Generics of antibiotics: Are you sure of what you get?
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1 Generics of antibiotics: Are you sure of what you get? Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Health Science Sector Université catholique de Louvain Brussels, Belgium 22 January 2013 Hôpital Erasme, Bruxelles 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 1
2 Disclosures and slides availability Research grants Theravance, Astellas, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), and Walloon and Brussels Regions Speaking fees Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma, AstraZeneca Decision-making and consultation bodies General Assembly (current) and steering committee (part) of EUCAST European Medicines Agency (external expert) US National Institutes of Health (grant reviewing) Slides: Lectures 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 2
3 Whay are generics knocking at your doors? Generics are cheaper! 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 3
4 Whay are generics knocking at your doors? Lead generic companies resort to multiple strategies for growth These include applying for generic approvals with Food and Drug Administration (FDA) and European Medicines Agency (EMA); merger and acquisitions; developing a strong and innovative generic drug pipeline; improving infrastructure to enhance manufacturing and R&D capabilities; new product launches, and geographic expansion January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 4
5 A well known antibiotic in Belgium Before patent expiration 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 5
6 1 2 A well known antibiotic in Belgium After January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 6
7 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 7
8 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 8
9 The EU Directive * * Legislative act of the European Union that is then translated into country-specific laws for actual implementation, which may vary (in details) between countries (vs regulations that are self-executing and do not require local adaptations) ummaries/internal_market/si ngle_market_for_goods/phar maceutical_and_cosmetic_p roducts/l21230_en.htm 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 9
10 The EU Directive By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of preclinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community. generic medicinal product shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines. 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 10
11 EU rules: what needs to be supplied for non-biological product Data for Modules 1, 2 and 3 * together with data showing bioavailability and bio-equivalence with the original medicinal product Special attention needs to be paid to: the grounds for claiming essential similarity; a summary of impurities (with an evaluation of these); an evaluation of the bio-equivalence studies or a justification why studies were not performed; an update of published literature relevant to the substance and the present application; every claim not known from or inferred from the properties of the medicinal product should be discussed and substantiated by published literature and/or additional studies. equivalence of safety and efficacy properties of different salts, esters or derivatives of an authorised active when he claiming essential similarity. * Module 1 = administrative information: Module 2 = Summaries: Module 3 = Chemical, pharmaceutical and biological information for medicinal products containing chemical and/or biological active substances; Module 4 = non-clinical reports; Module 5 = clinical reports 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 11
12 The US Law FDA works along the provisions of the Drug Price Competition and Patent Term Restoration Act ("Hatch-Waxman Act" [Public Law ]), which encouraged the manufacture of generic drugs Marketers of generic drugs can file an Abbreviated New Drug Application (ANDAs) to seek FDA approval 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 12
![Act" [Public Law 98-417]), which encouraged the manufacture of generic drugs Marketers of generic drugs can file an](/docs-images/42/1896658/images/page_12.jpg "Abbreviated New Drug Application (ANDAs) to seek FDA approval 22 January 2014 Séminaire de microbiologie-maladies")
13 US "Abbreviated New Drug Application" reviatednewdrugapplicationandagenerics/default.htm 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 13
14 FDA requirements in a nutshell * Published literature (for data for which the applicant has no right of reference to the original raw data supporting the application) FDA's findings (safety and effectiveness of the already approved drug) Comparison with the original NCE/NME (New Chemical Entity/New Molecular Entity) application for dosage form, strength, route of administration substitution of an active ingredient in a combination product or change such as different salt, ester, complex, Bioequivalence study The proposed product does not need to be shown to be clinically better than the previously approved product; however, the application should not be used as a route of approval for poorly bioavailable generic drug products unable to meet the standards for bioequivalence. * 505 (B) (2) Application (Guidance to Industry) 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 14
15 FDA approved generic drugs: "Orange book" * * 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 15
16 FDA approved generic drugs: "Orange book" * The list is 3 pages long * 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 16
17 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 17
18 Bioequivalence: principles Bioequivalence is an accepted surrogate for therapeutic equivalence 1 (including for branded drugs when the mareketed form differs from the form used in development ) 2 Primary metrics are 1,3 AUC (area under the plasma concentration-time profile of the active substance) extent of absorption C max (the maximum plasma concentration of the active substance) extent and rate of absorption T max (the time at which C max is reached) rate of absorption 1. Hauschke et al. Bioequivalence Studies in Drug Development Methods and Applications, John Wiley & Sons Ltd. (UK), Benet LZ: Understanding bioequivalence testing. Transplant.Proc. 31 (Suppl 3A): 7S-9S, Niazi SK: Handbook of Bioequivalence Testing, Drugs and the Pharmaceutical Sciences, vol. 171, Informa Healthcare (New York), January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 18
19 C max T max 5 C max 4 concentration (mg/l) time (h) T max 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 19
20 AUC 5 C max 4 concentration (mg/l) 3 2 AUC time (h) T max 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 20
21 What if the absorption is decreased? 5 4 C max concentration (mg/l) AUC time (h) 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 21
22 What if absorption is delayed? 5 C max 4 concentration (mg/l) 3 2 but AUC is = time (h) T max 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 22
23 Criteria of bioequivalence (EMA* / FDA**) Calculate the 90% confidence interval around the geometric mean ratios of both AUC and C max for Test (generic) and Reference (innovator). The 90% confidence intervals should, in most cases, be within the acceptance limits. 90 % CI around point estimate ratio Notes: 1. if both AUC and C max are within range, the generic should have the same bioavailability than the reference 2. statistical evaluation of T max only makes sense if there is a clinically relevant claim for rapid release or action or signs related to adverse effects (see next slide) 3. For drugs with narrow therapeutic index, EMA recommends "tightened acceptance inervals, Health Canada requires , but FDA accepts * Guideline to the Investigation of Bioequivalence, London, 20 January Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** ** Guidance for Industry (BIOEQUIVALENCE GUIDANCE) - Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 23
24 If absorption is markedly delayed, you also have a lower initial AUC fast 4 concentration (mg/l) 3 2 concentration (mg/l) 3 2 slow time (h) time (h) 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 24
25 Additional criteria for early AUC (EMA) * concentration (mg/l) 3 2 concentration (mg/l) time (h) time (h) Use the partial AUC truncated at the population median of T max for the reference formulation for for products where rapid absorption is of importance * Guideline to the Investigation of Bioequivalence, London, 20 January Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 25
26 Unsolved problems with PK-based bioequivalence (application to antibiotics) Is PK equivalence leading to pharmacological equivalence? in vitro testing (MIC, MPC, impact on hetero-resistance) PK/PD models (animals) Clinical studies (?) What about intravenous forms? (that, by definition, are not amenable to conventional bioequivalence studies) What about dissolution times (critical in a nursing environment) stablility (penems, e.g.) impurities (do you like them?) 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 26
27 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 27
28 MIC determinations (piperacillin) Using the incremental MIC assay (Jones et al. Diagn Microbiol Infect Dis 2008; 61:76 79). Moet et al. Diagnostic Microbiology and Infectious Disease 2009;65: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 28
29 MIC determinations (meropenem) MICs determined by arithmetic dilutions for strains displaying MICs ranging from to 128 mg/l (geometric values) susceptible strains (MIC 2 mg/l) intermediate strains (2 MIC < 8 mg/l) resistant strains (MIC > 8 mg/l) MIC (% meronem value) MIC (% meronem value) MIC (% meronem value) Hospira Sandoz Fresenius brand 50 Hospira Sandoz Fresenius brand 50 Hospira Sandoz Fresenius brand mean = SD= mean= SD= mean = SD= Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 29
30 MIC determinations (vancomycin) Fujimura & Watanabe J Infect Chemother (2012) 18: MICs were often higher than for the reference product 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 30
31 Zone diameters (oxacillin) Rodriguez et al. BMC Infectious Diseases 2010, 10: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 31
32 Post-exposure hetero-resistance (vancomycin) unexposed ATCC strain recovered from failed vancomycin treatment Rodriguez et al. Antimicrob Agents Chemother. 2012; 56: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 32
33 Post-exposure hetero-resistance (vancomycin) unexposed ATCC strain recovered from failed vancomycin treatment Rodriguez et al. Antimicrob Agents Chemother. 2012; 56: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 33
34 Resistance frequencies after in vivo exposure (vancomycin) Rodriguez et al. Antimicrob Agents Chemother. 2012; 56: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 34
35 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 35
36 Vancomycin: evidence of non-equivalence in a dose-response mouse tight model (fauc/mic) Neutropenic tight mouse model Vesga et al. Antimicrob Agents Chemother. 2010; 54: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 36
37 Oxacillin: evidence of non-equivalence in a dose-response mouse thight model (total dose) Neutropenic tight mouse model Rodriguez et al. BMC Infectious Diseases 2010, 10: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 37
38 Gentamicin: evidence of non-equivalence in a dose-response mouse thight model (total dose) Neutropenic tight mouse model Zuluaga et al. PLoS ONE 2010; 5: e doi: /journal.pone January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 38
39 Gentamicin: evidence of non-equivalence in survival in the neutropenic mouse model Neutropenic tight mouse model 2 h post-infection treatment 6 h post-infection treatment Zuluaga et al. PLoS ONE 2010; 5: e doi: /journal.pone January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 39
40 Vancomycin: complete equivalence in the rabbit endocarditis model Antimicrob Agents Chemother Mar;57(3): PMID: ; PMCID: PMC January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 40
41 Vancomycin: complete equivalence in the rabbit endocarditis model Antimicrob Agents Chemother Mar;57(3): PMID: ; PMCID: PMC T0: no antibiotic T1 T6: generics of vancomycin Differences in terms of no. of organisms in vegetations 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 41
42 Metronidazole: complete equivalence in a dose-response animal model (AUC/MIC) Agudelo & Vesga, Antimicrob Agents Chemother. 2013; 56: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 42
43 Clinical alerts (efficacy and safety)? J Pharmacol Pharmacother Dec;4(Suppl 1):S January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 43
44 Clinical alerts (efficacy and safety)? J Pharmacol Pharmacother Dec;4(Suppl 1):S January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 44
45 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 45
46 Dissolution of amoxicillin Afr Health Sci Jun;13(2): doi: /ahs.v13i2.25. PMID: ; PMCID: PMC January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 46
47 Dissolution of amoxicillin Afr Health Sci Jun;13(2): doi: /ahs.v13i2.25. PMID: ; PMCID: PMC January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 47
48 Dissolution of meropenem (Japan) Fujimura & Watanabe J Infect Chemother (2012) 18: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 48
49 Crystals size of meropenem (Japan) Fujimura & Watanabe J Infect Chemother (2012) 18: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 49
50 Dissolution of meropenem in Belgium Drug concentration : 50 mg/ml (~ solution used for infusion) gentle manual shaking followed by turbidity measures; room temperature manual gentle shaking Turbidity (% initial value) Meronem Hospira Sandoz Fresenius Time to reach minimal turbidity (% Meronem value) Time (sec) 100 Meronem Hospira Brand Sandoz Fresenius Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 50
51 Dissolution of meropenem in Belgium Drug concentration : 50 mg/ml (~ solution used for infusion) gentle manual shaking followed by turbidity measures; room temperature manual gentle shaking Turbidity (% initial value) Meronem Hospira Sandoz Fresenius Time to reach minimal turbidity (% Meronem value) Time (sec) 100 Meronem Hospira Brand Sandoz Fresenius Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 51
52 Are nurses happy with generic meropenem (in Belgium)? dissolution time 180 Repeated Measures ANOVA P value P value summary ns questionnaire - solubilisation Repeated Measures ANOVA P value P value summary ns seconds seconds MERONEM FRESENIUS SANDOZ HOSPIRA 0 MERONEM FRESENIUS SANDOZ HOSPIRA Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 52
53 Impurities 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 53
54 Impurities in ciprofloxacin Trefi et al. Journal of Pharmaceutical and Biomedical Analysis 44 (2007) January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 54
55 Instability and release of coloured compounds with meropenem are you happy with the colour? Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 55
56 Impurities in meropenem: coloured compounds OD - 24 C OD - 37 C OD (410 nm) Meronem Hospira Sandoz Fresenius OD (410 nm) Meronem Hospira Sandoz Fresenius incubation time (hours) incubation time (hours) Van Bambeke et al., in preparation 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 56
57 True content and release: the colistimethate/colistin problem 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 57
58 1. HPLC True content and release 1. colistimethate diversity Atlantic Forest 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 58
59 1. HPLC of colistimethate True content and release 2. colistine release Atlantic 2. Release of colistin Forest 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 59
60 Substandard drugs in the world? Figure 1. Examples of recent accounts of substandard drugs around the world Johnston & Holt. Substandard drugs: a potential crisis for public health. Br J Clin Pharmacol Nov 29. doi: /bcp [Epub ahead of print] PubMed PMID: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 60
61 What shall we discuss? 1. The EU and US legal framework 2. What is bioequivalence (for a generic)? 3. Microbiological equivalence? potency, heteroresistance, selection of resistance 4. Pharmacodynamic equivalence? PK/PD animal models, clinical alerts 5. Dissolution, impurities/instability, true content, "substandard drugs" 6. Over-consumption of "low cost" antibiotics? 7. Economic considerations in antibiotic discovery, development and use 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 61
62 A Journey to the statins in Belgium. introduction des génériques de la simvastatine Dépenses DDD patients Tous ces patients ont-ils vraiment besoin d'une statine? Goed voor de begroting! Source: INAMI / RIZIV 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 62
63 "Low cost antibiotics" and "prudent use" The sour Danish experience consumption Jensen et al. J Antimicrob Chemother 2010; 65: January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 63
64 Antibiotic reimbursements in Belgium millions of DDD/year anti-infectives for systemic use (ATC level J) year Source: Belgian National Institute for Sickness and Invalidity Insurance "Tableaux de bord pharmaceutiques: Délivrances pharmaceutiques dans le secteur ambulant année 2012" Last accessed: 20/01/ January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 64
65 Antibiotic reimbursements in Belgium millions of DDD/year anti-infectives for systemic use (ATC level J) year Source: Belgian National Institute for Sickness and Invalidity Insurance "Tableaux de bord pharmaceutiques: Délivrances pharmaceutiques dans le secteur ambulant année 2012" Last accessed: 20/01/ January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 65
66 A recent economic US study about "free of charge antibiotics" A "natural experiment" in which Meijer, a popular Midwestern retail chain, offered 14-day supplies of certain generic oral antibiotics free of charge to customers with prescriptions from October 2006 (about 2 millions prescriptoins analayzed from 2004 trough 2008) We find that the program increased the filled prescriptions of covered (free) antibiotics while reducing those of not-covered (paid) antibiotics, with an increase in overall antibiotic prescriptions. 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 66
67 The situation may be worse in veterinary medicine 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 67
68 The situation may be worse in veterinary medicine In France, introduction of generics of fluoroquinolones increased their use by 30% in turkey (n=5500) production and 50% in chicken broiler (n=7000) production. The level of resistance in Spain where cheap generics are available is associated with a higher use of fluoroquinolones in poultry and pigs vs Germany, UK, or Denmark where prices are higher and practice better controlled Generic drug promotion in veterinary medicine is not consistent with the general objective of Public Health authorities to restrict the use of antibiotics in veterinary medicine 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 68
69 A spiral to death (in Belgium)? For antibiotics and antifungals, if a medical doctor or a dentist prescribes for an acute treatment: under the name of the active compound: the rules of prescription under INN (*) are of application (delivery of the cheapest preparation available) under a trade name: as from 1 st Mai 2012, the pharmacist must deliver the product available in the group of «the cheapest drugs». Official text in French available at: (last accessed: 7 November 2013) The drug acquisition cost for the treatment of a community acquired pneumonia following the recommandations of BAPCOC (**) (amoxicillin [3 g per day in 3 administrations for 5 to7 days] is only (ex-factory price: 7 ) Source: Belgian "Répertoire commenté des médicaments" available at (last accessed: 7 November 2013) * INN: International International Nonproprietary Name ** BAPCOC: Belgian Antibiotic Policy Coordination Committee 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 69
70 A spiral to death (in Belgium)? For antibiotics and antifungals, if a medical doctor or a dentist prescribes for an acute treatment: under the name of the active compound: the rules of prescription under INN (*) are of application (delivery of the cheapest preparation available) under a trade name: as from 1 st Mai 2012, the pharmacist must deliver the product available in the group of «the cheapest drugs». Official text in French available at: (last accessed: 7 November 2013) The drug acquisition cost for the treatment of a community acquired pneumonia following the recommandations of BAPCOC (**) (amoxicillin [3 g per day in 3 administrations for 5 to7 days] is only (ex-factory price: 7 ) Source: Belgian "Répertoire commenté des médicaments" available at (last accessed: 7 November 2013) This infernal spiral (to low prices) explains why innovators leave the field * INN: International International Nonproprietary Name ** BAPCOC: Belgian Antibiotic Policy Coordination Committee 22 January 2014 Séminaire de microbiologie-maladies infectieuses - Université libre de Bruxelles 70
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