Medicines use in UK aquaculture. David Verner - Jeffreys Cefas Weymouth Laboratory

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1 Medicines use in UK aquaculture David Verner - Jeffreys Cefas Weymouth Laboratory

2 Veterinary Medicine : Definition Medicinal purpose : treating or preventing disease diagnosing disease contraception anaesthesia otherwise preventing or interfering with normal operation of a physiological function Medicinal product use by being administered (to animals) for a Medicinal Purpose

3 European Union and Veterinary Medicines The EU consists of 27 member states (with 6 candidate countries) Much of the law in this area also has EEA application (e.g. Norway) Since 1983 the very different medicines regimes have been in process of coordination This has produced a continuing series of changes Also moves for convergence with other WTO members. Eg VICH : trilateral (EU- Japan-USA) programme At a time when veterinary medicines legislation is becoming more restrictive

4 pharmakovigilence programmes Veterinary Medicines Regulations Veterinary Medicinal Products Directive 2001/82/EC (as amended) controls on VMP manufacture, authorisation, marketing, distribution and post-authorisation surveillance applicable in all European Member States In UK: implemented through Veterinary Medicines Regulations 2011 SI 2159 (VMR) (Revoked and updated annually) Veterinary Medicines Directorate In UK, controls manufacture and distribution VMP

5 MA routes Centralised procedure Applications to EMA, MAs valid in all EU Member States National Procedure applications made to VMD. MA valid in UK only Mutual Recognition procedure Apply to another MS to authorise where product already authorised in another MS (Reference Member State; in UK = VMD) Decentralised procedure Apply for new MA in more than one MS at same time

6 Three Scientific criteria Quality Safety: target animal, consumer and environment Efficacy

7 Quality Principally the chemistry and pharmacy Chemical nature, identity of excipients Stability, especially in relation to formulation and intended route of application (i.e. bath or in feed) Premix particle size and distribution

8 Safety (GLP) To consumer (principally MRL) To user - farm staff, feed medication etc. To target species (fish) To environment tiered EIA required May require ecotoxicology data

9 Efficacy For vaccines - RPS Composition (adjuvant) Dose (antigen) Duration of immunity For therapeutants Dose titration Duration (of therapy)

10 Guidelines Rules Governing Medicinal Products in the European Community Volume IV Establishment of maximum residue limits (MRLs) for residues of veterinary medicinal products in foodstuffs of animal origin Volume VII Guidelines for testing of veterinary medicinal products CVMP guidelines: target animal safety VICH guidelines: residue depletion EC Pharmacopaeia: Vaccine Testing Monographs

11 Antibacterial agents licensed for use in fish in the United Kingdom 2012 (source VMD Product Information database 12/10/2012) Generic name Trade name Fish species* Dose (mg/kg/day)** Withdrawal period (degree days) Oxytetracycline Aquatet AS, RT Florfenicol florocol AS, RT, BT AS Amoxycillin trihydrate Vetremox AS *AS = Atlantic salmon, RT = rainbow trout, AC = Arctic char, BT = brown trout ** usual duration of treatment is 7-10 days Saprolegnia treatments : bronopol (Pyceze)

12 Use of antimicrobial agents in salmon farming in Norway Kg antibiotic Salmon (x1000 metric tonnes) Sulphamerazine Tribrissen OTC Sodium oxolinate Oxolinic Nitrofurazolidone Flumequine Florphenicol Salmon production 0 Year Norwegian Ministry of Fisheriesand Norwegian Central Veterinary Laboratory, 1997

13 Antibiotic use on Scottish salmon farm A 1200 mg antibiotic /Kg production YEAR (source Marine Laboratory Aberdeen: Annual Production Survey of Scottish Fish Farms)

14 Antiparaciticides with MA 2012 Generic name Trade name Fish species* Dose Withdrawal period (degree days) Deltamethrin AMX AS, RT 2 µg /l 5 Teflubenzuron Calicide Teflubenzuron AS, RT 10 mg/kg/day 7 days Cypermethrin Excis AS 5 µg /l 40 Emamectin benzoate Slice AS, RT 50 µg/kg/day 0 Azimethos Salmosan AS 0.1 µg /l 24h *AS = Atlantic salmon, RT = rainbow trout, AC = Arctic char, BT = brown trout

15 Fish Vaccines Licensed in UK 2102 Name Purpose Route MA holder Aqua Vac ERM ERM Dip or spray Intervet Uk Alphaject 2-2 Furunculosis & IPN IP Pharmaq As Birnajen forte Furunculosis & IPN IP Novartis Norvax Comapct PD PD IP Intervet UK Ermogen ERM Dip, spray or ip Novartis Aqua Vac ERM ERM Dip Intervet UK AquaVac Oral ERM Oral Intervet UK AquaVac Relera ERM (BT2) Dip or IP Intervet UK Aqua Vac Furovac Furunculosis Dip, ip Intervet UK Aqua Vac FNM Furunculosis ip Intervet UK AquaVac Vibrio Oral Vibriosis Oral Intervet UK Furogen Immersion Furunculosis Dip Aqua Health Furogen Injection Furunculosis ip Aqua Health Aqua Vac Vibrio Vibriosis Dip or spray Intervet UK Aqua Vac Vibrio-Furovac IJ Vibriosis and furunculosis ip Intervet UK

16 Costs MRL and MA 2011 Centralised Procedure Fees (base fees): Veterinary Pharmaceuticals For establishing an MRL 63,400 Full MA (EU wide) application 127,000 Veterinary Immunologicals Full MA application 63,400 National procedure UK full MA pharmaceutical application 24,900 UK full MA immunological 19,190

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18 EU concern: availability of veterinary medicines 2000: all products with no MRL set withdrawn from market Created a crisis in the sector Number of measures instigated Changes in rules for MRL (extrapolation from others species etc, streamlining) Consultations: e.g. Better regulation of veterinary pharmaceuticals Review of MUMS legislations Introduction of Limited Marketing Authorisations

19 Off label use : Cascade Level 1 UK authorised VMP same species /another condition use in another species. Level 2 UK authorised human medicine or VMP authorised elsewhere in EU (Special Import Certificate). Level 3 Specially prepared (extemporaneous preparation) medicine includes Special Treatment Certificates. Food producing animals: approved under EC Reg 37/2010 (MRL)+ minimum withdrawal period specified (500 daydegrees in fish)

20 Salmonidae or Salmo salar? CVMP Position Paper EMEA/CVMP/477/03 : CVMP concluded that Salmonidae should be considered as major species. MUMS guidelines : Following subsequent consultation of the CVMP guidelines on data requirements for MUMS products, the CVMP agreed to change this classification as follows: Salmon should be considered a major species, however other species of the Salmonidae family such as rainbow trout should be considered minor species. Seeking clarification from VMD on their interpretation Potentially allows rainbow trout, brown trout and arctic char to be treated as minor species

21 Minor use/minor species (MUMS) Guidelines on pharmaceuticals safety, residue data, efficacy and immunologicals all recently revised for MUMS authorisations For some immunological products for salmon (Moritella viscosa, Vibrio salmonicida) characterised as minor use... Generally less onerous data requirements Significantly reduced fees 50% MRL applications (-90% for SMEs)

22 Autogenous and Emergency vaccines Manufactured from pathogens or antigens obtained from an animal/s and used for the treatment of that animal and/or other animals within the same epidemiological unit or in the same rearing chain Widely used in UK aquaculture industry E.g control of ERM in salmon Vibriosis in cod farming VMD reserve the right, in the event of serious epizootic disease outbreaks, to permit the marketing and use of immunological products without an MA

23 Established use chemical treatments Broad group substances with long history routine use Hydrogen peroxide, Chloramine T, formalin, salt Technically illegal to market or apply products for control, of disease non authorised products However, such substances typically listed under Biocides Regulation (EU) No 528/2012 / REACH regulations etc. Formaldehyde listed under EC Regulation 1451/ Annex II.

24 Immunomodulators Probiotics Other products Technically could be defined as either medicines or feed additives (EU Regulation 1831/2003) Considered by industry to be valuable adjuncts to conventional medicies Some substances (eg β 1-3 glucans) naturally present in yeast etc. LRP? Caution with claims made?

25 Future prospects Continued Industry adaptation to reduced range of pharmaceutical treatments. Evidence: antimicrobial useage decline Generic bulk chemical treatments? One possible solution: generation of Product Master Files for product safety (target animal, residue depletion & EIA) and efficacy at public expense : open access. Continued promotion of vaccine devt; incl. use of new technologies (recombinant subunit, DNA etc.) Further explore MUMS and Limited Marketing Authorisations Mixing inspections/authorisations: FHI?

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27 Questions referred to VMD Q1. In the context of animal welfare and specifically the availability of medicines, what progress has been made to ensure small sectors like aquaculture have appropriate access to the medicines they need to care for their animals? Q2. How does DG SANCO view the progress on the revision of EC Regulation 1451/2007 on the placing of biocidal products on the market, with specific reference to Product type 3: Veterinary hygiene biocidal products like Formalin used in aquaculture for the control of Saprolegnia?

28 Residues Directive 96/23/EC was enacted in April 1996 and was brought into action in January 1998 The intention of Regulation 2377/90 was to control veterinary drug residues in food Directive 96/23/EC introduced fish meat, poultry meat, milk and honey into Member States monitoring programmes