Examining the Quality, Safety, Efficacy of Generic Drugs

1. Examining the Quality, Safety, Efficacy of Generic Drugs Jake J. Thiessen, Ph.D. Founding Director, School of Pharmacy, University of Waterloo Professor Emeritus, Leslie Dan Faculty of Pharmacy, University of Toronto

2. Canadian Government Mandate(Health Canada) • To ensure that the Canadian public gets medicines that are (therapeutically) safe, effective and of high quality. • To ensure that manufacturers provide suitable scientific and clinical evidence -- • Obviously this implies safety and efficacy in humans…. • ….which will ultimately be demonstrated in valid clinical trials… • The Canadian government does not assess whether a drug is superior to similar therapeutic agents, nor does it determine whether the new drug is cost-effective for publicly-funded formularies.

3. The Focal Point of Today’s Talk Are Canada’s Approved Generic Drugs ‘TheSAME’ as the Originator’s Drugs? • ‘The SAME’ in terms of: • Quality • Safety • Efficacy • But, what is meant by ‘The Same’? • How much variability can be tolerated with ‘The Same’? • Are there exceptions to Canada’s common criteria?

4. What is Different or ‘The Same’? All have ‘The Same’ purchasing power.

5. What is Different or ‘The Same’?

6. Permitted Product Content Variability *USP 34 NF 29 Suppl 1 (2011)

7. Critical Dose Drugs Content Variability *USP 34 NF 29 Suppl 1 (2011)

8. Reported Product Variability A Yacobi et al: Clin. Pharmacol. Ther. 65: 389-394 (1999) Carbamazepine data: 200 mg Taro Carbamazepine vs Tegretol

9. Content Variability - -Within and Between Products • It is impossible for all capsules/tablets in a prescription to be identical and to contain the exact amount on the label. • It is impossible for all batches from the same manufacturer to be identical. • A quality product (originator or subsequent entry, i.e. generic) meets regulatory requirements when its variability is within an approved range (e.g. most commonly 10% of label claim). • The permitted variability is really a ‘probability’ or ‘confidence limit’ that a tested sample meets the quality specification and that now all the tablets in the lot also meet that criterion.

10. Variability as a Fundamental Issue

11. View of the Body?? Planck’s Is It Like These Constants??

12. View of the Body?? Is It Really Variable??

13. The Variable Human Illustrated Body Normal Temperature Body Normal Lab Values

14. Sources of Inter – and Intra-Human Variability Source: Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. Figure 4-1; Originally by E. S. Vesell

15. Sources of Variability Age, gender, size, genetic traits, health status, food, etc. • Absorption • First-pass effect • Liver – • Metabolism • Bile • Distribution • Excretion Understanding Physiologic Realities After Administering a Drug

16. Homeostasis Drug Drug Receptor Response Patient Response to a Drug Blood/Int. fluid Biophase Cellular Barrier

17. Variability in Therapeutic Effect TPD Critical Dose Drugs * Not Available in the USP ** Health Canada or elsewhere

18. Evaluating Drugs • Effect or response in the body is relatively insensitive for most drugs -- • Frequently one is unable to distinguish a difference when the dose is doubled. • Even though blood concentrations change by 50%, as usually occurs between doses, one usually cannot tell the difference in effect. • Blood concentrations are a much more sensitive way of evaluating the entry or presence of drugs in the body.

19. Variability as a Fundamental Issue

20. The Science of Comparing Two Products

21. AUC • Area under the concentration- time curve • Cmax • Maximum concentration • Tmax • Time to maximum concentration

22. Bioequivalence Testing: The Complicating Problem of Variability Propafenone 300 mg IR; fasting study H.H. Blume et al: Application of single dose vs. multiple-dose studies. Biointernational 2002

23. Variability Encountered With a Dose Intra- and Inter-Individual Variability!!

24. Variability With the Same Product Nifedipine - Adalat M. Spino “Non-Linear Drugs: A Pragmatic Perspective”; TPD Workshop, 2002 People/Products are Not Constant!!

25. Intra-Product Variability (0.25 mg Lanoxin) People/Products are Not Constant!! A Yacobi et al: J. Clin. Pharmacol. Ther. 21: 301-31 (1981) Lanoxin vs Generic Digoxin: n=12 4-way crossover trial

26. Intra-Product Variability (5 mg Coumadin) People/Products are Not Constant!! A Yacobi et al: J. Clin. Pharmacol. Ther. 40: 1-10 (2000) Coumadin vs Taro-warfarin: n=26(23completed) 4-way crossover trial Intra-subject CV ~ 20%

27. AUC A AUC B Cmax A Cmax B Tmax A Tmax B Quantifying Comparative Study Results

28. Variability as a Fundamental Issue

29. Variability as a Fundamental Issue

30. So, what do we mean when we say a product meets the criterion of 80-125%??What is this ‘confidence interval’ criterion all about?

31. Bioequivalence Confidence Intervals • It is a reasoned measure of product comparison • It is quantitative limit of the in vivo performance of a test product relative to a reference product (ie in a controlled clinical test) • The estimate is a “probability” [eg 90%]: • Based on the results of a completed study • Applies mostly to AUC, which defines the comparative fraction of the dose absorbed • A forecast or projection of what the average (egAUCtest/AUCref) would be if literally millions of people/patients were enrolled in a similar bioequivalence trial • For most products this range is 80-125%

32. Bioequivalence: Mean Ratios and Confidence Intervals (CI) . This case ‘passes’: ratio and CI is within 80-125% [Bioequivalent] 125 This case‘fails’: acceptable mean ratio but not within 80-125% % Mean Ratio 100 This case ‘fails’: unacceptable 90% CI 80

33. Health Canada’s Criteria: • Apply to generic and innovator companies • Apply to all products, with a few exceptions - • AUC must meet the 90% confidence limits of 80-125% • Cmax average must be between 80-125% • Exceptions: • Critical dose drugs (cyclosporin, digoxin, flecainide, lithium, phenytoin, sirolimus, tacrolimus, theophylline, warfarin) • AUC must meet the 90% confidence limits of 90-112% • Cmaxmust meet the 90% confidence limits of 80-125% • Fasting and Fed studies • Rapid onset of action drugs • Common requirements, plus • The relative mean AUCReftmaxof the test to reference formulation should be within 80 to 125%

34. Concluding Comments • Bioequivalence requirements are a robust international standard for designating products as ‘The Same’. They are the primary basis for decisions about interchangeability. • The requirements apply to both the originator and generic companies. • Originators who make changes in formulations, sites of manufacture, etc. • Generics who seek to create competitive products. • Interchangeability means that products can be switched with no change in therapeutic response. • The public is well-served by the bioequivalence requirements.