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ANTIMICROBIAL RESISTANCEHow to tackle an issue in the new legislative for
veterinary medicinal products
Lucie PokludováInstitute for State Control of Veterinary Biologicals and Medicines
Czech Republic
EPP Group Public Hearing, Brussells, 22.4.2015
Main motivations to adopt new rules for VMPs
• Improve availability, in particular for „limited markets“ • Reduce administrative burden for the veterinary
pharmaceutical companies
• Enhance innovation in veterinary medicine
• Strengthen internal market …while not reducing the quality, safety and
efficacy standards for veterinary medicinal products
Antimicrobial resistance:Two pillars
Example from practice: Dairy cows: ceftiofur (newer, last resort) x amoxicillin (older, first choice)
AMR: Prudent use warningsCeftiofur: •„Ceftiofur VMP“ selects for resistant strains such as bacteria carrying extended spectrum betalactamases (ESBL) => a risk to human health if these strains disseminate to humans. Therefore should be reserved for the treatment of clinical conditions which have responded poorly, or are expected to respond poorly (refers to very acute cases when treatment must be initiated without bacteriological diagnosis), to more narrow spectrum ATMs first line treatment. •Official, national and regional antimicrobial policies should be taken into account when the product is used. Increased use, including use of the product deviating from the instructions given in the SPC, may increase the prevalence of resistance to ceftiofur.•Whenever possible „ceftiofur VMP“ should only be used based on susceptibility testing.•Do not use as prophylaxis in case of retained placenta.•„Ceftiofur VMP“ is intended for treatment of individual animals. Do not use for disease prevention or as a part of herd health programmes. Treatment of groups of animals should be strictly limited to ongoing disease outbreaks according to the approved conditions of use.
Amoxicillin: ATM to be used based on susceptibility testing or knowledge of epidemiological situation in the herd.
Economy: Withdrawal period
Ceftiofur: Milk: zero daysMRL : milk: 100 µg/ kg
Amoxicillin: Milk: max 9 days (differs across VMPs )
MRL : milk: 4 µg/ kg
Antimicrobial resistance:Responsibilities & Stakeholders
Antimicrobial resistance:Risk assessment : Risk management
RA
RM
How we are going to use the new Regulation in practice in terms of AMR ?• Definition of antimicrobial resistance in the COM draft
– based on wild type resistance pattern – ECOFF values to be used as benchmark for regulatory actions
? What do we want to achieve by the new Regulation? Do we want to use ECOFFs for resistance assessment? Do we want to use the same criteria for VMPs evaluation in case of animal health, public health and the environment? What impact will be on innovations / new products development• COM draft does not indicate the goals to be achieved / brings
uncertainty
… We need to define clearly how the benefit : risk will be assessed for antimicrobial VMPs
AMR in the new regulation on VMPsMarketing authorisation
Benefits Risks Neutral
Clear requirement: antimicrobials prescription only medicines
Benefit:risk balance definition:Benefits: no longer „therapeutic benefit“
Data to support MA for antimicrobials:Consolidates requirements
Antimicrobials presented for use as performance enhancer in order to promote the growth of treated animals or to increase yields from treated animals cannot be granted a MA
BR not consistently used throughout the Regulation for outcome of assessment
Instructions to be included in the product literature (SPC, PI):Consolidates requirements
MRP/DCP – no dossier (data) available to CMSs for assessment
Ground for refusal MA: Where antimicrobial is reserved for treatment of certain infections in humans;Classification criteria / list of substances to be defined by the CommissionImpact difficult to evaluate (avaialability, innovation..)
GMP for active substances no longer requiredReduced requirements for QP in manufacturersGMP requirement for VMPs not explicitly stated
AMR in the new regulation on VMPsPost authorisation / Continuous benefit:risk
Benefits Risks Neutral
Extended data protection period for new antimicrobial VMPs:Will delay cheaper generics and thus reduce exposure of animals to the new compounds
Variations to the MA: Major reductions in quality variations foreseen – impact on S / E
Possibility to require post-authorisation studies in order to ensure that the benefit-risk balance remains positive with a view to the possible development of antimicrobial resistance.In line with the options provided under current legislation, but mentioned specifically for antimicrobials
SPC harmonisation:„group“ approach, administrative not evidence based, direct risks
Legal base for data collection system on sales and use
BUT: The regulation must be clear what data shall be collected and for such data will be used Establishment of such system – very costlyFinancial/administrative burden for governments and private sector Rules adopted by EP / Council
Union interests referral:to include free movement of products
Pharmacovigilance:Requirement significantly reduced, requirement for PSUR (period benefit :risk re-evaluation by MAH) has been waived -signal detection
AMR in the new regulation on VMPsUse of VMPs
Benefits Risks Neutral
Retail of antimicrobials by person qualified to prescribe:Only animals under their care in the amount needed for treatment
Wholesale distribution – no definition - risk for illegal activities
Internet sales Includes prescription only medicines
What is missing in the new legislationMarketing authorisation Post-marketing Use of VMPs
Clear reference to detailed benefit:risk methodology for assessment of VMPs (incl. Data to be submitted for fixed combinations, metaphylactic indications).Clinical trial parameters, in dossiers, that indicate performance enhancement or growth promotion should not be part of the benefit-risk balance of a veterinary antimicrobial marketing authorization.
Clear responsibility for the MAHs to ensure positive benefit:risk balance on a continuous basis – risk based PSURs and proactive pharmacovigilance by MAHs
Prophylactic use of VMPs shall be prohibitedRules for metaphylactic use should be defined
Risk based Target pathogens resistance monitoring programme: Allowing to asses trends in AMRPublic dataCo-financed by EU (as the zoonoses resistance monitoring programme)Shall also include establishment of standardised laboratory methods / interpretation criteria
Attending veterinarian shall be definedDetailed knowledge about the animals, clinical diagnosis
SPC shall include a clear statement of the benefit-risk that formed the basis of the marketing authorization
Obligation to follow instructions in the SPC
MSs to draft detailed guidelines on use of antimicrobial VMPs reflecting local conditions
Reference products for generics applications: reference products with a clearly positive benefit:risk balance should only be used as reference products
Role of veterinarians in decision making on use of antimicrobials to be definedGood husbandry practice, including regular visits by the vets
Main concerns:
• The new Regulation on VMPs as proposed by COM would lead to deterioration of Quality/Safety/Efficacy standards for VMPs with a direct negative impact on AMR.
• Main gaps identified as for:– Variations– SPC harmonisation – Reduced pharmacovigilance– MRP/DCP
• Post-marketing – in consequence to MA : NOT in line with „One Health“ Concept
• Proper balance is missing in terms of internal market and animal/public health/environmental protection
Restrictions
QSE of VMPsVMPs lifecycle
Innovation of VMPsOne Health / Responsible use of VMPs / Preventive veterinary medicine / Good
animal husbandry practices
