Generic Medicines: Sorting the science from spin

1. Generic Medicines:Sorting the science from spin Andrew McLachlanandrewm@pharm.usyd.edu.au

2. I have received research funding, payment for educational sessions and acted as a paid consultant for innovator and generic pharmaceutical manufacturers I serve on government committees which review applications for new medicines and their use Conflict statement

3. Sorting the science from spin • Science versus clinical issues for generic medicines • Does the science of bioequivalence extend to all medicines? • How can we improve patient awarenessto enhance safety

4. “scientific concerns”

5. Bioequivalence • Pharmacological basis of drug response • Key principle in drug development and regulation of BOTH branded and generic medicinal products

6. Concentration-effect relationship Effect Probability Toxicity DrugConcentration

7. Concentration-effect relationship Effect Probability Toxicity DrugConcentration

9. Aus Pharmacist July 2005

11. Adapted from Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006

12. MYTH ……not supported by credible data Adapted from Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006

13. A cause for concern? Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006

14. “It was of interest to note that very few articles described randomised controlled clinical trials comparing generic and branded products. The majority of articles consisted of case reports, letters discussing case reports, or opinion pieces without presentation of new data. “ Adapted from Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006

15. Few controlled trials Not all in patient of interest Small numbers of patients Not all studies blinded Clinical endpoints (underpowered) No significant pharmacokinetic differences detected Seizure frequency unchanged (overall) Adapted from Crawford P et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006

16. Drug interactions Environmental factors Renal disease Obesity pregnancy Genetic differences Age Hepatic disease Others diseases Pharmacokinetics Pharmacodynamics Variability in Drug Response adherence Pharmacodynamic monitoring Therapeutic drug monitoring Dose individualisation

17. A common misconception held by some health care practitioners and the general public is that generic drug products may differ by as much as 40% from their brand name equivalents. Aus Pharmacist July 2005

18. Analysis of 1636 crossover fasting BE studies from approved ANDAs (1996-2005) Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents AAPS conference 2006 San Antonio

19. Analysis of 1636 crossover fasting BE studies from approved ANDAs (1996-2005) Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents AAPS conference 2006 San Antonio

20. CONCLUSIONSfrom FDA review of 1636 BE studies 􀀹 Generic drug products approved over the 10-year period differed by an average of less than 4% in extent of absorption (exposure) relative to their brand name counterparts. 􀀹 The fact that observed differences have remained quite small, illustrates the effectiveness of the BE criteria used in the approval of generic drug products in the US. Haidar SH et al, A Review of ANDAs Approved 1996 – 2005 Reveals Small Differences in Bioavailability for BCS Class I and Other Generic Drug Products Relative to the Brand Name Equivalents AAPS conference 2006 San Antonio

22. Narrow safety margin medicines • Should the same criteria apply? • How should they be tested by the same criteria? ………Clinical (but no scientific) concerns remain – care is needed

24. Between and within subject variability Benet LZ. Relevance of Pharmacokinetics in Narrow Therapeutic Index Drugs. Transplantation Proceedings 1999 Wagner JG. Inter- and intrasubject variation of digoxin renal clearance in normal adult males. Drug Intell Clin Pharm. 1988

25. Benet on cyclosporin BE ….. to establish bioequivalence of generic cyclosporine formulations, the fact that thousands of transplant patients have safely been switched between the innovator's bioequivalent and even bioinequivalent cyclosporine formulations for more than a decade, and that bioequivalence data of generic cyclosporine formulations in healthy volunteers and transplant patients is available, the present FDA guidelines for approving bioequivalence can be considered adequate and sufficient for generic cyclosporine formulations. Christians U, First MR, Benet LZ. Recommendations for bioequivalence testing of cyclosporine generics revisited. Ther Drug Monit. 2000

26. “Clinical concerns”

27. QUALITY USE OF MEDICINES • Quality Use of Medicines is defined as: • selecting management options wisely; • choosing suitable medicines if a medicine is considered necessary; and • using medicines safely and effectively. “Better health through quality use of medicines”

28. a hypothetical 79-year-old woman with chronic obstructive pulmonary disease, type 2 diabetes, osteoporosis, hypertension, and osteoarthritis If the relevant Clinical Practice Guidelines were followed, the hypothetical patient would be prescribed 12 medications (costing her $US406 per month) and a complicated non-pharmacological regimen Guidelines, co-morbidities, polypharmacy Boyd CM et al. Clinical Practice Guidelines and Quality of Care for Older Patients With Multiple Comorbid Diseases. JAMA Aug 2005

29. “Polypharmacy” More than 5 medicines 75 ±13 years Less than 5 medicines 66.7 ± 19 years Viktil KK et al , Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Brit J Clin Pharmacol 2006

30. DRPs = Drug Related Problems Viktil KK et al , Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Brit J Clin Pharmacol 2006

31. www.nps.org.au

32. http://www.nps.org.au/resources/Case_Studies/Case_41/case.pdfhttp://www.nps.org.au/resources/Case_Studies/Case_41/case.pdf

33. www.nps.org.au/resources/Case_Studies/Case_41/results.pdf

34. Practitioner responses n = 300 responses of 1353 Patient suitability for brand substitution 88.3% of respondents considered Anne a suitable candidate for brand substitution. — had no cognitive impairment (64.9%) — could, and was interested in, saving money (33.5%) — was independent and self-caring (11.3%) — had family support available (10.9%) —understands the concept of brand substitution (10.1%). 11.7% said not suitable because of potential confusion and because some of her medicines had narrow therapeutic windows. www.nps.org.au/resources/Case_Studies/Case_41/results.pdf

35. Practitioner responses Strategies to avoid confusion during brand substitution Respondents (n = 299) suggested strategies to avoid confusion could be implemented: — when prescribing and selecting drugs (e.g. using the same generic brand consistently) — labelling (e.g. stating ‘this medicine replaces Brand X’ or ‘same as Brand X’) — by informing and explaining (e.g. identifying and discussing differences in appearance between old and new brands). — regular follow-up and review (e.g. considering a Home Medicines Review), — dose administration aids www.nps.org.au/resources/Case_Studies/Case_41/results.pdf

36. How can patients avoid being confused by thebrand name of generic products? • Patients should be encouraged to know and record the name of the active ingredient in the medicine • Understand that the same medicine may be available in different brands. • Active ingredient in the product should be displayed with greater or equal prominence to the brand name ….as recommended by the TGA in the 'Best practice guideline on prescription medicine labelling'

37. Medicine Talk, Autumn 2007

39. Make a list ……and check it twice? • As patients move in and out of hospital it is likely that generic substitution will occur to a greater extent. • reinforce the need for patients to be aware of and carry a list of the name of the active ingredient or generic name of their medicines www.nps.org.au/resources/content/medimate_medicine_list.pdf

40. Extra care in those most at risk • Confusion can lead to dose duplication • Unless the patient or carer fully understands the difference between the various brands of the same medicine. • Older patients with cognitive impairment and patients taking multiple medicines for serious chronic illness are at greatest risk of misadventure

41. Summary • important to disentangle the scientific, clinical and business issues around generic medicines • many of the issues raised apply equally to branded and generic medicines • clinical issues remain a concern when medicines are switched without clear communication • where clinicians/companies/advocates have concerns then we need rigorous controlled trials

43. Prescribability refers to the choice of two products when therapy is started in a drug-naïve patient Switchability , when a patient stabilized on the innovator's product is switched to a generic formulation, is of greater clinical impact Average bioequivalence testing, which is as discussed earlier the basis of approval of generic drugs in the United States and most other countries, measures prescribability rather than switchability.

44. “Currently, individual bioequivalence is a theoretical solution to solve a theoretical clinical problem.” • Individual bioequivalence takes a possible subject-by-formulation interaction into account in the computation of the metric. • A large subject-by-formulation interaction is an indicator for a lack of switchability between the test and the reference formulation in some individuals • Individual bioequivalence studies require a replicate design, where each subject receives the generic formulation twice and the innovator formulation twice. • This study design allows also for estimation of interindividual and intraindividual variances.

45. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.