1. WHO Prequalification Program Workshop, Kiev, Ukraine, June 25-27,2007

5. Visit FDA website: www.fda.gov

8. Parent Compound Metabolite(s)? P’dynamic Response Single Dose Multiple Dose Set at 5%

9. Innovator Pharmaceutical Product ( Safety and efficacy) A generic product should not be a comparator as long as an innovator product is available. Selection should be made at the national level by the drug regulatory agency –National Innovator –WHO comparator product ( quality-safety-efficacy and has reference to manufacturing site) –ICH or associated country comparator product Comparator Product

10. In The Case that Innovator Product cannot be identified Important Criteria for Selection –Product is in the WHO list –Approval in an ICH – Associate Country- Pre-qualified by WHO –Extensive documented use in clinical trials reported in peer-reviewed scientific journals –Long unproblematic post-market surveillance (“well selected comparator”) A product approved based on comparison with A non domestic comparator product may not be interchangeable with currently marketed domestic products

11. Set at 5%

12. Producer Risk The risk of declaring two products NOT BE when they truly are BE is called the ‘producer risk’ In statistical terms, this is a Type II error –The risk of accepting the null hypothesis when it’s false

13. The risks are related If the consumer risk is reduced, the producer risk increases In statistical terms, if you lower the acceptable risk of making a Type I error, the risk of making a Type II error increases

14. Consumer Risk The risk of declaring two product BE when they’re not is called the ‘consumer risk’ In statistical terms, this is a Type I error –The risk of rejecting the null hypothesis when it’s true The consumer risk is set at 5%

16. Stavchansky’s Recommendation: FDA should pressure the Innovator Companies to put forward a Confidence Interval for their HVP

20. GE = PE + TE

23. Therapeutic Equivalence can be assured when the multisource product is: pharmaceutically equivalent and bioequivalent. TE = PE + BE Therapeutic Equivalence of Multisource Product The concept of interchangeability applies to: 1. - the dosage form and 2. - the indications and instruction for use.

27. AVERAGE BIOEQUIVALENCE A GLOBAL STANDARD OF PHARMACEUTICAL QUALITY ?

28. Origin of ABE A survey of physicians suggested that for most drugs, a difference of up to 20% in dose between two treatments would have no clinical significance

29. Average Bioequivalence two drug products are Bioequivalent ‘on the average’ when the (1-2α) confidence interval around the Geometric Mean Ratio falls entirely within 80-125% (regulatory control of specified limit)

31. Some International Criteria Country/RegionAUC 90% CI Criteria Cmax 90% CI Criteria Canada (most drugs)80 – 125%none (point estimate only) Europe (some drugs)80 – 125%75 – 133% South Africa (most drugs)80 – 125%75 – 133% (or broader if justified) Japan (some drugs)80 – 125%Some drugs wider than 80 – 125% Worldwide (WHO)80 – 125%“acceptance range for Cmax may be wider than for AUC”

33. Least Square Means from ANOVA t-statistic with 0.05 in one tail Standard Error

34. BE Limits The concept of the  20% difference is the basis of BE limits (goal posts) If the concentration dependent data were linear, the BE limits would be 80-120% On the log scale, the BE limits are 80- 125% The 90%CI must fit entirely within specified BE limits e.g. 80-125%

35. The width of the 90%CI In the Two One-Sided Test, the width of the 90%CI depends on –The magnitude of the WSV (ANOVA-CV) –The number of subjects in the BE study The bigger the WSV, the wider the CI If the WSV is high, more subjects are needed to give statistical power compared with when the WSV is low

41. Limitations of 2-Period Designs The intra subject variance associated with the Test and Ref products may not be the same A poor pharmaceutical product may have inflated intrasubject variance because of high within formulation variability The residual variance in 2-period designs averages the intrasubject variance of the two products –The Test and Ref intrasubject variance cannot be separated

44. Replicate Designs Yields information on the Intrasubject Variance Ideally, intrasubject variance of the Test product should be similar to the intrasubject variance of the Reference product

46. What do we learn from ANOVA Analysis The sources of variance in the model are –Product –Period –Sequence –Subject (Sequence) –Residual variance These account for all the inter-subject variability This estimates Intra-subject variability Source: Modified from K. Midha

47. ‘Fixed Effects” in ANOVA Product Period Sequence Subject nested within sequence is usually significant (f-test) because of large variability between subjects These fixed effects usually are not significant in the f-test Source: Modified from K. Midha

48. The Residual Variance (S W 2 ) Sources of Variability –Intra-subject variance in Pharmacokinetics –Analytical variability –Subject by formulation interaction –Unexplained random variation Source: Modified from K. Midha

58. The ‘ANOVA-CV’ The ANOVA-CV which is easily calculated from the residual variance is an estimate of WSV

59. Variability It is well known the Between Subject Variance (BSV) can be very high –Biological variation –Within Subject Variance (WSV) contributes to BSV WSV can also be high e.g. highly variable drugs and highly variable drug products Drugs with an ANOVA-CV  30% are defined as ‘highly variable drugs’

60. Thank you Muchas Gracias

61. The residual variance (WSV) is used in the calculation of a 90% confidence interval (90%CI) products on the geometric mean ratio (GMR) of the Test and Ref Geometric means are used because measures based on plasma concentration data (e.g. Cmax & AUC) are not normally distributed –They are log normal

62. The standard error of the difference between the (log) mean Test & the (log) mean Ref n 1 and n 2 are the number of subjects in each sequence S W 2 is the residual variance

63. t-statistic with 0.05 in one tail Least Squares Means From ANOVA SE (of the difference) from previous slide Take the antilog

65. Individual Bioequivalence ‘Two products are individual BE if the bioavailability of the new formulation is “sufficiently close” to that of the standard in “most” individuals’ a