuses only on population average • Ignores distribution of the metric • Ignores subject-by-formulation interaction • Does not address the right question • Comments • One size fits all BE criteria • Clinical evidence • Post-approval process validation/control

24. Drug Prescribability • The physician’s choice for prescribing an appropriate drug for his/her patients between the brand-name drug and its generic copies • Population Bioequivalence (PBE) • Anderson and Hauck (1990) • Chow and Liu (1992) • Post-approval meta-analysis for BE review • Chow and Liu (1997) • Chow and Shao (1999)

25. Drug Switchability • The switch from a drug (e.g., a brand-name drug or its generic copies) to another (e.g., a generic copy) within the same patient whose concentration of the drug has been titrated to a steady, efficacious and safe level • Individual Bioequivalence (IBE) • Anderson and Hauck (1990) • Schall and Luus (1993) • Holder and Hsuan (1993) • Esinhart and Chinchilli (1994) • Post-approval meta-analysis for BE review • Chow and Liu (1997) • Chow and Shao (1999)

26. Type of Bioequivalence • Average Bioequivalence (ABE) • Current regulatory requirement • Population Bioequivalence (PBE) • Prescribability • Individual Bioequivalence (IBE) • Switchability

27. Ideal IBE/PBE Criteria Chen, M.L. (1997). Individual Bioequivalence - A Regulatory Update. Journal of Biopharmaceutical Statistics, 7, 5-11. • Should take into consideration for both average and variance • Should be able to assume switchability • Should encourage or reward formulations that reduce within subject variability • Should have a statistically valid method that controls consumer’s risk at the level of 5%

28. Ideal IBE/PBE Criteria • Should be able to estimate appropriate sample size for the study in order to meet the criteria • The software application for the statistical method should be user-friendly • Should provide interpretability for scientists and clinicians • Statistical methods should permit the possibility of sequence and period effect, as well as missing data.

29. IBE/PBE Criteria • Notations mT = mean of the test product mR = mean of the reference product sWT2 = within-subject variability for the test product sWR2 = within-subject variability for the reference product sD2 = variability due to the subject-by-formulation interaction

30. FDA’s Recommendation • Aggregate criterion • Moment-based approach • Scaling method • Weighing factors • One-sided test

31. IBE Criterion Where

32. Comments on IBE Criterion • It is a non-linear function of means and variance components • The selection of weights lack of scientific and statistical justification • The determination of bioequivalence limit is subjective • IBE criteria may lead to a negative value (over-corrected)

33. Comments on IBE Criterion • Aggregate criteria cannot isolate the effects due to average intrasubject variability and variability due to the subject-by-formulation interaction • Masking effect for distributions of individual components • Offsetting effect • Bias versus intrasubject variability • Two-stage test procedure

34. Offsetting Effect • One actual data set from the US FDA • Four-sequence, four-period crossover design • N=22 subjects • Average Bioequivalence • The ratio of average AUC is 1.144 with a C.I. of (1.025, 1.280) • Individual Bioequivalence • The upper bound of the 90% confidence interval based on 2000 bootstrap samples is 1.312, which is less than IBE limit. • The ratio of intrasubject standard deviation between the test and reference formulation is 0.52.

35. Offsetting Effect • The 14% increase in the average is offset by a 48% reduction in the variability • We may conclude IBE even though the distributions of PK responses are totally different.

36. Study Design for IBE • The IBE criteria recommended by the FDA involves the estimation of sWR2, sWT2, and sD2. • The standard 2 x 2 crossover design is not appropriate. • FDA recommends a replicated design be used TRTRRTRT TRTRTR (recommended) (possible alternative)

37. General Approaches for IBE/PBE Let yT be the PK response from the test formulation, yR and be two identically distributed PK responses from the reference formulation, and if if where is a given constant.

38. General Approaches for IBE/PBE  If , , and are independent observations from different subjects, then the two formulations are population bioequivalence when .  If , , and are from the same subject, then the two formulations are individual bioequivalence when .

39. General Approaches for IBE/PBE  is a measure of the relative difference between the mean squared errors of yR- yT and yR -  is the within-subject variance of the reference formulation  for PBE  for IBE

40. Assessment of IBE  Hypotheses Testing versus  IBE is claimed if a 95% confidence upper bound of is less than and the observed ratio of geometric means is within bioequivalence limits of 80% and 125%.  References 1. FDA (1999). In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches. Food and Drug Administration, Rockville, Maryland, August, 1999. 2. FDA (2001). Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Food and Drug Administration, Rockville, Maryland, January, 2001.

41. Assessment of IBE  Testing versus is equivalent to testing the following hypotheses versus where

42. Assessment of IBE  If , then an approximate upper confidence bound can be obtained as where is an unbiased estimator of , is an estimator of the variance of , and Lm are some constants.  Note that are independent. References - Howe, W.G. (1974). JASA, 69, 789-794. - Graybill, F. and Wang, C.M. (1980). JASA, 75, 869-873. - Hyslop, T., Hsuan, F., and Holder, D. (2000). Statistics in Medicine, 19, 2885-2897.

43. Assessment of IBE  Hyslop, Hsuan, and Holder (2000) considered the following decomposition of where  Note that

44. Assessment of IBE The reason to decompose as suggested by Hyslop, Hsuan and Holder (2000) is because independent unbiased estimator of , , and can be derived under the 2 4 crossover design, recommended in the 2001 FDA guidance.

45. Assessment of IBE Let and Zjk and be the sample mean and sample variance based on Zijk

46. Assessment of IBE , , , and are independent.

47. Assessment of IBE An approximate 95% upper confidence bound for is

48. Assessment of IBE U is the sum ofthe following quantities: where is the percentile of the chi-square distribution with b degrees of freedom

49. Assessment of IBE Testing for versus If , then reject H0.

50. FDA’s Approach to Establishing PBE • The 2001 FDA guidance provides detailed statistical method for assessment of PBE under the recommended 2x4 crossover design. • Statistical procedure was derived following the method by Hyslop, Hsuan, and Holder (2000) for IBE. • Statistical validity of the method is questionable because the method fails to meet the primary assumption of independence. • The method is conservative with some undesirable properties. • Reference Wang, H., Shao, J., and Chow, S.C. (2001). On FDA’s statistical approach to establishing population bioequivalence. Unpublished manuscript.