Transcript Diapositive 1 - Physiologie et Thérapeutique Ecole Véto Toulouse

AAVPT/ECVCP Workshop on Bioequivalence Issues in Veterinary Medicine
Potomac, June 2010
Consequences of generics marketing on the
antibiotic consumption and on the spread of
resistance:
facts and hypotheses
A. Bousquet-Mélou & P.L. Toutain
National Veterinary School, Toulouse, France
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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 of antimicrobials
3. 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?
1. to cut health-care
expenses for the benefit
of consumer, healthcare
services insurance
companies and public
organizations aiming to
guarantee social
protection
2. To facilitate drug access
for the poorest world
populations
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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
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Change in the Average Relative Price of a Drug as the
Number of Generic Versions Increases.
Introduction of generics sharply decrease drug pricing
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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?
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Justifications to promote
marketing of generics in
veterinary medicine ?
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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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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
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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%
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Generics in the Animal Health Industry:
Opportunities or Threats ?
But what about antibiotics, generics and public health?
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The case of antibiotics
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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 ?
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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 ?
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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)
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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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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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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 isolates (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 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
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Antibiotic generics in veterinary
medicine:
In veterinary medicine, we have
now first evidence 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 about 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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Resistance and use of veterinary
quinolones in EU
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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
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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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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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?
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Reasons to challenge old antibiotics in
veterinary medicine
1. 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….)
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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Possible solutions
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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.
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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
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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?
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Possible 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 (national, EU?) or at least suppress all
incentives as “back margin”
4.
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
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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 …
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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
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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
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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
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