A. Bousquet-Mélou & P.L. Toutain National Veterinary School, Toulouse, France

1. Consequences of generics marketing on the antibiotic consumption and on the spread of resistance: facts and hypotheses AAVPT/ECVCP Workshop on Bioequivalence Issues in Veterinary Medicine Potomac, June 2010 A. Bousquet-Mélou & P.L. Toutain National Veterinary School, Toulouse, France

2. Points addressed in the presentation • Justifications for marketing generics • human medicine is not veterinary medicine • The specific case of antibiotics • Does generics policy encourage overuse and misuse of antimicrobials • Possible solutions

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

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 • To facilitate drug access for the poorest world populations

5. Promotion of generics marketing was regulated to reduce drug pricing • The Hatch-Waxman Act, was designed to promote generics while leaving intact a financial incentive for research and development. • It allows generics to win FDA marketing approval by submitting bioequivalence studies (as opposed to clinical data, which is costlier to compile) • Similar regulation followed in EU and in veterinary medicine

6. Change in the Average Relative Price of a Drug as the Number of Generic Versions Increases. Introduction of generics sharply decrease drug pricing

7. Justification to promote marketing of generics: the limits • Generic drugs are generally much cheaper than their branded counterparts and generics allow to achieved the goal of pricing reduction • According to basic economic models, when prices go down, products become affordable for a larger proportion of the population, which leads to increased consumption. • BUT • Is it a good news in terms of public health especially for antibiotics?

8. Justifications to promote marketing of generics in veterinary medicine ?

9. 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)

10. Justification to promote generics in veterinary medicine • For veterinary medicine, there is no crucial ethical motivation to promote generics as for human medicine where generic are expression of solidarity between wealthy and poor people/countries • In veterinary medicine, the priority is public health, • Nevertheless generics were promoted in veterinary medicine

11. Veterinary generic Drug Markets • Estimated at 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%

12. Generics in the Animal Health Industry: Opportunities or Threats ? But what about antibiotics, generics and public health?

13. The case of antibiotics

14. There are no doubt on the fact that: • Antibiotic resistance is a major public health threat • Factors responsible for increasing antibiotic resistance include the use of antimicrobial in veterinary medicine • The association between the consumption of an antimicrobial agent and the occurrence of antimicrobial resistance is well established. • Question: Does generics policy encourage overuse and misuse of antimicrobials ?

15. A first question on the overuse of antibiotic • Does flooding the market with different generics (and/or me-too branded drugs) had consequences on the overall antibiotic consumption, a major driving factor contributing to accelerate development of emergence and spread of resistance ?

16. A second question on the misuses of antibiotics • Does flooding the market with different generics had an influence on the prescribing patterns of clinicians ? (incentive to the use of some classes of antibiotics now cheaper)

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

18. 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 Nb of trade names

19. Generics and antibiotic consumption

20. The objective of this survey wasto evaluate, in a community setting, the effect of price on consumption of ciprofloxacin and on ciprofloxacinresistance in Escherichia coli urine isolates

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

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

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

24. Conclusion • After the introduction of generics of 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

25. Antibiotic generics in veterinary medicine:In veterinary medicine, we have now first evidence that market introduction of generics has influence on antibiotic consumption

26. 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.

27. 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 about 30% in turkey production and 50% in chicken broiler production) whereas it was stable (turkey) or decreasing (chicken) from 2004 to 2006.

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

29. Resistance and use of veterinary quinolones in EU

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

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

32. Generics for antibiotics (quinolones) : conclusions

33. Generics and misuse of antibiotics

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

35. 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.

36. 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.

37. 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 of resistance to use only old antibiotics in veterinary medicine?

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

39. Possible solutions

40. Possible solutions to antibiotic generics • Some lessons can be drawn from tobacco control where a combination of education, legal restrictions and taxes have reduced utilization.

41. Possible solutions to antibiotic generics • It is not the intention of this communication to challenge the principle of generics but rather to draw attention that to slavishly adopt in veterinary medicine all human regulations may be counterproductive for public health

42. Regulatory people are involved in the prudent/sustainable use of antibiotics • The sustainable use of antibiotics involves not only end users of antibiotics (prescribing veterinarians, farmers) but also regulatory bodies that are in charge to grant marketing authorization of veterinary drugs and up the line, those who are in charge to develop public policy and promote law • What is priority: free trading and exchanges or public health?

43. Possible solutions • Need of a pharmaco-economic assessment of the possible solutions • To reduce antibiotic use, the pricing should be increase, not decrease as it is the case of generics • Control pricing (national, EU?) or at least suppress all incentives as “back margin” • Establish a Pigouvian 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

44. Possible solutions • The objective of this study is to examine if a Pigouvian tax is an option for balancing the externalities and incentives for veterinary drug use. • A tax based in the expected costs of development new antibiotic substances may offer a practical option …

45. Possible solutions • Promote new and innovative antibiotics having as main feature to be without impact on the gut flora • Impact on gut flora is the main public health issue (food born pathogens, production and spreading of resistance genes from commensal flora) • Revenue from the Pigouvian tax invested in the research and development

46. Possible solutions • Revisit old antibiotics • Using current PK/PD paradigm to reassess dosage regimens • Probably leading to increase the doses in order to maintain indications OR to restraint the indications (lower breakpoints) to maintain the doses • Urgent need of clinical trials with placebo as control to assess the true value of old antibiotics, to justify treatment durations …with the goal to demonstrate superiority, not a non-inferiority

47. Conclusion • For veterinary medicine, the key issue for the antibiotic use is the public health and preservation of a rare societal resource by limiting the rapid development of resistance that is increased with the magnitude of antibiotic use. • Regarding this objective, marketing of generics to reduce pricing is counterproductive