1.
An agency of the European Union
Marketing Authorisation requirements for a
live recombinant (GMO) veterinary vaccine for
Foot-and-Mouth disease in the European Union
Immunological Veterinary Medicinal Products (IVMPs)
EuFMD Meeting
Cascais, Portugal 27 October 2016
Presented by Martin Ilott on 27 October 2016
Department of Veterinary Medicines at the European Medicines Agency (EMA), London, UK

2.
EMA in the EU
• >500m people
• ~27% of global pharmaceutical sales*
• 28 MS
• 24 official languages
• ~50 medicines regulatory authorities
• 1 EMA
The European Medicines Agency1

3.
2 The European Medicines Agency
Who are we?
• established in 1995
• 7 Committees
• 975 positive opinions for human medicines since 1995
• ~840 staff from 28 EU Member States
• 24 official languages
Over 200 veterinary products
Committee for Veterinary Medicinal Products
One member for each of the 28 Member
States plus one alternate
5 co-opted experts
Chair: David Murphy

4.
3

5.
4
Live Recombinant (GMO) vet vaccines authorised by the
EMA Product Name Authorisation Date
Purevax Rabies 18/02/2011
Porte West Nile 5/08/2011
Nobivac Myxo-RHD 07/09/2011
Poulvac E. coli 15/06/2012
Oncept IL-2 03/05/2013
Bovela 22/12/2014
Suvaxyn CSF Marker 10/02/2015
Innovax-ILT 03/07/2015
Vectormune ND 08/09/2015
Product Name Authorisation Date
Suvaxyn Aujeszky 783 + O/W 07/08/1998
Purevax FeLV 13/04/2000
Vaxxitek HVT+IBD 9/08/2002
ProteqFlu 6/03/2003
ProteqFlu-Te 6/03/2003
Equilis StrepE 07/05/2004
Purevax RCP FeLV 23/02/2005
Purevax RCPCh FeLV 23/02/2005
Hiprabovis IBR Marker Live 27/01/2011

6.
Regulatory requirements defined by intended claims on the
Summary of Product Characteristics (SPC)
5
“Does what
it says
On the Tin”
• Indications for use?
• Prevention/reduction of infection, clinical signs or lesions
• Improved production (daily growth and feed conversion) or
reproductive performance
• Prevent or reduce transmission
• Influence of maternally (naturally) derived antibody MDA
• Target species?
• Cattle, sheep, pigs, goats, buffalo etc.
• Route of administration?
• Intramuscular or subcutaneous or oral
• Use during pregnancy?

7.
Regulatory requirements defined by intended claims on the SPC
6
“Does what
it says
On the Tin”
• Fixed formulation or flexible combinations of strains formulated
to match the epidemiological situation at the time of need?
• Monovalent or multi-valent product?
• Dose volume and vaccination schedule?
• Minimum age for vaccination
• Primary & Booster dose recommendations?
• Immunological properties?
• DIVA claim
• Interactions with other medicinal products?
• Combined or Associated use

8.
EU Regulations and Directives for authorisation of a live
recombinant veterinary vaccine
• EU Regulation:(EC) No 726/2004 Establishing the European Medicines Agency
• Recombinant DNA technology (compulsory)
• Vaccines for Community prophylactic measures i.e. FMD, BTV, AI (optional)
• EU Directive (2001/82/EC) including Technical Annex (2009/9)
• Legal, Procedural & Technical requirements relating to veterinary medicinal products
• EU GMO Directives (2001/18/EC): deliberate release of GMOs into the
environment
• EU Regulation:(EC) No 470/2009 & No 37/2010
• Establishment of residue limits of active substances for food producing animals
7

9.
• European Pharmacopoeia
• FOOT-AND-MOUTH DISEASE (RUMINANTS) VACCINE (INACTIVATED) 01/2015:0063
• VACCINES FOR VETERINARY USE (04/2013: 0062),
• EVALUATION OF SAFETY & EFFICACY OF VETERINARY VACCINES (5.2.6 & 5.2.7)
• CVMP Guidelines
• Data requirements for multi-strain dossiers for inactivated vaccines against foot-and-
mouth disease (FMD) EMA/CVMP/IWP/105506/2007
• Requirements for the production & control of IVMPs EMA/CVMP/IWP/206555/2010
• Live recombinant vector vaccines for veterinary use EMEA/CVMP/004/04
• CVMP Position papers
• Requirements for vaccines against foot-and-mouth disease EMA/CVMP/775/02
8
Technical requirements for a recombinant FMD vaccine

10.
9
• Organism: any biological entity capable of replication or transferring genetic
material
• GMO: an organism, with the exception of human beings, in which the genetic
material has been altered in a way that does not occur naturally by mating
and/or natural recombination
• 2001/18/EC: deliberate release of a GMO into the environment requires
notification to the GMO Competent Authority in the MS e.g. field trial with a
GMO vaccine
• Notification requirements (Annex IIIA & IV)
• Environmental risk assessment (ERA) (Annex II)
• Under 2001/82 notification to the designated GMO CAs is waived
• 726/2004 (Rec 36) & Dir 2001/82/EC Part 3.E Assessment for GMOs
• Data should be in accordance with 2001/18/EC (Art 2 & Annexes)
• See NTA Vol 6C (currently refers to II.H rather than 3.E)
Genetically modified organism (GMO) 2001/18/EC

11.
Consultation with environmental Competent Authorities (CAs)
for Environmental Risk Assessment (ERA)
10
Application for
veterinary vaccine
GMO
CA
GMO
CA
GMO
CA
EMA
- Confidentiality agreements
- sends “ERA extract” of (Co-)Rap ERA sections
Part IIIE to GMO CAs
- Forward overview of comments
to rapporteurs CVMP (Co-)Rap
ERA assessment

12.
11
• The objective of an ERA is, on a case by case basis, to identify and evaluate potential
adverse effects of the GMO, either direct or indirect, immediate or delayed, on human
and the environment (including animal health)
• The ERA should be conducted with a view to evaluating if there is a need for risk
management, and if so, the most appropriate methods to be used.
• ERA and environmental risk management particulars should be kept under continuous
review after the granting of an MA
• When submitting a variation to the terms of the MA, the marketing authorisation holder
should consider any possible impact on the ERA.
• Guidance on how to approach an ERA Commission Decision 2002/623/EC
Objectives of the Environmental Risk Assessment (ERA)

13.
Safety study requirements for a live recombinant FMD vaccine
Safety for each target species, by each recommended route of administration
using the maximum titre from production. To GLP standards.
• Laboratory safety of a single dose & 10x overdose
• Each category including minimum age: 8 animals per group, 14 day study
• Observe local & systemic effects and macroscopic & microscopic lesions at the injection site
• Laboratory safety of a repeat dose:
• If primary schedule is greater than one dose and/or booster dose required
• Laboratory safety of reproductive performance:
• 8 animals in each trimester (24 for each species and route) plus examination of progeny
• Field Studies
• if justified, results from laboratory studies do not need to be supplemented with field studies
• EMA authorised multi-strain FMD vaccine included no EU field studies12

14.
• Specific laboratory safety studies for live vaccines & especially relevant for the ERA
• Spread of the vaccine strain
• Master Seed and the recommended route most likely to lead to spread
• Spread of the vaccine strain from vaccinated to unvaccinated target animals
• Spread to non-target animals
• Dissemination in the vaccinated animal
• Faeces, urine, milk, eggs, oral, nasal and other secretions for the virus
• Dissemination of the vaccine strain in the body, especially predilection sites
• Reversion to virulence
• Master seed & the recommended route most likely to lead to reversion.
• Serial passage in 4 groups of 2 animals. Final passage in 8 animals
• Repeat passage in 10 animals if recovery unsuccessful13
Safety of a live recombinant FMD vaccine (cont.)

15.
Efficacy of a live recombinant FMD vaccine
• Efficacy for each target species, by each recommended route of administration
using the proposed schedule of administration for each component.
• Studies using minimum titre in minimum age animals. Challenge strain?
• Onset of immunity
• Immunogenicity test in cattle in accordance with Ph.Eur 0063 challenged at 21 days?
• PD50 challenge test with 17 cattle using graded doses
• Percentage of protection against generalised foot infection using 18 animals with single dose
• Established or justified models for sheep, pigs, goats etc.? OIE manual
• Duration of immunity
• Challenge or serum neutralising antibodies is correlation with protection established
• Efficacy of a booster dose
• MDA studies may be relevant with a vaccination to live policy14

16.
EMA routes for advice on developing novel veterinary vaccines
Overview of authorisation systems in the European Union15
• Innovation Task Force (ITF)
• Fostering development of veterinary medicines
• ITF is a multidisciplinary group that includes scientific, regulatory and legal experts
• To apply for a briefing meeting, complete the request form and return it
to vet.applications@ema.europa.eu
• Scientific Advice Procedure Article 56(3) of Regulation (EC) No 726/2004
• Scientific advice on the appropriate tests and studies in the development of a veterinary medicine.
• “Guidance for companies requesting scientific advice” EMEA/CVMP/172329/2004-Rev. 4
• Scientific Advice Working Party of experts providing advice to CVMP http://www.ema.europa.eu
• If you seek further information on any of the included topics and/or want to apply for a scientific
advice pre-submission meeting please contact: VetScientificAdvice@ema.europa.eu

17.
Thank you for your attention
martin.ilott@ema.europa.eu
European Medicines Agency
30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom
Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555
Send a question via our website www.ema.europa.eu/contact
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