A Case Study

Mutual Recognition in East Africa

Gillian CowanRegulatory Consultant

GALVmed

Background & Current Status

Introduction

• About GALVmed

• Background to GALVmed’s project

on Harmonised Registration for

Veterinary Immunologicals in Africa

• Technical Working Group (TWG)

• Mutual Recognition Procedures

• Adoption by East African Community (EAC)

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• Worked in Regulatory Affairs for several multinational pharmaceutical companies

– Hoechst :1976 – 1996 in UK; 1996 – 2000 in Germany

– Intervet : 2000 in Boxmeer, NL

– Aquaculture Vaccine Ltd (AVL) : Aug 2000 – Aug 2002

– Schering Plough : 2002

– Pfizer Animal Health; Director of Regulatory Affairs, Biologicals: Aug 2002 – retired April 2010

• Member of IFAH- Europe Biologicals WP• Currently a consultant, mainly for GALVmed

Regulatory experience

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• A not-for-profit Public-Private Partnership – registered charity

• Projects sponsored by the Bill & Melinda Gates Foundation and the UK Government via UKAID.

• Pro-poor focus: working with key partners to make a sustainable difference in access to animal health products for poor livestock keepers

GALVmed - GLOBAL ALLIANCE LIVESTOCK VETERINARY MEDICINES

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GALVmed’s Contribution

• Developing, registering and launching vaccines, pharmaceutical and diagnostic products for neglected livestock diseases

• Partnering with organisations in developing countries to ensure sustainable research, production and delivery

• Educating stakeholders on the links between livestock and poverty

• Facilitating dialogue and collaboration in research efforts for new livestock vaccines, medicines and diagnostic systems

East Coast Fever vaccine

Newcastle Disease Virus vaccine

Porcine Cysticercosis vaccine

Protecting livestock, saving human lives by:

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QC labs in Tanzania and Senegal

to check quality of trypanocides

COUNTRY Region COUNTRY Region1 Algeria N 15 Burundi E2 Egypt N 16 Comoros E3 Morocco N 17 Djibouti E4 Tunisia N 18 Kenya E5 Cameroon C 19 Rwanda E6 Congo - Brazzavile C 20 Seychelles E7 Burkina Faso W 21 Sudan E8 Cote D'Ivoire W 22 Tanzania E9 Ghana W 23 Uganda E

10 Mali W 24 Angola S11 Mauritania W 25 Botswana S12 Nigeria W 26 Dem Rep Congo S13 Senegal W 27 Lesotho S14 Togo W 28 Madagascar S

29 Malawi S30 Mozambique S31 Namibia S32 South Africa S33 Swaziland S34 Zambia S35 Zimbabwe S

North: 4Central: 2West: 8East: 9 Southern: 12

Two main activities were conducted in 2010:

• Information on current status of vaccine regulation through a questionnaire sent to 49 countries.

• GALVmed-OIE-PANVAC Workshop in South Africa on future of harmonisation for vaccine registration.

Baseline status of vaccine registration in Africa

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Many African countries asked for :• Harmonised Registration system• Mutual Recognition• Training for their Regulators in Registration of Veterinary Vaccines

Outcome of OIE/GALVmed Conference in Johannesburg, 2010

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Capacity building:Workshop in Nairobi, East Africa

East Africa (Nairobi – Nov 2011)

• Capacity building of regulatory authorities in charge of vaccine registration in Africa• First training for East Africa, in Nairobi, November 2011. 8 countries:

Djibouti, Burundi, Rwanda, Kenya, Ethiopia, Tanzania, Sudan and Uganda.

• Activity conducted with AU-PANVAC, with contribution of OIE

• Gilly Cowan engaged to follow up activities as lead consultant.

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2011 Training Course in Nairobi

• Preceded by a Questionnaire about current status of veterinary vaccine registration per country.

• Some represented countries already had a medicines registration system. Some were developing the legislation to establish a system. Others had nothing.

• Of the countries which already had a Regulatory Authority it was recognised that their requirements for veterinary vaccines were based on pharmaceutical requirements.

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Outcome of Nairobi Workshop 2011

• Participants identified tools required for establishing a harmonised registration system.

• Participants volunteered to work on assignments:

- Uganda: Application Form (Elizabeth Okello)

- Kenya: Guidelines for SPC for IVMPs (Jafred Kitaa)

- Tanzania: Collate all existing Guidelines from participating countries (Charys Ugullum)

- Djibouti: Dossier Structure (Ibrahim Djama Ismael)

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Part 1Summary

Part 2Quality

Part 3Safety

Part 4Efficacy

Part 5Particulars and

Documents

1.A: Application form & Annexes,

2.A: Composition, Product Development,

3.B1 - B3: GLP Lab Safety, Single Dose, Overdose, Repeated Dose

4.B: Lab Efficacy (challenge)

Applicants Summaries of Safety and Efficacy studies including objective discussion of results

1.B:SPC & Packaging

2.B: Manufacture 3.B.4-6: Other Safety Studies

4.C: Field Efficacy

Part 6 Bibliographical

references

1.C: Expert Reports on

2.C: Control of SMs

3.B.7: User Safety; residues; interactions.

C1 Quality 2.D: In-Process Controls

3.C: Field Safety

C2 Safety 2.E: Controls on Finished Product

3.D: Environmental risk assessment

C3 Efficacy 2.F: Batch consistency

3.E: GMOs

D. Benefit-Risk 2.G:Stability

Nairobi 2011

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TWG formed in March 2012

Technical Working Group (TWG) formed to progress harmonised registration of veterinary immunological products (IVPs)

Regional representatives from 6 of the 9 countries requested that regulators from the 3 countries with most regulatory experience should draft the 4 Technical Documents:• Kenya (PPB) • Tanzania (TFDA) • Uganda (NDA)

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Date Location Participants

9-12 July 2012 Dar es Salaam 6 regulators

Draft documents refined Topic leader• Harmonised Application Form Elizabeth Okello• Label, leaflet, SPC templates James Mbaria• Dossier Structure Gilly Cowan• Guideline Rosemary Aaron

Documents sent to Regulatory Authorities for comment

First Technical Working Group Meeting

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TWG’s Dossier Structure, Dar es Salaam July 2012

Part 1Administrative

Part 2Quality

Part 3Safety

Part 4Efficacy

1.A Application form

2.A: Composition 3.A.1 – A2: Safety, Single Dose, Overdose, Repeated Dose

4.A Lab Efficacy

1.B.1 SPC

2.B: Method of Manufacture

3.A.3: Other Safety Studies, e.g. Reversion to Virulence.

4.B: Field Efficacy

1.B.2Label and carton text

2.C: Control of SMs 3.B: Field Safety

1.B.3Package Leaflet

2.D: In-Process Controls

3.C: Safety to user and environment; residues, interactions.

Part 5 Bibliographical

references

2.E: Controls on Finished Product

2.F: Batch consistency

2.G:Stability

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Held on 24-25 Oct. 2012 in Dar es Salaam

Participants: 6 regulators, Representative from DVS Kenya, Representative from EAC

• Feedback and suggestions provided on Technical Documents by NDA (Uganda) and TFDA (Tanzania).

• Suggestions considered and incorporated into the Technical Documents

Second Technical Working Group Meeting

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Second Technical Working Group Meeting October 2012

• Dr. Timothy Wesonga (EAC Senior Livestock Officer) indicated EAC would support the initiative.

• The East African Community Treaty already contains provisions for adopting a common mechanism for ensuring quality, safety and efficacy of veterinary vaccines.

• EAC Treaty Chapter 21, Article 108(e) on Plant and Animal Diseases Control.

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By end of meeting, TWG accomplishments were:

1. Harmonised Application Form for use in National and Mutual Recognition Procedures (MRP)

2. Structure for a Registration Dossier for Immunological Veterinary Products (IVPs)

3. Templates for Labels, Outer Packaging and Summary of Product Characteristics (SPC)

4. Guideline on the requirements for each section of a registration dossier for an IVP

Second Technical Working Group Meeting October 2012

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2nd TWG meeting, Dar es Salaam, October 2012

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Meeting in Arusha in June 2013 with Heads of Regulatory Authorities, DVSs, GALVmed, PANVAC, TWG and EAC:

1. The tools for harmonised registration of IVPs were accepted and recommended for use.

2. A recommendation was made for initiating Mutual Recognition Procedures (MRP).

• The recommendation document was signed by representatives from all 5 Ministries of Agriculture, Livestock, etc.

Next Step

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Examples of establishing Registration Systems

Normal sequence for development of Regulatory Requirements

1.Human Medicines Regulations

2.Veterinary Pharmaceuticals

3.Veterinary Biologicals

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Biologicals are not Pharmaceuticals!

• Question - What is the easiest option for introducing a registration system for biologicals?

• Answer - copy/paste legislation and guidelines directly from pharmaceutical documents.

• Consider mode of action:- Pharmaceuticals – pharmacological

- Vaccines - immunological

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Pharmaceuticals Not necessarily pharmaceuticals

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What is the difference?

Biologicals are not Pharmaceuticals

• Molecule/Drug substance

• Pharmacology• Pharmacokinetics• Metabolism• Toxicology in Lab animals & TS• Residues• Withholding time

• Efficacy – dose / kg bw

Biologicals• Antigen (live or

inactivated)

• Not applicable• Not applicable• Not applicable• Safety in Target

Species• Not applicable*• Zero days

• Efficacy –Immunity/protection

Part 2 :Active ingredient

Part 3:Safety

Part 4Efficacy

Dossier

*Exceptions, e.g. live zoonotic organisms

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Pharmaceuticals

Meeting of Experts

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Progress in East Africa

• During meeting in Arusha in June 2013 Dr. David Adwok of South Sudan adopted the TWG’s registration procedure for immediate implementation.

• At the Regional Training meeting in Nairobi in June 2013, Dr.Terzu Daya of Ethiopia adopted the TWG’s registration procedure for immediate implementation.

• Later that year, the EAC requested a document explaining how Mutual Recognition Procedures would work.

• Provided to Sectoral Council of Ministers July 2014

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Mutual Recognition Procedure for IVPs

MRP allows Marketing Authorisations to be issued without long delays

• If no questions raised: <170 days to issue an Authorisation

• If questions raised: <230 days to issue an Authorisation

Two types of MRP:1. For new product applications2. For expansion of existing Marketing Authorisations

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Mutual Recognition Procedure for IVPs

1. Applicant selects one EAC Member State to act as Reference Country (RC). Coordination Group for Mutual Recognition (CGMR) is notified of intention to request a MRP, indicating the Concerned Countries (CCs) in which Marketing Authorisations will be sought.

2. One week before <CLOCK START> the Applicant sends dossier and Application Form to RC and National Authorities of CCs simultaneously.

Applicant

RCCCs

MR Coordinator issues a calendar of critical dates for the MRP to CGMR

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Mutual Recognition Procedure for IVPs

CLOCK STARTS Duration• Step 1: day 0 RC prepares Assessment Report (AR) 90

days• Step 2: day 90 RC sends AR to CCs for review 30

days• Step 3: day 120 If CC’s raise no objections, move to step 5• Step 4: If CCs raise additional questions on AR, RC and Applicant

try to resolve them between days 120 - 180*60 days

• Step 5: day 180 Applicant sends final (or revised) labels and SPC to RC and CCs for approval 20

days• Step 6: day 200 CLOCK STOPS • RC and CCs issue National Marketing Authorisations 30 days

Total: if no questions – 170 days; if questions – 230 days

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Appeal during MRPs

Step 4: Day 180“If CCs raise questions on AR, RC and Applicant try to resolve them between days 120 - 180*”Day 180* – 240 If no agreement has been reached by day 180, APPEAL is triggered.4.1 Applicant has opportunity to generate more data and ask for hearing by CGMR and appropriate technical experts. 4.2 CGMR take final decision by Day 240.4.3 If decision is positive, Steps 5 and 6 are followed and National MAs issued = 290 days to issue licence.

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Other Regulatory Meetings & Workshops

Location Event When

1. East Africa Nairobi Workshop 21-23 Nov 2011

2. UEMOA West Africa Workshop 8-9 Dec 2011

3. CEEAC Libreville Workshop 2-4 Oct 2012

4. EAC* Arusha Meeting 24-25 June 2013

5. EA region (9) Nairobi Workshop 27-28 June 2013

6. Inspectors Kampala Workshop 24 Sept 2013

7. ECOWAS Abuja Workshop 19-21 Dec 2013

8. Inspectors + Debre Zeit Workshop 1-3 July 2014

9. Manufacturers Lilongwe, Nairobi Dossier Training 2013 - 2014

10.Assessors Nairobi Training 4-7 May 2015

11. SADC Gaborone Meeting Planned

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Recent updates:

1. The Sectoral Council of Agriculture and Food Security adopted the Concept of Mutual Recognition Procedures and the Terms of Reference for the Technical Working Group (TWG) and the Coordination Group on Mutual Recognition (CGMR) on the 5th September, 2014, in Kigali, Rwanda.

• The decisions of the Sectoral Council of Agriculture and Food Security were adopted by the EAC Council of Ministers on the 28th of November, 2014 in Nairobi, Kenya resulting in a Decision Number:

EAC/CM 30/Decision 34.

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Recent updates:

2. Constitution of TWG and CGMR by the EAC

17 March 2015, in Arusha, Tanzania.

Representatives from: Burundi, Kenya, Rwanda, Tanzania, Uganda, EAC, PANVAC

6th TWG 18/19 March 2015 Mock MRP rehearsedPublicity to Applicants and Stakeholders needed.

EAC to to seek funding for publicity to stakeholders to give them access to Technical Documents and MRPs.

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Latest updates:

3. Joint Assessments: Workshop on Dossier Assessment of Immunological Veterinary Products• 4 – 7 May 2015, Nairobi• 20 Participants from 8 East African countries• Training provided by PANVAC and experienced

Regulators from TWG.• After receiving training, participants invited to write

Assessment Reports on a mock dossier.• Assessment Reports reviewed and feedback provided.

• Regulators from outside EAC requested MRP of dossiers reviewed and approved by Regulators in EAC.

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4. Joint Inspections:• Team of inspectors from NDA Uganda, PPB Kenya

and TFDA Tanzania planned to visited a veterinary vaccine manufacturer to perform a joint inspection.

5. Publication of Technical Documents:• The Guidelines and other Technical Documents are

being published by EAC Regulatory Authorities.• Workshops proposed with Applicants and Regulators• Applicants are expected to start requesting Mutual

Recognition Procedures in 2016.

Latest updates:

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ConclusionsThe value of MRP:

Accelerates availability of good quality, safe and efficacious veterinary medicines.

Avoids duplication of assessment.

Improves predictability.

Builds trust between Regulators.

Allows rapid introduction of new

vaccines against new diseases.

The tools are now available. Other African regions are interested in using the process.

“Thank you for your attention”

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BACK UP SLIDES

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VICH Guidelines relevant to BiosGL17: Stability testing of biotechnological/biological veterinary medicinal products (– well characterised proteins, recombinants)

GL25: Biologicals:Testing for residual formaldehyde

GL26: Biologicals:Testing for residual moisture

GL34: Testing for the detection of mycoplasma contamination

GL41: Target animal safety: Examination of live veterinary vaccines in target animals for absence of reversion to virulence

GL44: Target animal safety for veterinary live and inactivated vaccines (TAS)

GL50: Biologicals: harmonisation of criteria to waive target animal batch safety testing for inactivated vaccines for veterinary use (TABST)

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MRP replaces lots of this….

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