Regulatory Requirements for Pharmaceutical Generics MFPD Conference Montreal June 21, 2010

1. Regulatory Requirements for Pharmaceutical Generics MFPD Conference Montreal June 21, 2010 Eric Ormsby Therapeutic Products Directorate

2. Outline • History of bioequivalence • Regulations to support generic drugs • Guidance relevant to generic drugs • Proposed changes to guidance

3. History of bioequivalence in Canada • Research done in HC labs in 60s indicated generics could be accepted based on blood levels • 1967 Harley Parliamentary report on drug costs recommended compulsory licensing • 1969 Amendment to the Patent Act allows compulsory licensing • First developed country to allow generics • First generic => Valium (diazepam) • Special Advisory Committee established in 1974 to provide recommendations on scope and data requirements

4. History con’t • Expert Advisory Committee re-established for 1986-1993 and provided recommendations in reports A, B, C • Report A => Conduct and Analysis of Bioequivalence Studies (1992) • Report B => Modified-release Dosage Formulations (1996) • Report C => stayed as a report – complicated PK drugs and PD studies

5. History con’t • 1989 Bio-international conference in Toronto • 1990 Crystal City meeting on Bioanalytical validation • 1993 Patent Act amended to respect existing patents • 1995 Abbreviated New Drug Submission regulations • 2002- present - Scientific Advisory Committee established to provide recommendations on revisions to guidances • January 2010 – two guidances issued for consultation => combines 11 guidances

6. Regulations

7. C.08.002.1.- Abbreviated New Drug Submission (ANDS) (1) A manufacturer of a new drug may file an ANDS for the new drug where in comparison with the Canadian reference product (CRP), (a) the new drug is the pharmaceutical equivalent of the CRP; (b) the new drug is bioequivalent with the CRP, based on the pharmaceutical and, where the Minister considers it necessary, bioavailability characteristics; (c) the route of administration of the new drug is the same as that of the CRP; and (d) the conditions of use for the new drug fall within the conditions of use for the CRP.

8. C.08.002.1.(2)Regulation Con’t • Safety and effectiveness - evidence of pharmaceutical equivalence - information on the CRP - when needed bioavailability characteristics that are bioequivalent with the CRP through bioavailability, pharmacodynamic or clinical studies

9. Canadian Reference Product • Defined in regulation as (a) a drug in respect of which a NOC is issued pursuant to Section C.08.004 and which is marketed in Canada by the innovator of the drug (b) a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, where a drug in respect of which a NOC has been issued cannot be used for that purpose because it is no longer marketed in Canada, or (c) a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence …. in comparison to a drug referred to in paragraph (a).

10. Pharmaceutical Equivalent • Defined in regulations as: a new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients.

11. Guidances

12. Use of Foreign Reference Product • Requirements for using a foreign reference product instead of the product on the Canadian market are given in the Policy entitled: Canadian Reference Product - must be simple dosage form - drug must have simple PK - other criteria such as dissolution testing, labelling, manufacturer, etc

13. Identical medicinal ingredients • What can be considered identical is defined in the policy document entitled: Interpretation of “Identical Medicinal Ingredient” - hydrated forms are identical - unsolvated and solvated forms are identical with supporting data - different complexes (esters, salts, etc) are non-identical - different isomers are non-identical

14. Bioequivalence • Comparative bioavailability study - almost always measured by collecting blood levels over time after dosing in fasted volunteers on two separate occasions the test and reference formulations in a crossover design • Comparative pharmacodynamic study - must be a measure which directly relates to action of the drug (FEV1, acid reduction) • Comparative clinical endpoint study

15. Biowaivers • Solutions - these products do not need bioavailability data only chemistry and manufacturing data • Proportional Dosage Forms - only one strength in a dosage line needs to show bioequivalence if they are proportional - must have similar dissolution rates

16. Proposed 2 new guidances

17. Guidance 1: Conduct of Bioequivalence Studies • GMP • GCP • A well designed study • Must control type I error at 5% • Validated bioanalytical method • Validated statistical methods and programs • Appropriate standards met

18. Food studies • Currently: only fed study for complicated kinetics and MR formulations • Proposal: for certain IR formulations and for all MR formulations • Issue: no problems identified with current standard but when innovator PM states food effect or lack of one how should this be applied to subsequent-entry product?

19. Metabolites • Currently: unclear when metabolites can be used to determine BE • Proposal: BE to be determined on the drug which was formulated, if not possible then metabolite, preferably a primary metabolite. Metabolite must be justified and stated in protocol (can use metabolite as a covariate) • Why: It is the formulated drug that is being absorbed

20. Guidance 2:Standards • All standards in one document • No complicated vs uncomplicated drugs • Offer points to consider for pharmacodynamic studies

21. Bioequivalence intervals • These have been redefined with increased precision from e.g. 80% to 80.0% • Only affects rounding off

22. Potency Correction • Currently: BE must be shown in both the observed data as well as after potency correction • Proposal: Only require analysis on observed concentrations … but potency content should be within 5% of reference • Why: 5% rule should keep test and reference formulations comparable

23. Steady-state studies for MRs • Currently: steady-state study required when accumulation is indicated in single-dose study • Proposal: remove requirement • Why: steady-state does not give any better comparison of the two formulations

24. The basic standard for most drugs • The 90% confidence interval for the mean geometric ratio of AUCt must be between 80.0-125.0% , and, • Mean geometric ratio of Cmax must be between 80.0-125.0%

25. Critical Dose Drugs • The 90% confidence interval for the mean geometric ratio of AUCt must be between 90.0-112.0% , and, • The 90% confidence interval for the mean geometric ratio of Cmax must be between 80.0-125.0% • Fed and fasted states • Any drugs need to be added to list????

26. Combination products • Each drug in a combination must meet its own standard

27. Time to onset important • The 90% confidence interval for the mean geometric ratio of AUCt and Cmax must be between 80.0-125.0% , and, • Mean geometric ratio of AUCreftmax must be between 80.0-125.0% • Is there a better measure for rate????

28. Long Half-life drugs • terminal elimination half-life >24 hours • The 90% confidence interval for the mean geometric ratio of AUC0-72 must be between 80.0-125.0% , and, • Mean geometric ratio of Cmax must be between 80.0-125.0%

29. Non-linear drugs • Currently: draft guidance states what dose to use and that fed and fasted studies should be run, non-linearity determined from literature • Proposal: same only for highly soluble drugs possible waiver for fed study • Why: the fed study does not provide any addition information for a non-linear highly soluble drug • Do we need a fed study at all ????

30. Highly Variable Drug Products • HVDP has greater than 30% intra-subject CV • Should we allow a wider bioequivalence interval for HVDP????? • Some issues: - HVDP or a Highly Variable Study - should the single study determine BI - influence of outliers

31. Endogenous substances • Adjustment for baseline based on the average of three pre-dose concentrations • negative results set to zero • Positive values found after a negative value past Cmax should also be set to zero • Analysis of distribution of zeros between formulations suggested

32. Urine data • Unchanged drug only • 90% CI for relative mean AeT should be within 80.0 and 125.0 % • Relative mean Rmax should be within 80.0 and 125.0 % • Are these appropriate????

33. Thank you for your attention… Send comments on guidances and other issues to policy_bureau_enquiries@hc-sc.gc.ca Hope to receive many thoughtful comments and proposals