Transcript Diapositive 1

NATIONAL
VETERINARY
SCHOOL
TOULOUSE
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
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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
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Human medicine: it is a political goal
(WHO, US, EU etc) to reduce pricing of
drugs by promotion of generics
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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
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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)
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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 :3040%.
• Antibiotics: >80%
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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
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Generics and antibiotic consumption
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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
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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.
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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.
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Number of ciprofloxacin trade names (black line)
and the median price per DDD (red line) and the
influence of the introduction of generics
Generics
Number of
trade names
Price
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The influence of the introduction of generics on the
total use of ciprofloxacin (black line) and median
price per DDD (red line)
Consumption
Generics
price
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Trends in the frequency of ciprofloxacin resistance among
E. coli urine (brown line) and the consumption of
ciprofloxacin (black line) from 1995 to 2005
Resistance
Consumption
Generics
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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
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Antibiotic generics in veterinary
medicine:
In veterinary medicine, we have
now first evidences that market
introduction of generics has
influence on antibiotic consumption;
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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.
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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.
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Influence of generics marketing on the
fluoroquinolone use (oral route) in poultry (20032008); national survey in France
Total
Generics
Pioneers
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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
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In: Clinical infectious deseases 2005 41 114-117
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Correlation between community use and the
number of trade names for oral-use agents for 6
antibacterial classes in EU
High consumption countries
Nb of trade names
Low consumption countries
Nb of trade names
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Use of fluoroquinolones in veterinary
medicine: Germany, DK, UK
From Hellmann: Assoc Vet Consult. SAGAM 2005
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Use of fluoroquinolones in veterinary
medicine: Eastern EU, Spain, Portugal
From Hellmann: Assoc Vet Consult. SAGAM 2005
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Generics for antibiotics (quinolones) :
conclusions
More generics/”me too”
Decrease relative price
Increase antibiotic consumption
(not true for all antibiotics)
Increase resistance
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Generics and misuse of
antibiotics
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Generics and misuse of
antibiotics
• Another possible undesirable
consequence of generic promotion is
the encouragement to use old rather
than more recent antibiotics.
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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?
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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.
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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.
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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.
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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
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Reasons to challenge old antibiotics in
veterinary medicine (tetracyclines)
AB: oral route
Proximal
G.I.T
1-F% =80-90%
Blood
Low AB
concentration in the
Target biophase
Efficacy?
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Food chain
Tetracyclins are
stable in enviroment
Résistance = public health concern
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Aggressive promotion for the
use of antibiotics
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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.
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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 antibiotics
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Generics, bioequivalence and
therapeutic equivalence of
antibiotics
Test
Reference
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Quality of Generics
(vancomycin, gentamicin, oxacillin)
•Bioequivalence does not imply in vivo
therapeutic equivalence when using the
neutropenic mouse tigh infection model;
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
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?
Generic 2
Generic 1
yes
yes
?
yes
Pionneer
Generic 3
No information on the substituability of
generics between them.
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Non-bioequivalence of various
trademarks of enrofloxacin in cow
Mexico
Sumano & al 2001 Dtsch tierärztl Wschr 108 281-320
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EMA facilitate introduction of generics by considering that the
withdrawal period is the same for the pioneers and generics if
bioequivalence is demonstrated
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Bioequivalence and the
problem of drug residues
• Bioequivalence studies in foodproducing animals are not
acceptable in lieu of residues
data: why?
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Definitions and statistics
associated to bioequivalence and
withdrawal time are
fundamentally different
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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"
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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
- 46
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
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Innovation: PK selectivity of antibiotics
G.I.T
AB: oral route
Proximal
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
0%
100%
Food chain
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
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Innovation: PK selectivity of antibiotics
G.I.T
Proximal
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
AB: IMroute
Food chain
Quinolones, macrolides
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
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Innovation: PK selectivity of antibiotics
Trapping or destruction of the antibiotic
G.I.T
Proximal
Distal
Gut flora
•Zoonotic (salmonella, campylobacter
•commensal ( enterococcus)
Efflux
90%
0%
Food chain
Quinolones, macrolides
IM
environment
Blood
Kidney
Biophase
Résistance = public health concern
Animal health
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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?
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Possible economical solutions
1.
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 or at least suppress all incentives
as “back margin”
Establish a Pigovian tax?
2.
3.
4.
•
•
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
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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
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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?
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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.
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