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FDA/CVM International Workshop Minor-Use and Minor Species: A Global Perspective Rockville, Maryland, USA 7-8 October

FDA/CVM International Workshop Minor-Use and Minor Species: A Global Perspective Rockville, Maryland, USA 7-8 October 2004. Human Food Safety Issues Dr Kornelia Grein Head of Sector – Safety of Veterinary Medicines European Medicines Agency (EMEA). Points addressed: . What is the concern?

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FDA/CVM International Workshop Minor-Use and Minor Species: A Global Perspective Rockville, Maryland, USA 7-8 October

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  1. FDA/CVM International Workshop Minor-Use and Minor Species: A Global PerspectiveRockville, Maryland, USA 7-8 October 2004 Human Food Safety Issues Dr Kornelia GreinHead of Sector – Safety of Veterinary Medicines European Medicines Agency (EMEA)

  2. Points addressed: • What is the concern? • Approach in the EU • Data requirements for MUMS • Extrapolation of MRLs

  3. MUMS - Human Food Safety • Protection of consumer from harmful residues in food • MRLs and withholding periods • Data requirements and risk assessment approach • same as for major species/major uses? • or is deviation possible? • Consumer health must not be put in jeopardy

  4. Approach in the EU (1) Definition • No definition of minor species or minor uses in legislation • Definition minor species in CVMP guidelines Major species: • Cattle dairy and meat animals • Sheep (meat animals) • Pigs • Chickens (including laying hens) • Salmonidae Minor species (food producing) • Other ruminants • Sheep (dairy) • Other avian species (including laying animals) • Other fin fish species • Other mammalian species (e.g. horse, rabbit) • Honey bees

  5. Approach in the EU (2) • CVMP guidelines • Note for guidance on the establishment of maximum residue limits for minor animal species (EMEA/CVMP/153a/97) and for Salmonidae and other fin fish (EMEA/CVMP/153b/97) • Definition, assessment approach/extrapolation, data requirements for MRLs exclusively for minor species • Note for Guidance on Risk Analysis Approach for Residues of Veterinary Medicinal Products in Food of Animal Origin (EMEA/CVMP/187/00) • Definition, review assessment approach and further development of extrapolation, data requirements for extrapolations

  6. Establishment of MRLs • Approach to establish MRLs in EU very similar to JECFA approach • Target tissues: muscle, fat (+skin), liver, kidney; milk, eggs, honey (as appropriate) • First MRLs established for all food-producing species (penicillins, sulfonamides and tetracyclines) • Later on distinction of species as by JECFA • Specific data on residues / analytical method • Following completion of MRL assessments for all active substances used in EU for veterinary medicines in food animals in 1999, the CVMP reviewed approach considering wealth of data available  Note for Guidance on Risk Analysis Approach for Residues of Veterinary Medicinal Products in Food of Animal Origin (EMEA/CVMP/187/00)

  7. Data requirements • In legislation no distinction between major and minor uses and species MRL and MA dossier : • Pharmacological studies (pharmacodynamics, pharmacokinetics) • Single & repeated dose toxicity • Reproductive toxicity/teratogenicity • Mutagenicity • Carcinogenicity • Studies on other effects,e.g. • Immunotoxicity • Microbiological properties of residues • Observations in humans • Metabolism and residue kinetics • Pharmacokinetics • Depletion of residues • Routine analytical method specifications as agreed in VICH apply (not yet fully implemented)

  8. Data requirements • Certain reduction in data requirements if MRLs requested for minor species only (according to guideline EMEA/CVMP/153a/97) • Pharmacological studies: • no pharmacodynamics, study to establish oral bioavailability in place of pharmacokinetics • Repeated dose toxicity: • 2 species 28 days, or 1 species 90 days • Reproductive toxicity/teratogenicity: • One generation reprotox. study instead of 2-generation • Tests for teratogenicity/embryotoxicity • Mutagenicity: no deviation • Carcinogenicity: not required • Studies on other effects, e.g. • Immunotoxicity: not required • Metabolism and residue kinetics: no deviation • Routine analytical method: no deviation

  9. Data requirements Recent CVMP considerations on MUMS • Currently review of data requirements for minor uses and minor species for MRLs and MAs • No presentation of final conclusions possible at present, only information of considerations by working party MRLs • Repeated dose toxicity: • 28 days studies not of much value • Questioned, if only one 90 days study can be justified. • Reproductive toxicity/teratogenicity: • One generation reprotoxicity study not of much value • If study, should be 2-generation • Absence of study to be justified • Teratogenicity/embryotoxicity: VICH approach seems appropriate • Mutagenicity: VICH approach • Carcinogenicity: not required if criteria set would apply • Routine analytical method:largely similar to major species

  10. Data requirements Recent CVMP considerations on MUMS (contd.) • Considerations regarding MAs: • Toxicity data : see MRLs • Are there situations where withdrawal periods can be extrapolated from those for other species ? • Analytical method: Is fully validated method necessary? • Consultation of draft guideline expected begin 2005

  11. Extrapolation of MRLs Note for Guidance EMEA/CVMP/187/00 Extrapolation from major to minor species:

  12. Extrapolation of MRLs • In addition: If identical or similar MRLs were derived in cattle (or sheep), pigs and chicken (or poultry), MRLs can be extrapolated to all food‑producing species • Rationale: • Cattle (or sheep), pigs and chicken (or poultry represent major species with different metabolic capacities and tissue composition • according to extrapolation principles same MRLs can also be set for ovine, equidae and rabbits, i.e. an extrapolation is possible to all food producing animals except fish • Considering the CVMP guideline on the establishment of MRLs for Salmonidae and other fin fish, then also extrapolation to all food-producing animals incl. fish possible (provided that parent compound is acceptable as marker residue in fish) • Data for extrapolations to minor species: - confirmation of marker residue - proof of applicability of analytical method

  13. Implementation of EMEA/CVMP/187/00 • “Automatic” extrapolation (without applications) if possible to extend MRLs to all food-producing species • 15 substances eligible • For 3 substances analytical method did not fulfill requirements of NfG • CVMP recommended extension of existing MRLs to all food producing species for 12 substances in January 2002 Danofloxacin Difloxacin Enrofloxacin Erythromycin Florfenicol Flumequine Lincomycin Paromomycin Spectinomycin Tilmicosin Trimethoprim Tylosin

  14. Implementation of EMEA/CVMP/187/00 (contd.): • Further implementation plans : Extensions to additional species by extrapolation of MRLs upon applications from sponsors, and no “automatic” extrapolation without application and fee • However, not many applications for extensions received • CVMP considerations: • MRLs only first step in pathway to obtain marketing authorization and introduction of product to market • MRL could nevertheless provide incentive for industry to develop products • CVMP agreed to examine possibilities to establish MRLs for essential substances in certain species, where no alternatives are available without applications from sponsors

  15. Extrapolation of MRLs • Proposal to extrapolate MRLs for essential substances for sheep and goats as first step • Criteria • Essential for therapy • Old “lost” products • Fulfill requirements of EMEA/CVMP/187/00 • Substance list for consultation

  16. Extrapolation of MRLs Recommendations (December 2003): • Albendazole: to all ruminants, incl. milk • Febantel: to all ruminants, incl. milk • Fenbendazole: to all ruminants, incl. milk • Oxfendazole: to all ruminants, incl. milk • Oxyclozanide: to all ruminants, incl. milk • Thiabendazole: to goats, incl. milk • Amitraz: to goats, incl. milk • Cypermethrin: to all ruminants, incl. milk • Deltamethrin: to all ruminants incl. milk • Dexamethasone: to goats, incl. milk

  17. Extrapolation of MRLs Future: • Annex II substances: extension of species specific entries, where possible, upon request • Extrapolation of MRLs following applications from sponsor companies • Possibly similar actions as for substances to treat sheep and goats and extrapolations without applications for other species, if “essential

  18. Summary • Reduction of data requirements possible only to a very limited extent if MRL or MA exclusively for minor species • If MRL and MA for major species: extrapolation of MRLs; also some reduction of data for withdrawal periods and analytical method appears possible

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