1. - 1 Consequences of generic marketing on antibiotic consumption and the spread of resistance: facts and hypotheses P.L. Toutain National Veterinary School ; Toulouse,, France The responsible use of antibiotics in animals 14-16 November, Egmond aan Zee, The Netherlands NATIONAL VETERINARY S C H O O L T O U L O U S E

2. - 2 Points addressed in the presentation 1.Justifications for marketing generics human medicine is not veterinary medicine. The specific case of antibiotics: 2.Does generics policy encourage overuse and misuse and of antimicrobials 3. Some scientific issues 4.Possible solutions

3. - 3 Human medicine: it is a political goal (WHO, US, EU etc) to reduce pricing of drugs by promotion of generics

4. - 4 Why reduce pricing of drugs? to cut health-care expenses for the benefit of consumer, healthcare services insurance companies and public organizations aiming to guarantee social protection

5. - 5 The economical model for veterinary drugs is fundamentally different of the human one it is neither a patient at risk nor a public health system that pay for drugs (branded or generics) but a farmer that will pass this amount on the final consumer by adjusting the price of its marketed product. This amount should be considered as rather a negligible input (veterinary drug market is about only 4% of the human market) that will diluted by all other inputs (feed etc)

6. - 6 Generic global drug markets All drugs:≈ 50% of the total global sales of animal health products. – Generic products are very prevalent in the developing regions (Latin American, African and Asian countries) :60-70%.;US & EU :30- 40%. Antibiotics: >80%

7. - 7 Points addressed in the presentation 1.Justifications for marketing generics human medicine is not veterinary medicine. The specific case of antibiotics: 2.Does generics policy encourage overuse and misuse and of antimicrobials 3. Some scientific issues 4.Possible solutions

8. - 8 Generics and antibiotic consumption

9. - 9 The objective of this survey was to evaluate, in a community setting, the effect of price on consumption of ciprofloxacin and on ciprofloxacin resistance in Escherichia coli urine isolates

10. - 10 Methods A retrospective study collecting monthly national data on the number of marketed versions and sales of ciprofloxacin during January 1995– December 2005. Data were compared with a median price per defined daily dose (DDD) of ciprofloxacin during September 1999–December 2005. Yearly consumption data were compared with the antimicrobial resistance profiles of E. coli urine isolates.

11. - 11 Results 1.During 2002, the number of marketed versions increased from 3 to 10 2. the median price per DDD decreased by 53%. In December 2005 the difference between the cheapest and most expensive formulation was from 1 to 10. 1.From 2002 to 2005, the total consumption of oral ciprofloxacin in PHC increased significantly from 0.13 DDD/1000 inhabitant-days to 0.33 DDD/1000 inhabitant-days. 2. During the same period, the frequency of ciprofloxacin resistance increased by 200%. 3.A statistically significant correlation was found between the consumption of ciprofloxacin and the ciprofloxacin resistance rate in E. coli urine isolates, independent of the introduction of generic ciprofloxacin.

12. - 12 Number of ciprofloxacin trade names (black line) and the median price per DDD (red line) and the influence of the introduction of generics

13. - 13 The influence of the introduction of generics on the total use of ciprofloxacin (black line) and median price per DDD (red line)

14. - 14 Trends in the frequency of ciprofloxacin resistance among E. coli urine (brown line) and the consumption of ciprofloxacin (black line) from 1995 to 2005

15. - 15 Conclusion After the introduction of generic ciprofloxacin, a significant increase in the total consumption of oral ciprofloxacin was observed in Denmark. The increase in consumption was significantly correlated with ciprofloxacin resistance in E. coli obtained from urine isolates

16. - 16 Antibiotic generics in veterinary medicine: In veterinary medicine, we have now first evidences that market introduction of generics has influence on antibiotic consumption;

17. - 17 Impact of generic on antimicrobial usage in veterinary medicine Leipzig, 2009 In France Chauvin investigated the Impact of generic introduction on antimicrobial usages using a time-series analysis focusing on fluoroquinolones usages in poultry production.

18. - 18 Antibiotic generics in veterinary medicine (Chauvin JVPT 2009) Exposure from about 7000 chicken and 5500 turkey flocks from 2003 to 2008 were analyzed to check whether generic introduction led to an increase in exposure. There was a marked increase in fluoroquinolone usage in flocks slaughtered from spring 2007 (by means of 30% in turkey production and 50% in chicken broiler production) whereas it was stable (turkey) or decreasing (chicken) from 2004 to 2006.

19. - 19 Influence of generics marketing on the fluoroquinolone use (oral route) in poultry (2003- 2008); national survey in France

20. - 20 The “Me too” competition Competition among agents within one antibacterial class exists between branded agents with a similar mechanism of action, –the introduction of levofloxacin to the Belgian market resulted in an increase in the overall use of fluoroquinolones

21. - 21 In: Clinical infectious deseases 2005 41 114-117

22. - 22 Correlation between community use and the number of trade names for oral-use agents for 6 antibacterial classes in EU High consumption countries Low consumption countries Nb of trade names

23. - 23 Use of fluoroquinolones in veterinary medicine: Germany, DK, UK From Hellmann: Assoc Vet Consult. SAGAM 2005

24. - 24 Use of fluoroquinolones in veterinary medicine: Eastern EU, Spain, Portugal From Hellmann: Assoc Vet Consult. SAGAM 2005

25. - 25 Generics for antibiotics (quinolones) : conclusions

26. - 26 Generics and misuse of antibiotics

27. - 27 Generics and misuse of antibiotics Another possible undesirable consequence of generic promotion is the encouragement to use old rather than more recent antibiotics.

28. - 28 Generics and misuse of antibiotics in veterinary medicine Many recommendations to establish list of essential antibiotics for human medicine Where is the science demonstrating the benefit in terms or resistance to only use old antibiotics in veterinary medicine?

29. - 29 Is it a good medicinal practice to encourage the use of old antibiotics rather new ones? Traditionally, from a public health perspective, it was encouraged not to employ newer drugs, but rather to use the older antibiotics. The recommendation whether to choose older rather than newer antibiotics was recently challenged on an epidemiological basis (Amyes et al., 2007) and shown to be flawed for quinolones, cephalosporins and carbapenems.

30. - 30 For three antibiotic classes (quinolones, cephalosporins and carbapenems), it was observed that the less active drugs could be worse at hastening the spread of resistance than more active drugs in the same class. This led the authors to qualify the (WHO) stratagem of recommending the use of old antibiotics as part of microbiological folklore.

31. - 31 The case of tertracyclines One of the first major products to face the loss of patent cover in the animal health sector was Pfizer’s Terramycin (oxytetracycline). with the expiry of the relevant patents, generic companies were able to offer tetracyclines at prices considerably lower than those required by Pfizer Consequently, while oxytetracycline has been on the veterinary market for more than 40 years, it remains one of the best-selling drugs in the animal health industry, with total annual sales of some $450 million, a considerable part of which is still generated by Pfizer’s original product.

32. - 32 Reasons to challenge old antibiotics in veterinary medicine 1.They were developed when PK/PD concepts does not exist and when regulation was less demanding Inappropriate dosage regimen (e.g. same dose for marbofloxacin in all domestic species…) low and erratic bioavailability (tetracyclines in pigs….) 2.Wear of old antibiotics Less susceptible strains encourage the systematic increase of dosage regimen with possible negative impact on commensal flora etc

33. - 33 Reasons to challenge old antibiotics in veterinary medicine (tetracyclines) G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) 1-F% =80-90% 10% Low AB concentration in the Target biophase Efficacy? AB: oral route Résistance = public health concern Food chain Tetracyclins are stable in enviroment

34. - 34 Aggressive promotion for the use of antibiotics

35. - 35 Aggressive promotion for the use of antibiotics Competition between generics and also between generics and branded antibiotics (usually forced to lowered their prices in order to compete with the cheaper generic versions) lead to a more aggressive promotion for the use of antibiotics both in human and veterinary medicine.

36. - 36 in 2008, Wal-Mart, the largest retailer in US announced it was offering deeply-discounted $4.00 prices for a 30-day supply for generic prescriptions of antibioticsWal-Mart

37. - 37 Bioavailability of oral tetracyclins Chlortetracycline: –Chickens:1% –Pigs Fasted or fed: 18 to 19% –Turkeys:6% Doxycycline: –Chickens:41.3%. –Pigs :23% Oxytetracycline: –Pigs:4.8% –Piglets, weaned, 10 weeks of age: by drench: 9%;in medicated feed for 3 days: 3.7%. –Turkeys: Fasted: 47.6% ;. Fed: 9.4% Tetracycline: –Pigs fasted:23%.

38. - 38 Generics, bioequivalence and therapeutic equivalence of antibiotics Test Reference

39. - 39 Quality of Generics (vancomycin, gentamicin, oxacillin) It is suggested that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure Bioequivalence does not imply in vivo therapeutic equivalence when using the neutropenic mouse tigh infection model;

40. - 40 Generic 1 Pionneer ? yes Generic 2 Generic 3 ? No information on the substituability of generics between them.

41. - 41 Non-bioequivalence of various trademarks of enrofloxacin in cow Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320 Mexico

42. - 42 EMA facilitate introduction of generics by considering that the withdrawal period is the same for the pioneers and generics if bioequivalence is demonstrated

43. - 43 Bioequivalence and the problem of drug residues Bioequivalence studies in food- producing animals are not acceptable in lieu of residues data: why?

44. - 44 Definitions and statistics associated to bioequivalence and withdrawal time are fundamentally different

45. - 45 Bioequivalence and withdrawal time Bioequivalence is related to a confidence interval for a parameter (e.g. geometric mean AUC-ratio for 2 formulations) Withdrawal time is related to a tolerance limit (quantile 95% EU or 99% in US) and it is define as the time when the upper one-sided 95% tolerance limit for residue is below the MRL with 95% confidence“ The fact to guarantee that the 90% confidence interval for the AUC-ratio of the two formulations lie within an acceptance interval of 0.80-1.25 do not guarantee that the upper one-sided 95% tolerance limit for residue is below the MRL with 95% confidence for both formulations"

46. - 46 Points addressed in the presentation 1.Justifications for marketing generics human medicine is not veterinary medicine. The specific case of antibiotics: 2.Does generics policy encourage overuse and misuse and of antimicrobials 3. Some scientific issues 4.Possible solutions

47. - 47 Pharmaceutical innovations Encourage veterinary drug companies to invest in R&D to bring new and innovative antibiotics that fits public health requirements We need antibiotics having a good selectivity –PK selectivity (selective distribution to the targeted bugs) –PD selectivity (spectrum) Difficult (no diagnostic tool) A legitimate Justification of high prices

48. - 48 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase AB: oral route Résistance = public health concern Food chain 0% 100% Animal health Kidney

49. - 49 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase AB: IMroute Résistance = public health concern Food chain Animal health Kidney Quinolones, macrolides

50. - 50 Innovation: PK selectivity of antibiotics environment G.I.T Proximal Distal Blood Gut flora Zoonotic (salmonella, campylobacter commensal ( enterococcus) Biophase Résistance = public health concern Food chain 90% 0% Animal health Trapping or destruction of the antibiotic Efflux Quinolones, macrolides IM Kidney

51. - 51 Extended protection The viability of R&D-based pharmaceutical companies is governed by the protection of its intellectual property. the most obvious legal mechanism to limit generics is patent law. Why not to extend data protection for innovative (regarding public health issues) antibiotics as for minor species?

52. - 52 Possible economical solutions 1.Need of a pharmaco-economic assessment of the possible solutions 2.To reduce antibiotic use, the pricing should be increase, not decrease as it is the case of generics 3.Control pricing or at least suppress all incentives as “back margin” 4.Establish a Pigovian tax? A tax that is intended to correct the market outcome. in the presence of negative externalities (here antibioresistance), the social cost of a market activity is not covered by the private cost of the activity

53. - 53 Conclusion 1 It is not the intention of this communication to challenge the very principle of generics but rather to draw attention that to slavishly adopt in veterinary medicine all human regulations may be counterproductive for public health

54. - 54 Conclusion 2 The sustainable use of antibiotics in animals involves not only good end-user practices (prescribing veterinarians, farmers) but also regulatory bodies What is priority: free trading, exchanges or public health?

55. - 55 Conclusions 3 it is my opinion that veterinary antibiotics should be innovative, expensive, with a strictly regulated market rather than old, cheap and freely available drugs.