1. An agency of the European Union Presented by: Kornelia Grein Role of VICH and VICH guidelines in marketing authorizations 2 nd VICH Outreach Forum meeting, Washington D.C., 19-20 February 2013

2. 2 Principles of a marketing authorization Role authorities / role VICH Technical data required for a marketing authorisation and their role for assessment –Quality –Safety –Efficacy VICH guidelines available Conditions of a marketing authorization Issues addressed

3. Role of VICH guidelines 3 Principles for marketing authorizations for veterinary medicines (1/5) Before a veterinary medicinal product can be sold or used, it should be authorized by the country/region where it will be used Marketing authorization (or ‘registration’ or ‘licence’) : Approval by the responsible authority in the country/region concerned that the product can be sold and used A marketing authorization includes details of the product. Related to data provided and outcome of assessment of application.

4. 4 Details/conditions of marketing authorization: –Name of product –Name of active substance, strength –Animals for which product can be used –Indications for use –Dose and duration of treatment –Conditions of use (e.g. storage conditions, shelf life, withdrawal period, instructions for safe use / instructions for safe disposal of waste) –Any precautions or warnings for safe use, including possible contraindications. Details and instructions for use are part of labelling and package leaflet of the product Principles for marketing authorizations for veterinary medicines (2/5)

5. Role of VICH guidelines 5 Principles for marketing authorizations for veterinary medicines (3/5) Regulatory system needs to be established by governments for the authorization and control of veterinary medicinal products. The company that will bring the veterinary medicine on the market (also called sponsor or applicant) must submit an application to the responsible authority in the country concerned in order to obtain a marketing authorization (or registration or licence) The application is accompanied by a package of data on the quality, safety and efficacy of the veterinary medicinal product. (This data package is often called ‘dossier’ or ‘application’).

6. Role of VICH guidelines 6 Principles for marketing authorizations for veterinary medicines (4/5) Assessment of application and data submitted is performed by responsible regulatory authority in country where product is intended to be marketed In general after initial assessment questions to applicant/sponsor arise Once all questions have been satisfactorily answered: –Benefit - Risk balance –No risks have been identified that would outweigh the efficacy and other benefits of the veterinary medicinal product –Appropriate risk mitigation measures, e.g. warnings The responsible authority issues a marketing authorization, with specific conditions of use

7. Role of VICH guidelines 7 Principles for marketing authorizations for veterinary medicines (5/5) As the process of assessing all scientific data requires a large amount of resources and to avoid unnecessary repetition of animal testing, countries may wish in some instances to rely on assessments already carried out for the same medicine by the authorities in other countries, at least for some parts of the dossier, e.g. the documentation regarding food safety (MRLs). The VICH regions also permit derogation from some studies in particular situations, e.g. off-patent or end of regulatory data protection period (generics|), ‘Well-established use’ / bibliographic applications. Countries may also chose to work together and share work or accept mutually assessments. Decision of countries, what is most suitable for them.

8. Role of VICH guidelines 8 Role of VICH guidelines in marketing authorization application VICH = International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products Technical requirements for registration (or marketing authorization) = Data to be provided to the responsible authority for assessment and decision on application for registration Data on Quality, Safety and Efficacy –For both pharmaceuticals and vaccines, other biologicals Examples of data for a marketing authorization for a veterinary medicinal product is given in next slides

9. 9 Marketing authorization application

10. 10 Marketing authorization application No VICH “Common Technical Dossier” as for medicines for human use by ICH Example of an outline for a dossier is described in Annex III to the document “VICH and its role in providing harmonised data requirements to support the authorisation of veterinary medicinal products” (VICH/10/008) Defining the outline contents of a dossier is the responsibility of countries/authorities Harmonised VICH guidelines describing data requirements for specific studies available for large parts of a dossier

11. 11 Administrative information Name of the product, name of the active substance(s), pharmaceutical form. Description of how the finished product appears when it is brought onto the market. Who is responsible for application/product? Name and contact details of the applicant. Where and by whom is the veterinary medicinal product produced? Where and how the active substance? Information of manufacturing site. Do conditions of manufacturing of finished product and active substance(s) ensure safety and efficacy of product? Good Manufacturing Practice (GMP)? Inspections?

12. 12 Technical data for MA and their role for assessment: Quality

13. 13 Technical data for MA and their role for assessment: Quality (1/4) Aim: to assess components, manufacturing, and final product so that product has appropriate quality to ensure safety and efficacy during entire lifecycle from production to end of shelf-life Quality is essential element for assessment of products; Quality has to be assessed for each product anew; “Vulnerable” to changes in processes. Variations during life of product Potential quality defects Hazards/risks of inadequate quality: e.g. impurities, degradation products, non-compatibility of components: may have consequences on safety and/or efficacy

14. Role of VICH guidelines 14 Technical data for MA and their role for assessment: Quality (2/4) Quality documentation (14 VICH GLs): Composition of the product (active + excipients, for immunologicals also adjuvants, if appropriate) Method of preparation: manufacturing method, in-process control tests and validation incl. batch analysis Control of starting materials: Active substance(s): specifications, impurities in the starting material, suitability of the manufacturing method, stereoisomerism, where relevant, and stability Excipients: specifications, suitability and safety data, where appropriate –Active and excipients: also important: compliance with Pharmacopoeia standards, or other standards.

15. Role of VICH guidelines 15 Technical data for MA and their role for assessment: Quality (3/4) Quality documentation (contd.)(14 VICH GLs) Packaging material (immediate packaging): specifications and suitability Control tests on intermediate products Control tests on finished product (General characteristics, max. deviation of active, degradation?, assay of excipient components, safety tests :  establishes if product can be produced with adequate quality Stability of the finished product :  establishes storage conditions, shelf life

16. 16 Quality (4/4) Outcome of assessment for benefit – risk assessment of product, marketing authorisation conditions Result of quality testing MA conditions, stated in product literature: –Information on composition of product –Storage conditions, shelf life Quality data and assessment necessary for all products: new products and generics.

17. Overview of VICH guidelines 17 VICH guidelines available – Quality –GL 1: Validation of analytical procedures: definition and terminology –GL 2: Validation of analytical procedures : methodology –GLs 3, 4, 5, 8: Stability new active substances and products, dosage form, photostability, premixes –GLs 10, 11, 18: Impurities new active substances, products, residual solvents –GLs 39, 40: Test procedures and acceptance criteria for new active substances and products: Chemical Substances, Biotechnological/Biological Veterinary Medicinal Products –GL 45: Bracketing and matrixing design –GL 51: Statistical evaluation of stability data

18. 18 Role of data for assessment of MA: Safety

19. 19 Technical data for MA and their role for assessment: Safety (1/7) Aim: to assess risk to –target animals; –for food producing animals safety to consumer of food derived from animals –to human user of product and persons that come into contact (e.g. vet, farmer, animal owner, children hugging pet); –impact for the environment; –for antimicrobials: risk of resistance development For benefit – risk assessment Identify appropriate conditions of use; necessary risk mitigation measures / warnings in product literature

20. 20 Technical data for MA and their role for assessment: Safety (2/7) Safety documentation (16 VICH GLs) Pharmacology (pharmacodynamics, pharmacokinetics) Toxicology (Single dose toxicity, Repeated dose toxicity (2X), Reproductive toxicity including teratogenicity, Genotoxicity, Carcinogenicity, other) Residue studies (Metabolism and residue kinetics, Pharmacokinetics, Depletion of residues, Analytical method) Target animal safety Safety of users Environmental impact assessment (Phase I and Phase II) Antimicrobial safety (Microbiological ADI, Data to assess antimicrobial resistance)

21. 21 Technical data for MA and their role for assessment: Safety (3/7) Consumer safety Aim: MRLs, withdrawal periods Pharmacology data, toxicity data (data on active substance):  No Observed (Adverse) Effect Level (NO(A)EL, Acceptable Daily Intake (ADI), MRL Data for microbiological ADI, where approp. (data on active substance):  ADI, MRL Pharmacokinetics, residues depletion studies, analytical method: MRL (active substance), withdrawal period (residue depletion study with product, formulation/excipients) Also important to consider: Codex MRLs, MRLs of other countries.

22. 22 Technical data for MA and their role for assessment: Safety (4/7) User safety Aim: to assess potential risk to user, for benefit - risk assessment and risk mitigation measures, where appropriate Toxic effects are related to type and extent of human exposure to product Level of detail/studies required are linked to type of product and exposure. Usually the available toxicity data are adequate for assessment è Appropriate safety advice or warnings/risk mitigation measures to users (e.g. wear gloves; if accidental self injection occurs consult doctor immediately; not to be used by pregnant women; children should not get into contact with treated animal for x days). Child proof closure

23. 23 Technical data for MA and their role for assessment: Safety (5/7) Environmental impact assessment Aim: Assess potential impact / risk of product on environment for decision on marketing authorisation and conditions. Extent depends on exposure of environment to product. Phase I (VICH GL6): exposure based screening, in most cases no studies required. –If low exposure for environment (e.g. companion animals. For herd treatment: Predicted environmental concentration (PEC) below trigger value water or soil) EIA can be stopped at phase I, no specific data requested, –or possibly degradation data for PEC (for PEC refinement).

24. 24 Technical data for MA and their role for assessment: Safety (6/7) Environmental impact assessment Phase II assessment (VICH GL 38): all endo- and ectoparasiticides for food animals, often antimicrobials for herd treatment. Then ecotoxicity data (Predicted No Effect Concentration, PNEC) and environmental fate data (e.g. degradation, accumulation) required. Quantitative risk assessment (PEC/PNEC), refinement if risk quotient above 1. Outcome: Benefit – risk assessment of product Risk mitigations measures, e.g. advice to use to minimize exposure to environment, e.g. is toxic for aquatic organisms. Treated dogs should not be allowed to enter surface water for hours/days after treatment; Waste disposal advice

25. 25 Technical data for MA and their role for assessment: Safety (7/7) Antimicrobial resistance VICH GL 27 lists data, for food producing animals. Assessment is up to countries/regions Target animal safety Aim: identify potential risks for target animal, establish appropriate advice to vet, farmer, animal owner how to use product, specify target animals (e.g. minimum age, breeds), contraindications, where appropriate, advice on potential side effects, as conditions of MA, and information in product literature. Target animal safety studies (VICH GL 43), and results of toxicity studies available in laboratory animals

26. 26 Technical data for MA and their role for assessment: Efficacy

27. 27 Technical data for MA and their role for assessment: Efficacy (1/2) Aim: Establish efficacy, determine indications, dosage regimen, as well as special precautions of use for marketing authorisation.

28. 28 Technical data for MA and their role for assessment: Efficacy (2/2) Pharmacology (partly same data as safety) –Pharmacodynamics : to study mechanisms underlying the therapeutic effect –Pharmacokinetics –Studies in target animals to establish effective dosage regimen –Bioavailability studies Development of resistance (antimicrobials, antiparasitics) Pre-clinical trials (might partly already be included in safety or residues data) Dose determination Results of clinical trials

29. 29 Biologicals (vaccines)

30. 30 Technical data for MA and their role for assessment: Biologicals (vaccines) (1/5) Principles, i.e. Quality, safety and efficacy, same as for pharmaceuticals Specific studies often differ due to nature of product

31. 31 Technical data for MA and their role for assessment: Biologicals (vaccines) (2/5) Quality Aim: see before. Essential part of dossier. Qualitative and quantitative particulars of constituents Product development Manufacturing method Production and control of starting materials –Pharmacopoeia –Non-pharmacopoeia Control tests during manufacturing process: potency test, efficacy Control tests on finished product: batch safety TSE statement

32. 32 Technical data for MA and their role for assessment: Biologicals (vaccines) (3/5) Safety Aim: assess potential risk on target animals, user, environment, (consumer/residues) Target animal safety: –Administration of one dose –Overdose –Repeated administration of one dose –Examination reproductive performance –Examination immunological functions: effect on immune response

33. 33 Technical data for MA and their role for assessment: Biologicals (vaccines) (4/5) Safety (contd.) Target animal safety (contd.): Special requirements live vaccines –Spread of vaccine strain –Dissemination in vaccinated animal –Reversion to virulence –Recombination of strains GMO environmental risk assessment (ERA), if appropriate User safety, standard ERA, residues: usually qualitative, usually no issues, standard precautionary SPC warnings

34. 34 Technical data for MA and their role for assessment: Biologicals (vaccines) (5/5) Efficacy tests Laboratory trials (challenge studies) Field trials è Establishes if vaccine has efficacy, Duration of immunity vaccination scheme

35. Overview of VICH guidelines 35 VICH guidelines available – Examples Biologicals –GL 17: Stability Biotechnological/Biological Veterinary Medicinal Products –GL 25, 26: Testing of residual formaldehyde, residual moisture –GL 34: Test for the detection of Mycoplasma contamination –GL 50: Criteria to waive target animal batch safety testing for inactivated vaccines for veterinary use –GL 41: Examination of live vaccines in target animals for absence of reversion to virulence –GL 44: Target animal safety testing for veterinary live and inactivated vaccines

36. Role of VICH guidelines 36 Conclusions (1) VICH harmonises which data are required for a marketing authorization and how studies are conducted Harmonisation of requirements beneficial for bringing product on market/availability of medicines, reducing costs, reducing animal testing through acceptance of same studies by all countries which accept VICH guidelines VICH guidelines cover large part of marketing authorization dossier, in particular for pharmaceuticals Presentation intended to better understand the role the studies play in assessments of marketing authorization and how the conditions of marketing authorizations are derived

37. Role of VICH guidelines 37 Conclusions (2) VICH does not provide guidance on assessment of studies (exceptions: EIA, microbiological ADI) VICH does not discuss assessment or decisions on marketing authorizations But: Harmonised VICH guidelines and forum for scientific exchange support – indirectly - consistency in approach for assessments in different countries Any country can use VICH guidelines if they wish

38. Role of VICH guidelines 38 Thank you for your attention!

39. 39 Questions ? Discussion ?