Veterinary Pharmaceutical Registration in the EU

Transcription

1 Veterinary Pharmaceutical Registration in the EU May 2017 Prof Dr Erik De Ridder Elanco Animal Health

2 Objectives Introduction and overview of EU reg system for pharmaceutical products Quick overview of the dossier content for pharmaceuticals Understand how the regulatory framework is used to handle some issues around availability of medicines, such as for instance MUMS or minor use & minor species

3 And my objective today? Show you how smart I am 3

4 Regulatory Procedures for VMP s in the EU 4

5 Agenda procedures Procedures and legislative framework Essential preconditions for a licence in the EU GMP or Good Manufacturing Practice, and MRL or Maximum Residue Limit Procedure types, application types and data requirements 5

6 Different procedures cover different products 4 main product types encountered in animal health Veterinary products pharmaceuticals and vaccines no difference in procedures Feed additives Feed materials Biocides

7 Also different agencies EMA European Medicines Agency in London - UK Veterinary products both pharmaceuticals and vaccines Human and veterinary products EFSA European Food safety Authority in Parma - Italy Feed additives (FEEDAP) EU Commission DG SANCO (Health and Consumers) in Brussels - Belgium Feed materials Feed additives (Standing Committee on the Food Chain and Animal Health) EU Chemicals Board and EUCommission DG Environment in Brussels - Belgium Biocides

8 Veterinary Medicinal Products: Legal framework for the procedures? EU Directives Require transposition into national law of the Member State Example: Directive 2001/82 as amended by 2004/28: MA issued by MSs Mutual Recognition Procedure Decentralised Procedure National Procedure EU Regulations and Decisions Apply throughout the EU without transposition in national law Example: Regulation 726/2004: MAs issued by Commission Centralised Procedure Pharmacopoeia monographs Have force of law

9 Veterinary Medicinal Products Legal framework

10 Veterinary Medicinal Products Directive 2001/82 as amended by 2004/82 Establishes the legal framework for national authorisations Assessment by National authority By Mutual Recognition of the MA of another MS Decentralised Procedure Annex 1: lists data requirements Annex 1 was revised in 2009 by Directive 2009/ :EN:PDF

11 Veterinary Medicinal Products: Regulation 726/2004 Centralised Procedure for European veterinary product licences European Medicines Agency (EMA) administers: CVMP: Committee for Veterinary Products MRL procedures Centralised Procedure All appeal procedures and arbitrations («Referrals») Coordination of Quality issues and inspections (GMP, GLP, GCP) Committee for Veterinary Medicinal Products or CVMP One member per MS plus one chair Assessments Assesses the applications in Centralised Procedures Delegates the assessment to the agencies of the MSs Assesses and judges referrals Advise and guidance Drafts and adopts CVMP Guidelines Provides Scientific Advise to applicants

12 Veterinary Medicinal Products Guidelines Guidelines are guidelines: NOT law Obligation to take into account Also Notice to Applicants (NtA) is advisory VICH Guidelines Agreed between EU, USA and Japan Adopted by the EU Take precedence over CVMP Guidelines CVMP Guidelines Other, e.g. OECD, are advisory

13 Me, babysitting 14

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15 Veterinary Medicinal Products Good Manufacturing Practices Applicability? Applicable to active substance Audit by QP of site for finished product Applicable to finished product Inspection and certification by Member States GMP compliance «desirable» for development batches incl. Clinical trial material Qualified Person personaly responsible at given site Mutual Recognition between Member States

16 Veterinary Medicinal Products Maximum Residue Limits Regulation 2377/90 replaced by 470/2009 MRL dossier to be submitted > 6 months before MA application MRL established in name of molecule (<-> Feed additive per product) MRLs needed for all pharmacologicaly active products (incl. excipients!!!) MRL needed for all food animal products incl. horses MRLs can be extrapolated from major to minor species If no MRL for major then no MRL for minor possible MRLs are in the public domain but NOT the data

17 the wedding 18

18 The Application Procedures The National Procedure one Member State only The Centralised Procedure all Member States simultaneously The Mutual Recognition Procedure a selected number of Member States > 1 (chosen by the applicant) The Decentralised Procedure a selected number of Member States > 1 (chosen by the applicant)

19 EU Regulatory MAA procedures & application types The 4 routes to an MA represent different licensing procedures, but share identical data requirements!! Differences in application type possible within each procedure: Full application: demonstration of quality, safety and efficacy Abridged applications: not all data need to be provided

20 Veterinary Medicinal Products: Types of application Article 12(3): Full application Article 13: Abbreviated applications Article 13: Generic Reference product authorised >10 years Same QQ composition of active ingredient Same pharmaceutical form Part III and IV: demonstration of bio-equivalence Article 13a: Bibliographic Active substance has well established use Article 13b: New combination Already authorised active substances Article 13c: Informed Consent Agreement to cross refer

21 EVOLUTION OF REGULATORY PROCEDURES Jan 95 Jan 98 Oct 05 National Procedures for all National Procedure only for first registration Mutual Recognition Procedure Decentralised Procedure Centralised Procedure for innovative products

22 Mutual Recognition Procedure National Procedure

23 NATIONAL PROCEDURES (NP) Prior to 1 January 1995, all registration procedures for veterinary medicines were National Procedures Since 1 January 1998, National Procedures are only permitted for new applications for the first application of a particular product in the European Union A national procedure concerns the submission of a Marketing Authorisation (MA) application to the Regulatory Authorities of a single Member State (MS) That MS assesses the dossier and decides (independently) whether or not to grant the MA The MA is valid only in the MS where the assessment was made Prior to 1998, the same product could be granted a different MA in each MS where an application was submitted i.e. different label claims, different withdrawal periods, different safety warnings, different specifications, different shelf life, etc.

24 MUTUAL RECOGNITION PROCEDURE (MRP) First introduced on 1 January 1995 Mandatory since 1 January 1998 for all applications where there already exists one (or more) MA for the same product in another MS A Mutual Recognition Procedure concerns the submission of a MA application to the Regulatory Authorities of one or more Concerned Member States (CMSs) Application includes the Assessment Report of the MS where the product is already registered (Reference Member State; RMS) CMSs assess the dossier and Assessment Report, and decide (together) whether or not to grant the MA MAs are valid only in the MSs where the assessment was made, and must be identical between all MSs in the procedure i.e. same label claims, same withdrawal periods, same safety warnings, same specifications, same shelf life, etc.

25 Decentralised Procedure

26 DECENTRALISED PROCEDURE (DCP) First introduced on 30 October 2005 Optional for all applications concerning a new product which has not been registered in any MS by any procedure A Decentralised Procedure concerns the submission of a MA application to the Regulatory Authorities of two or more Member States RMS takes the lead and prepares an Assessment Report for the product CMSs assess the dossier and Assessment Report RMS and CMSs decide (together) whether or not to grant the MA MAs are valid only in the MSs where the assessment was made, and must be identical for all MSs in the procedure i.e. same label claims, same withdrawal periods, same safety warnings, same specifications, same shelf life, etc.

27 Centralised Procedure: 210 days plus clock stop

28 CENTRALISED PROCEDURE (CP or CEP) First introduced on 1 January 1995 Optional for all applications concerning a new product which has not been registered in any MS by any procedure A Centralised Procedure concerns the submission of a MA application to the Regulatory Authorities of all Member States via EMA & CVMP (European Medicines Agency & Committee for Veterinary Medicinal Products) CVMP is independent scientific committee of experts CVMP appoints (co)rapporeur who takes the lead and prepares an Assessment Report for the product CVMP members assess the dossier and Assessment Report and votes an opinion whether or not to grant the MA Only one EU MA valid in all MSs and per definition identical for all MSs (except for language) i.e. same label claims, same withdrawal periods, same safety warnings, same specifications, same shelf life, etc.

29 COMPARISON CP-MRP-DCP Centralised Procedure Mutual Recognition Procedure Decentralised Procedure 1 Competent Authority 1 Application / 1 dossier 1 Assessment/1 Decision 1 Marketing Authorisation Valid in 28 European countries 1 Trade name Qualified majority decision Company cannot choose Rapporteur transparent process only one authority (EMA) maintenance = 1 variation Relatively high fees Timeline: days Existing national MA a prerequisite National MA typically should take 210 days (but up to 3yrs) 1 harmonised dossier 1 harmonised decision up to 28 applications up to 28 NCA up to 28 MAs free choice of the RMS different trade names possible possibility to withdraw a submission in specific countries if negative opinion some MS may cause delay decision process +/- transparent maintenance = up to 28 variations Timeline: >420d (max >4 yrs) Existing national MA not necessary at time of application Removes the timeline to obtain a national MA first Submission simultaneously to RMS and all CMS up to 28 NCA up to 28 MAs free choice of the RMS Assessment Report prepared by the RMS and approved by all CMS simultaneously decision process +/- transparent maintenance = up to 28 variations more moderate fees Timeline: days 30

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31 Content of an NCE dossier 32

32 Objectives Introduction and overview of EU reg system for pharmaceutical products Quick overview of the dossier content for pharmaceuticals Understand how the regulatory framework is used to handle some issues around availability of medicines, such as for instance MUMS or minor use & minor species

33 Presentation and content of the dossier (1) The application dossier for pharmaceutical products is presented in four parts. Part I Summary of the dossier Part II Chemical, pharmaceutical and biological documentation Part III Safety and residues documentation Part IV Pre-clinical and clinical documentation

34 Presentation and content of the dossier (2) Administrative documentation Part 1 A consists of the administrative data, incl Application form Part 1 B consists of the proposed SPC, labelling and package leaflet (in local language) Part 1 C consists of the Detailed and Critical Summaries (DACS) and their tabular formats (formerly referred to as Expert Reports). Technical documentation Parts 2, 3 and 4

35 Veterinary Medicinal Products: Dossier structure

36 Dossier Structure (1) Full dossier Food Producing Animals Part 1 Part 2 Part 3 Part 4 Legal Basis 2001/82 EC Article 12(3) Full dossier Companion Animals Part 3A only +++ Article 12(3) Generics/ Bio similar ERA Residue Depletion + Bioequivalence Article 13(1) Article 13 (4) Hybrid Case by case ++ Case by case Article 13 (3)

37 Dossier Structure (2) Well Established Use Part 1 Part 2 Part 3 Part 4 Legal Basis Literature and ERA + Literature and bioequivalence Article 13a Fixed Combination Can use some data from single product ++ Can use some data from single product ++ Can use some data from single product Article 13b Informed Consent +++ Must be identical to original dossier Must be identical to original dossier Must be identical to original dossier Article 13c Key: +++ Full data required + Limited data required

38 All parts of the dossier are linked Part 2 Part 3 Part 1 Part 4

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40 LEGISLATION AND AVAILABILITY 41

41 Objectives Introduction and overview of EU reg system for pharmaceutical products Quick overview of the dossier content for pharmaceuticals Understand how the regulatory framework is used to handle some issues around availability of medicines, such as for instance MUMS or minor use & minor species

42 What issue with avalability? 43

43 Issues relating to the availability of veterinary medicinal products include: Smaller countries tend to have fewer authorised products; There are very few authorised products for some minor species; There are very few authorised products for some therapeutic categories; The number of applications for new authorisations submitted each year is low, and few applications concern products aimed at minor species; High proportions of authorised products are not marketed in smaller countries; and, Availability problems mean that medicines sometimes have to be used off-label 44

44 Drivers? Reviews of products on the market in each EU Member State since the 1980s Impact of MRL legislation since 1990 Impact of expansion of original standards, e.g. environmental impact, Pharmacovigilance Development of EU guidelines, and gold-plating in their implementation by MSs, Increased complexity of the EU regulatory environment, leading to increased regulatory costs Expansion of the EU, leading to rationalisation of products in some MSs, National requirements affecting business case e.g. labelling, legal supply 45

45 # products for use with minor species (2010) 46

46 # of brands and products on national markets (2010) 47

47 Availability stimulation in the current EU regulatory framework Exclusion of scope (art 4) Autogeneous vaccine pet species medicines Cascade Conditions Exceptional epizootic Health issue MUMS Other issues MRL all food producing species GMO? 48

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49 AVAILABILITY AND CASCADE 50

50 Cascade? Applies where there is no authorised veterinary medicinal product in a MS Conditions : Exceptional use and under the direct personal responsibility of a vet To avoid causing unacceptable suffering For non-food animals A VMP authorised in the MS for another animal species or for another condition in the same species, or If none, either: A VMP authorised in another MS, or A medicinal product authorised for human use If none, a VMP prepared extemporaneously under prescription 51

51 Cascade for food-producing species? A VMP authorised in the MS for another animal species or for another condition in the same species, or If none, either: A VMP authorised in another MS, or A medicinal product authorised for human use If none, a VMP prepared extemporaneously under prescription Provided substance(s) is listed as being permitted under MRL Regulation 470/2009 and an appropriate withdrawal period is specified 52

52 Cascade for food-producing horses? List of essential substances established by the Commission for which a withdrawal period of at least 6 months applies List is reviewed occasionally; CVMP gives opinion to the Commission which decides 53

53 Cascade for food-producing animals and withdrawal? Withdrawal period shall not be less than: 7 days for eggs 7 days for milk 28 days for meat 500 degree days for fish meat Zero withdrawal period for homeopathics Records to be kept for at least 5 years 54

54 AVAILABILITY THROUGH EXCLUSION (ART4) 55

55 Discretionary exceptions by exclusion of scope Pet products Products intended solely for aquarium fish, cage birds, homing pigeons, terrarium animals, small rodents and ferrets and rabbits kept exclusively as pets...provided they do not contain substances requiring veterinary control [and are not used for other species] Autogenous vaccines non-inactivated immunological veterinary medicinal products which are manufactured from pathogens and antigens obtained from an animal or animals from a holding and used for the treatment of that animal or the animals of that holding in the same locality 56

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57 AVAILABILITY AND MUMS 58

58 MUMS? Actually: limited markets Minor use, minor species, minor market (sales potential) Regulation 726/2004 requires EMA to provide measures to assist applicants in respect of products for limited markets Classification by the CVMP No authorised alternative for the same indication Reduced technical data requirements for MUMS Financial incentives - 5 years, free scientific advice, reduced fees, reduced MRL fee 59

59 Species classed as minor? Major species Cattle (dairy and meat) Sheep (meat) Pigs Chickens (including laying hens) Salmon Cats Dogs Minor species are those species not classed as major 60

60 AVAILABILITY AND CONDITIONAL LICENCES 61

61 Exceptional authorisations Article 7 where the health situation so requires Article 8 (vaccine) in the event of a serious disease epizootic Article 9 clinical trial formulations 62

62 AVAILABILITY AND OTHER ISSUES 63

63 OTHER AVAILABILITY ISSUES IN THE EU GMO? MRL availability for all species? 64

64 Does MRL investment impact availability? MRL dossiers paid by innovative companies Risk : lack of investment in MRL minor species Solution: Some molecules got granted MRL for all foodproducing species Extrapolation allowed for MRL from major species to appropriate minor species. 65

65 Does GMO impact availability? Directive 2001/18/EC applies Dossier must be accompanied by: A copy of written consent of competent authorities for the deliberate release of GMOs into the environment Technical dossier allowing evaluation of environmental risk EMA coordinate with competent authorities regarding assessment 66

66 Surely, I have not answered all your questions? Thank you for your presence and attention! 67

67 Role of VICH and VICH guidelines in the approval process for veterinary medicinal products VICH & harmonization of all VMP globally 68

68 Principles for marketing authorisations for veterinary medicines Regulatory system needs to be established by governments for the authorisation and control of veterinary medicinal products. Marketing authorisation (or registration or licence ): Approval by the responsible authority in the country/region concerned that the product can be sold and used. The company that will bring the veterinary medicinal product 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 authorisation (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 ).

69 Role of VICH guidelines in a marketing authorisation application VICH = International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products Technical requirements for registration (or marketing authorisation) = 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 authorisation for a veterinary medicinal product are given in next slides

70 Marketing authorisation application No VICH Common Technical Dossier as for medicines for human use by ICH due to high resources required to develop. 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 are available for large parts of a dossier.

71 How much of the data dossier is harmonised? Quality documentation (14 VICH GLs) Composition of the product; Method of preparation: manufacturing method, in-process control tests and validation incl. batch analysis Safety documentation (15 VICH GLs) Pharmacodynamics Pharmacokinetics Efficacy tests (12 VICH GLs) Pharmacodynamic mechanisms underlying the therapeutic effect; Pharmacokinetics supporting the therapeutic effect Active substance(s): specifications, impurities in the starting material, suitability of the manufacturing method, stereoisomerism, where relevant and stability Toxicology (Single dose toxicity, Repeated dose toxicity, Reproductive toxicity including teratogenicity, Genotoxicity, Carcinogenicity, other) Bioequivalence (if applicable) Excipients: specifications, suitability and safety data, where appropriate Packaging material (immediate): specifications and suitability Target animal safety Residue studies (Metabolism and residue kinetics, Pharmacokinetics, Depletion of residues, Analytical method); microbiological ADI Dose determination Resistance development (if applicable) (antimicrobials, antiparasitics) Control tests on intermediate products Safety of users Clinical trials (GCP and Anthelmintics) Control tests on finished product Environmental impact assessment (Also biologicals quality) Stability of the finished product Post authorisation Pharmacovigilance

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

73 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 40: Test procedures and acceptance criteria for new active substances and products: Biotechnological/Biological Veterinary Medicinal Products 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 GL 50: Criteria to waive target animal batch safety testing for inactivated vaccines for veterinary use

74 hat are VICH guidelines used for? VICH harmonises which data are required for a marketing authorisation and how studies are conducted. Harmonisation of requirements increases availability of medicines, reduces costs, and reduces animal testing through acceptance of same studies by all countries which accept VICH guidelines. VICH guidelines cover large parts of a marketing authorisation dossier, in particular for pharmaceuticals. VICH does not provide guidance on assessment of studies (exceptions: Environmental Impact Assessment (EIA), microbiological ADI). VICH does not discuss assessment or decisions on marketing authorisations

75 How to use VICH guidelines (1/5) VICH guidelines are publicly available through the VICH website. They are also published on the websites of the regulatory authorities of the VICH members and observers. VICH member countries/regions are obliged to use the VICH guidelines. The use of the VICH guidelines is not restricted to the VICH members and observers. Any country or regional organisation can use these guidelines for the requirements for the authorisation of veterinary medicines in their country or region.

76 How to use VICH guidelines (2/5) There are different ways on how technical guidelines such as VICH guidelines can be implemented: Some countries use them as separate technical guidelines in support of legislation without making them part of legislation; Other countries implement them as a regulation or piece of legislation. It is the decision of the country or region and may depend on how the legislation in the country/region has been set up.

77 How to use VICH guidelines (3/5) If a country/region considers implementing VICH guidelines, please bear in mind that it is not necessary to implement all the guidelines as a package, but a country/region may choose to implement only selected guidelines, e. g. the most needed or suitable guidelines, or may consider a stepwise implementation process. The VICH member countries/regions have the obligation to implement the VICH guidelines as adopted and other countries are also encouraged to use VICH guidelines unchanged.

78 How to use VICH guidelines (4/5) Some countries/regions that are not part of the VICH process may not be able to apply particular parts of a guideline due to specific local conditions, e. g. climatic conditions, animal diseases or animal species relevant for that country/region. In such a case, a VICH guideline can be implemented adapted, to the minimum extent necessary, to fit local conditions.

79 How to use VICH guidelines (5/5) In the interest of promoting harmonisation of technical requirements for the registration of veterinary medicinal products, VICH would encourage the widest possible use of its guidelines, with the minimum changes only when absolutely necessary to adapt the guidelines to local conditions. Feedback to VICH on which guidelines have been implemented in your region, and how they were implemented, would be greatly appreciated.